Drug delivery from rapid gelling polymer composition

专利摘要:

公开号:AU2003300076A1
申请号:U2003300076
申请日:2003-12-30
公开日:2004-07-29
发明作者:Leanne Embree；David M. Gravett；Arpita Maiti；Aniko Takacs-Cox；Philip M. Toleikis
申请人:Angiotech International AG；
IPC主号:A61K9-06

专利说明:
WO 2004/060346 PCT/US2003/041580 DRUG DELIVERY FROM RAPID GELLING POLYMER COMPOSITION BACKGROUND OF THE INVENTION Field of the Invention This invention relates generally to compositions that afford drug 5 delivery from two-part polymer compositions that rapidly form covalent linkages when mixed together. Such compositions are particularly well suited for use in a variety of tissue related applications when rapid adhesion to the tissue and gel formation is desired along with drug delivery. For example, the compositions are useful as tissue sealants, in promoting hemostasis, in 10 effecting tissue adhesion, in providing tissue augmentation, and in the prevention of surgical adhesions. Description of the Related Art The use of polymer compositions in tissue engineering is now widely recognized, particularly those consisting of synthetic polymers. In 15 contrast to many naturally derived compositions, synthetic polymer compositions can be formulated to exhibit predetermined physical characteristics such as gel strength, as well as biological characteristics such as degradability. In a variety of tissue engineering applications, it is desirable to 20 use compositions that can be administered as liquids, but subsequently form hydrogels at the site of administration. Such in situ hydrogel forming compositions are more convenient to use since they can be administered as liquids from a variety of different devices, and are more adaptable for administration to any site, since they are not preformed. Many different 25 mechanisms have been described that can be used to promote hydrogel formation in situ. For example, photoactivatable mixtures of water-soluble co polyester prepolymers and polyethylene glycol have been described to create hydrogel barriers, as well as drug release matrices. In another approach, block 1 WO 2004/060346 PCT/US2003/041580 copolymers of polyalkylene oxide polymers (e.g., PLURONIC compounds from BASF Corporation, Mount Olive, NJ) and poloxamers have been designed that are soluble in cold water, but form insoluble hydrogels that adhere to tissues at body temperature (Leach, et al., Am. J. Obstet. Gynecol. 162:1317-1319 5 (1990)). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al., J. Otolaryngol. 19:68-72 (1990)). In yet another approach, two-part synthetic polymer compositions have been described that, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces. (PCT WO 97/22371, which corresponds to U.S. 10 application Ser. No. 08/769,806 U.S. Pat. No. 5,874,500.) In a similar approach involving a two-part composition, a mixture of protein and a bifunctional crosslinking agent has been described for use as a tissue adhesive (U.S. Pat. No. 5,583,114.) One difficulty encountered when designing in situ hydrogel 15 forming compositions is that optimizing the composition to enhance gel formation may worsen tissue inflammation at the site of administration. A possible explanation for this effect is that highly reactive composition components that are capable of rapid gel formation may adversely affect tissue surfaces. 20 The compositions of the present invention have been formulated to provide for rapid gelation, and also cause less tissue inflammation at the site of administration than previously described compositions. BRIEF SUMMARY OF THE INVENTION Briefly stated, the present invention provides compositions and 25 methods for drug delivery, including precursors to said compositions. For example, in one aspect, the present invention provides a biocompatible gel-forming drug-delivering composition for in vivo administration, comprising: a drug; 2 WO 2004/060346 PCT/US2003/041580 a first component comprising at least one sulfhydryl group containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 (SH)m, wherein m 2; and 5 a second component comprising at least one sulfhydryl reactive group-containing compound in either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n >; 10 wherein at least one of the first or second components is a polyalkylene oxide and wherein the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween when said components are mixed together. Preferably, the covalent bonds form a gel in less than one minute after mixing. 15 The invention also provides a method for treating tissues, comprising the steps of: administering to a tissue site a first component comprising at least one sulfhydryl group-containing compound in liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula 20 Compound 1 -(SH)m, wherein m 2; and simultaneously or subsequently administering to the tissue site a second component comprising at least one sulfhydryl reactive group-containing compound either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by 25 the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2, and wherein at least one of the first or second components is a polyalkylene oxide; and simultaneously or subsequently administering to the tissue site a drug; and 3 WO 2004/060346 PCT/US2003/041580 allowing the sulfhydryl groups and the sulfhydryl reactive groups to react with one another to form covalent bonds therebetween to form a gel in less than one minute. In another aspect, the invention provides a biocompatible gel 5 forming drug-delivering composition for in vivo administration with a gel time of less than one minute, comprising: polyalkylene oxide-(SH) 4 and drug in a liquid medium having a pH of between 8 and 10.5; and polyalkylene oxide-Y 4 , wherein Y is succinimidyl, in a liquid 10 medium having an acidic pH. In another aspect, the invention provides a biocompatible gel forming drug-delivering composition for in vivo administration with a gel time of less than one minute, comprising: polyalkylene oxide-(SH) 12 and drug in a liquid medium having an 15 alkaline pH; and polyalkylene oxide-Y 12 in a liquid medium having an acidic pH, wherein Y is a succinimidyl or maleimidyl group. In another aspect, the invention provides a biocompatible gel forming composition for in vivo administration, comprising: 20 a sulfhydryl group-containing polyalkylene oxide in a liquid medium having an acidic pH, wherein said sulfhydryl group-containing polyalkylene oxide is given by the formula Core-(SH)m, wherein m 2; a buffer solution with an alkaline pH; and drug in admixure with the polyalkylene oxide and/or the buffer 25 solution; wherein the sulfhydryl groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute. In another aspect, the present invention provides a biocompatible 30 gel-forming drug-delivering composition for in vivo administration, comprising: 4 WO 2004/060346 PCT/US2003/041580 at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; at least one sulfhydryl reactive group-containing compound either 5 a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; at least one drug in admixture with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl 10 reactive group-containing compound; and collagen; wherein at least one of either the sulfhydryl group-containing compound or the sulfhydryl reactive group-containing compound is a polyalkylene oxide, and wherein the sulfhydryl groups and the sulfhydryl 15 reactive groups are capable of reacting with one another to form covalent bonds therebetween. In another aspect, the present invention provides a biocompatible gel-forming drug-delivering composition for in vivo administration, comprising: (a) a first component in a liquid medium having an acidic pH 20 comprising: (i) at least one sulfhydryl group-containing compound given by the formula Compound 1 -(SH)m, wherein m 2; (ii) at least one sulfhydryl reactive group-containing compound given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group 25 and wherein n 2; and (iii) collagen; and (b) a second component comprising a buffer having a pH of between 8 and 10.5; wherein a drug is present in admixture with either or both of the 30 first component or the second component; and 5 WO 2004/060346 PCT/US2003/041580 wherein at least one of either the sulfhydryl group containing compound or the sulfhydryl reactive group containing compound is a polyalkylene oxide. Optionally, in each of these and other aspects of the invention as 5 disclosed herein, the drug is a hydrophobic drug in admixture with a secondary carrier to provide drug/carrier, the drug/carrier being in admixture with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl reactive group-containing compound. Furthermore, the present invention provides various methods that 10 are useful in preparing drug-containing delivery vehicles. For example, in one aspect the invention provides a method for forming a drug delivery composition, comprising a) selecting a first component, a second component and a drug, wherein 15 the first component comprises at least one sulfhydryl group containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound-(SH),n, wherein m 2; and the second component comprises at least one sulfhydryl reactive 20 group-containing compound in either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; at least one of the first or second components is a polyalkylene 25 oxide; the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute; b) combining the first and second components in the 30 presence of the drug, under conditions where the first component reacts with 6 WO 2004/060346 PCT/US2003/041580 the second component. The invention also provides a product produced by this method. In another aspect, the invention provides a method for forming a drug delivery composition, comprising 5 a) forming an admixture of polyalkylene oxide-(SH) 4 and drug in a liquid medium having a pH of between 8 and 10.5; and b) forming an admixture of polyalkylene oxide-Y 4 , wherein Y is succinimidyl and liquid medium, the admixture having an acidic pH. The invention may further include the step of combining the admixtures of steps a) 10 and b), and in addition the invention provides the product produced by this method. In another aspect, the invention provides a method for forming a biocompatible gel-forming drug-delivering composition for in vivo administration, preferably having a gel time of less than one minute, comprising: 15 a) preparing an admixture of polyalkylene oxide-(SH) 1 2 and drug in a liquid medium having an alkaline pH; and b) preparing polyalkylene oxide-Y 12 in a liquid medium having an acidic pH, wherein Y is a succinimidyl or maleimidyl group. In one aspect, this method further includes the step of combining a) and b), while in a related 20 aspect the invention provides the product produced by this method. In another aspect, the present invention provides a method for forming a biocompatible gel-forming composition for in vivo administration, the method comprising: a) preparing a sulfhydryl group-containing polyalkylene oxide 25 in a liquid medium having an acidic pH, wherein said sulfhydryl group containing polyalkylene oxide is given by the formula Core-(SH)mn, wherein m 2; b) providing a buffer solution with an alkaline pH; and c) adding drug to either or both of a) and b); wherein the sulfhydryl groups react with one another to form 30 covalent bonds therebetween when said components are mixed together to form a gel in less than one minute. Optionally, the method includes combining 7 WO 2004/060346 PCT/US2003/041580 a) and b), while in a related aspect the invention provides the produt produced by this method. In another aspect, the present invention provides a method for forming a biocompatible gel-forming drug-delivering composition for in vivo 5 administration, comprising: a) providing an at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; 10 b) providing an at least one sulfhydryl reactive group containing compound either in a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 9; 15 c) combining a drug with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl reactive group-containing compound; and d) providing collagen; wherein at least one of either the sulfhydryl group-containing 20 compound or the sulfhydryl reactive group-containing compound is a polyalkylene oxide; and wherein the sulfhydryl groups and the sulfhydryl reactive groups are capable of reacting with one another to form covalent bonds therebetween. Optionally, the method includes the step of combining a), b) and d), and in a 25 related aspect the invention provides the product produced by this method. A variety of drugs may be included in the compositions of the present invention, and used in the methods of the present invention. These drugs are set forth in detail below. The following are specific aspects of the present invention, which are exemplary only: in one aspect, the compositions 30 and methods of the invention employ (i.e., include in a composition, or use in a method) a cell cycle inhibitor; in one aspect, the compositions and methods of 8 WO 2004/060346 PCT/US2003/041580 the invention employ paclitaxel; in one aspect, the compositions and methods of the invention employ doxorubicin; in one aspect, the compositions and methods of the invention employ mitoxantrone; in one aspect, the compositions and methods of the invention employ podophyllotoxin (e.g., etoposide); in one 5 aspect, the compositions and methods of the invention employ an immunomodulatory agents; in one aspect, the compositions and methods of the invention employ rapamycin; in one aspect, the compositions and methods of the invention employ everolimus; in one aspect, the compositions and methods of the invention employ tacrolimus; in one aspect, the compositions and 10 methods of the invention employ biolimus; in one aspect, the compositions and methods of the invention employ a heat shock protein 90 antagonist; in one aspect, the compositions and methods of the invention employ geldanamycin; in one aspect, the compositions and methods of the invention employ a HMG CoA Reductase inhibitor; in one aspect, the compositions and methods of the 15 invention employ simvastatin; in one aspect, the compositions and methods of the invention employ an IMPDH Inhibitor; in one aspect, the compositions and methods of the invention employ mycophenolic acid; in one aspect, the compositions and methods of the invention employ 1-alpha-25 dihydroxy vitamin D3; in one aspect, the compositions and methods of the invention 20 employ an antimycotic agent; in one aspect, the compositions and methods of the invention employ sulconizole; in one aspect, the compositions and methods of the invention employ a P38 MAP kinase inhibitor; in one aspect, the compositions and methods of the invention employ SB220025; in one aspect, the compositions and method of the invention employ talcum powder; in one 25 aspect, the compositions and method of the invention employ metallic beryllium and oxides thereof; in one aspect, the compositions and method of the invention employ copper; in one aspect, the compositions and method of the invention employ silk; in one aspect, the compositions and method of the invention employ silica; in one aspect, the compositions and method of the 30 invention employ crystalline silicates; in one aspect, the compositions and method of the invention employ talc; in one aspect, the compositions and 9 WO 2004/060346 PCT/US2003/041580 method of the invention employ quartz dust; in one aspect, the compositions and method of the invention employ ethanol; in one aspect, the compositions and method of the invention employ a component of extracellular matrix; in one aspect, the compositions and method of the invention employ fibronectin; in one 5 aspect, the compositions and method of the invention employ collagen; in one aspect, the compositions and method of the invention employ fibrin; in one aspect, the compositions and method of the invention employ fibrinogen; in one aspect, the compositions and method of the invention employ polylysine; in one aspect, the compositions and method of the invention employ poly(ethylene-co 10 vinylacetate); in one aspect, the compositions and method of the invention employ chitosan; in one aspect, the compositions and method of the invention employ N-carboxybutylchitosan; in one aspect, the compositions and method of the invention employ a RGD protein; in one aspect, the compositions and method of the invention employ vinyl chloride; in one aspect, the compositions 15 and method of the invention employ a polymer formed from vinyl chloride; in one aspect, the compositions and method of the invention employ a cyanoacrylate adhesive; in one aspect, the compositions and method of the invention employ an adhesive comprising crosslinked poly(ethylene glycol) derived material and methylated collagen; in one aspect, the compositions and 20 method of the invention employ an inflammatory cytokine; in one aspect, the compositions and method of the invention employ ann inflammatory cytokine selected from the group consisting of TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, and growth hormone; in one aspect, the compositions and method of the invention employ a connective tissue growth 25 factor (CTGF); in one aspect, the compositions and method of the invention employ a bone morphogenic protein (BMP); in one aspect, the compositions and method of the invention employ a BMP selected from BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7; in one aspect, the compositions and method of the invention employ bleomycin; in one aspect, the compositions and method 30 of the invention employ an analogue or derivative of bleomycin; in one aspect, the compositions and method of the invention employ a proliferative agent that 10 WO 2004/060346 PCT/US2003/041580 stimulates cellular proliferation; in one aspect, the compositions and method of the invention employ dexamethasone and analogues and derivatives thereof; in one aspect, the compositions and method of the invention employ isotretinoin and analogues and derivatives thereof; in one aspect, the compositions and 5 method of the invention employ 17-3-estradiol and analogues and derivatives thereof; in one aspect, the compositions and method of the invention employ estradiol and analogues and derivatives thereof; in one aspect, the compositions and method of the invention employ diethylstibesterol and analogues and derivatives thereof; in one aspect, the compositions and method 10 of the invention employ cyclosporine A and analogues and derivatives thereof; in one aspect, the compositions and method of the invention employ All-trans retinoic acid (ATRA) and analogues and derivatives thereof. Additional drugs that may be employed in the present invention are set forth below. These and other aspects of the present invention will become 15 evident upon reference to the following detailed description. In addition, various references are set forth herein. Each of these references is incorporated herein by reference in its entirety as if each were individually noted for incorporation. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) Figure 1 is a tetrafunctionally activated PEG succinimidyl glutarate 20 (ester linkage) (SG-PEG). Figure 2 depicts the structure of various sulfhydryl-reactive groups, with "R" representing the chemical structure to which the reactive group is attached. Figure 3 is a schematic illustration showing sites of action within a 25 biological pathway where Cell Cycle Inhibitors may act to inhibit the cell cycle. Figure 4 depicts the rheometric measurements of gelation of a mixture of reactive tetrafunctional polyethylene glycols. Figure 5 depicts the formation of two "12-arm' PEG compounds from "4-arm" intermediates. 11 WO 2004/060346 PCT/US2003/041580 Figure 6 is a graph showing % inhibition of human fibroblast cell proliferation as a function of Mitoxantrone concentration. Figure 7 is a graph showing % inhibition of nitric oxide production in RAW 264.7 cells.as a function of Mitoxantrone concentration. 5 Figure 8 is a graph showing % inhibition of TNFca production by THP-1 cells as a function of Bay 11-7082 concentration. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to drug delivery via a two-part polymer composition that forms a matrix when mixed together. Each 10 component of the composition is generally administered separately to the tissue site, and the drug may be delivered with either component, or may be delivered separately. Then, within a very short time after being mixed together at the site of administration, the composition forms a gel with sufficient adhesive and cohesive strength to become anchored in place, and allow delivery of the drug 15 to this location. The components can be mixed prior to application to the tissue with the drug being mixed with the components prior to gellation or added after gellation has occurred. Definitions 20 The following definitions are provided to further describe various aspects of the preferred embodiments of the present invention. The term "gel" refers to the state of matter between liquid and solid. As such, a "gel" has some of the properties of a liquid (Le., the shape is resilient and deformable) and some of the properties of a solid (i.e., the shape 25 is discrete enough to maintain three dimensions on a two dimensional surface.) Accordingly, "gelation time", also referred to herein as "gel time", refers to the time it takes for a composition to become non-flowable under modest stress. This is generally exhibited as achieving a gel strength, G', of greater than or equal to 102 dynes/cm 2 in less than 1 minute. 12 WO 2004/060346 PCT/US2003/041580 The term "cohesive strength" refers to the ability of the compositions of the present invention to remain intact, i.e., not rupture, tear or crack, when subjected to physical stresses or environmental conditions. Cohesive strength is sometimes measured as a function of "burst strength". 5 The term "adhesive strength" refers to the ability of the compositions of the present invention to be able to remain attached to the tissues at the site of administration when subjected to physical stresses or environmental conditions. The term "polymer" refers to a molecule consisting of individual 10 chemical moieties, which may be the same or different, but are preferably the same, that are joined together. As used herein, the term "polymer" refers to individual chemical moieties that are joined end-to-end to form a linear molecule, as well as individual chemical moieties joined together in the form of a branched (e.g., a "multi-arm" or "star-shaped") structure. 15 The term "biocompatible" refers to the ability of the compositions of the present invention to be applied to tissues without eliciting significant inflammation and fibrosis or other adverse tissue responses. The term "synthetic polymer" refers to polymers that are not naturally occurring and that are produced by chemical or recombinant 20 synthesis. As such, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Proteins such as synthetic collagen, and carbohydrates such as synthetic hyaluronic acid, and their derivatives, are included. The term "activated synthetic polymers" refers to synthetic 25 polymers that have or have been chemically modified to have at least one functional group (e.g., a sulfhydryl group) that is capable of reacting with a corresponding reaction partner (e.g., a sulfhydryl-reactive group) to form a covalent bond. The term "multifunctionally activated" refers to synthetic polymers having two or more nucleophilic or electrophilic groups. Types of 30 multifunctionally activated synthetic polymers include di-functionally activated, 13 WO 2004/060346 PCT/US2003/041580 tri-functionally activated, tetra-functionally activated, and star-shaped activated polymers (that have four or more functional groups). "Fibrosis" or "Scarring" refers to the formation of fibrous tissue in response to injury or medical intervention. Fibrosis or scarring is defined to 5 involve biological processes which include an increase in one or more of the following: inflammation including production and release of cytokines and/or chemokines, angiogenesis, cellular proliferation (typically fibroblasts and/or smooth muscle cells), cell migration, ECM (extracellular matrix) production, tissue remodeling and cell adhesion. 10 Therapeutic agents which inhibit fibrosis or scarring can do so through one or more mechanisms including: inhibiting inflammatory processes such as production of cytokines and chemokines, inhibiting angiogenesis, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, and smooth muscle cells), reducing ECM production and/or 15 inhibiting tissue remodeling. In addition, numerous therapeutic agents described in this invention will have the additional benefit of also reducing tissue regeneration (the replacement of injured cells by cells of the same type) when appropriate. An agent that modulates any of these events is referred to herein as an anti-scarring or a fibrosis-inhibiting agent. 20 Therapeutic agents which increase fibrosis or scarring can do so through an increase in one or more of the following processes: inflammation including production and release of cytokines and/or chemokines, angiogenesis, cellular proliferation (typically fibroblasts and/or smooth muscle cells), cell migration, ECM (extracellular matrix) production, tissue remodeling, 25 cell adhesion and/or free radical production and release. Numerous therapeutic agents described in this invention are capable of inducing fibrosis or scarring and are referred to herein as fibrosing or scarring agents. Composition Components The compositions of the present invention comprise two or more 30 different compounds, and at least one of which is a polymer, that react with one 14 WO 2004/060346 PCT/US2003/041580 another to form a covalently crosslinked gel matrix. Depending on the reactivity of the compounds towards each other, the different compounds can be in separate parts of the starting compositions, or they can be in the same part of the starting composition. As such, they can easily be administered separately or 5 simultaneously, and rapidly form gels at the site of administration. The compositions can also be formed into gels prior to application to the desired site. The compositions also include a drug that will be contained with the gel and delivered to the tissue at the site of gel administration. In one aspect of the compositions of the present invention, each 10 component is present in one of the two separate parts, or "components", of the composition, along with other optional ingredients as described elsewhere herein. In total, at least three components are delivered, namely, two reactive components that together form a gel, and a drug. In another aspect of the compositions of the present invention, the 15 components are mixed together under conditions such that they do not form a gel immediately. There components can be mixed with an activating solution (e.g., buffer, peroxide, etc.) such that a gel is rapidly formed. The two reactive compounds and the gel matrix that forms when they are mixed together can be represented by Formula I as follows: 20 Compound -(S H)m+Compound 2 -Yn->CompoundI-Z-Compound 2 (I) Compound 1 has multiple (m >2) sulfhydryl groups (SH) that react with Compound 2 , which has multiple (n 2) sulfhydryl-reactive groups (Y). It should be understood that sulfhydryl groups are also "sulfhydryl reactive groups", since it is well known that sulfhydryl groups will react with one another 25 under certain conditions. When mixed together, the two compounds become interconnected via a covalent bond (Z). However, when m+n >5, and appropriate ratios of the two components are utilized as described elsewhere herein, Compound 1 and/or Compound 2 can form multiple attachments to Compound 1 and/or Compound 2 , resulting in an interconnected three 30 dimensional matrix. Preferably, both compounds contain four or more functional groups, since such multifunctionality results in a gel matrix with 15 WO 2004/060346 PCT/US2003/041580 greater overall cohesive strength. In a particularly preferred embodiment, each of the compounds is tetrafunctionally activated. In another preferred embodiment, the compounds each have 12 functional groups. Such compounds are formed from reacting a first 5 tetrafunctionally activated polymer with a second tetrafunctionally activated polymer, wherein the functional groups of each of the two compounds are a reaction pair, and react together to form "12-arm" functionally activated polymers. An example of such a "12-arm" compound is dodeca-sulfhydryl PEG, 50,000 mol. wt., which is constructed from a core tetra-functional 10 succinimide ester PEG coupled to four (exterior) tetra-functional sulfhydryl-PEG molecules. Such polymers range in size from over 10,000 mol. wt. to greater than 100,000 mol. wt. depending on the molecular weight of the tetra functionally activated polymer starting materials. Other types of multifunctional polymers can easily be synthesized 15 using routine synthesis. However, care should be taken to produce multi-arm products with consistent arm lengths to avoid steric hindrance of the reactive groups. Accordingly, activated polymers that are suitable for use in the present invention may have a variety of geometric shapes and configurations. 20 Exemplary polymers according to the present invention, as well as methods of their manufacture and use, are described in U.S. Patent Nos. 5,874,500; 6,051,648; 6,166,130; 6,312,725; 6,323,278; and 6,458,889. Compound Core As described above, each of the compounds has multiple 25 functional groups, either sulfhydryl groups or sulfhydryl-reactive groups. The non-reactive remainder of the compound is considered to be its "core". At least one of the two compounds must have a polymer core in order to form an efficient gel matrix. When one of the compounds contains a polymer core, the other compound can be a small organic molecule with multiple sulfhydryl 16 WO 2004/060346 PCT/US2003/041580 reactive groups. However, for most applications, it is preferred for both compounds to have the same or a different polymer core. The polymer core may be a synthetic polyamino acid, a polysaccharide, or a synthetic polymer. A preferred polymer core material is a 5 synthetic hydrophilic polymer. Suitable synthetic hydrophilic polymers include, inter alia, polyalkylene oxide, such as polyethylene oxide ((CH 2
CH
2 0)n), polypropylene oxide ((CH(CH 3
)CH
2 0)n) or a polyethylene/polypropylene oxide mixture ((CH 2
CH
2 0)n -(CH(CH 3
)CH
2 0)n). A particularly preferred synthetic hydrophilic polymer is a polyethylene glycol (PEG) having a molecular weight 10 within the range of about 100 to about 100,000 mol. wt., more preferably about 1,000 to about 20,000 mol. wt. More preferably still, when the polymer core is polyethylene glycol, it generally has a molecular weight within the range of about 7,500 to about 20,000 mol. wt. Most preferably, the polyethylene glycol has a molecular weight of approximately 10,000 mol. wt. 15 Multifunctionally activated polyalkylene oxides, such as polyethylene glycol, are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992); and Shearwater Polymers, Inc. Catalog, 20 Polyethylene Glycol Derivatives, Huntsville, Ala. (1997-1998). For use as a tissue sealant, the preferred combination of activated polymers is as follows: the sulfhydry-reactive group-containing compound is the tetrafunctional PEG, pentaerythritol poly(ethylene glycol) ether tetra-succinimidyl glutarate (10,000 mol. wt.); and the sulfhydryl group-containing compound is the tetrafunctional 25 PEG, pentaerythritol poly(ethylene glycol) ether tetra-sulfhydryl (10,000 mol. wt.). In both cases, these "four-arm" PEGs are formed by ethoxylation of pentaerythritol, where each of the four chains is approximately 2,500 mol. wt., and then derivatized to introduce the functional groups onto each of the four arms. Also preferred are analogous poly(ethylene glycol)-like compounds 30 polymerized from di-glycerol instead of pentaerythritol. 17 WO 2004/060346 PCT/US2003/041580 When only one of the reactive compounds comprises a polymer core, the other reactive compound is a multifunctionally active small organic molecule. Such compounds include the di-functional di-succinimidyl esters and di-maleimidyl compounds, as well as other well known commercially available 5 compounds (Pierce Chemical Co., Rockford, IL). In addition, one of skill in the art could easily synthesize a low molecular weight multi-functional reactive compound using routine organic chemistry techniques. On such compound is shown in FIG. 1, which is a penta-erythritol coupled to four glutarates, with each arm capped with N-hydroxy-succinimidyl esters (NHS). Analogous compounds 10 can be synthesized from inositol (radiating 6 arm), lactitol (9 arm) or sorbitol (linear 6-arm). The end-capped reactive group can just as easily be sulfhydryl, maleimidyl, vinyl-sulfone, vinyl, acrylate, acrylamide, etc., instead of NHS. The polymer or the small molecule can carry either reactive end group as long as there are reactive pairs in the composition such as NHS and SH, maleimidyl 15 and SH, etc. Reactive Groups and Matrix Linkages In the present invention, the linkage, Z, comprises a covalent bond between the sulfur atom in the sulfhydryl group-containing compound and, the carbon or sulfur atom in the sulfhydryl-reactive group-containing compound. 20 Accordingly, the linkage may be a thioester, a thioether, a disulfide, or the like. A wide variety of sulfhydryl-reactive groups and the types of linkages they form when reacted with sulfhydryl groups are well known in the scientific literature. For example, see Bodanszky, M., Principles of Peptide Synthesis, 2nd ed., pages 21 to 37, Springer-Verlog, Berlin (1993); and Lundbland, R. L., Chemical 25 Reagents for Protein Modification, 2nd ed., Chapter 6, CRC Press, Boca Raton, Fla. (1991). For most applications, sulfhydryl reactive groups that react with sulfhydryl groups to form thioester linkages are preferred. Such compounds are depicted in FIG. 2 and include, inter alia, the following compounds, with the 30 numbers in parentheses corresponding to the structures shown in FIG. 2: mixed 18 WO 2004/060346 PCT/US2003/041580 anhydrides, such as PEG-glutaryl-acetyl-anhydride (1), PEG-glutaryl-isovaleryl anhydride (2), PEG-glutaryl-pivalyl-anhydride (3) and related compounds as presented in Bodanszky, p. 23; Ester derivatives of phosphorus, such as structures (4) and (5); ester derivatives of p-nitrophenol (6) of p-nitrothiophenol 5 (7), of pentafluorophenol (8), of structure (9) and related active esters as presented by Bodanszky, pp. 31-32, and Table 2; esters of substituted hydroxylamines, such as those of N-hydroxy-phthalimide (10), N-hydroxy succinimide (11), and N-hydroxy-glutarimide (12), as well as related structures in Bodanszky; Table 3; esters of 1-hydroxybenzotriazole (13), 3-hydroxy-3,4 10 dihydro-benzotriazine-4-one (14) and 3-hydroxy-3,4-dihydro-quinazoline-4-one; derivatives of carbonylimidazole; and isocyanates. With these compounds, auxiliary reagents can also be used to facilitate bond formation. For example, reagents such as 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide] can be used to facilitate coupling of carboxyl groups (i.e., glutarate and succinate) with 15 sulfhydryl groups. In addition to the sulfhydryl reactive compounds that form thioester linkages, various other compounds can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups. Alternatively, 20 sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups, such as ortho pyridyl disulfide, 3-nitro-2-pyridenesulfenyl, 2 nitro-5-thiocyanobenzoic acid, 5,5'-dithio-bis(2-nitrobenzoic acid), derivatives of methane-thiosulfate, and 2,4-dinitrophenyl cysteinyl disulfides. In such instances, auxiliary reagents, such as the hydrogen peroxide or di-tert-butyl 25 ester of azodicarboxylic acid, can be used to facilitiate disulfide bond formation. Other classes of sulfhydryl reactive groups that form thioether bonds with sulfhydryl groups include, inter alia, iodoacetamide, N ethylmaleimide and other maleimides, including dextran maleimides, mono bromo-bimane and related compounds, vinylsulfones, epoxides, derivatives of 30 O-methyl-isourea, ethyleneimines, aziridines, vinyl derivatives, acrylate 19 WO 2004/060346 PCT/US2003/041580 derivatives, acrylamide derivatives and 4-(aminosulfonyl-)7-fluoro-2,1,3 benzoxadiazole. Chain Extenders Functional groups may be directly attached to the compound core, 5 or they may be indirectly attached through a chain extender. Such chain extenders are well known in the art. See, for example, PCT WO 97/22371, which describes "linking groups" that would be suitable for use as chain extenders in the compositions of the present invention. Chain extenders are useful to avoid steric hindrance problems that are sometimes associated with 10 the formation of direct linkages between molecules. Alternatively, chain extenders may be used to link several multifunctionally activated compounds together to make larger molecules. In a particularly preferred embodiment, the chain extender can also be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, 15 chain extenders can be incorporated into one or both of the multifunctionally activated polymers to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation. Chain extenders can also activate or suppress activity of sulfhydryl and sulfhydryl-reactive groups. For example, electron-withdrawing groups within one or two carbons of the sulfhydryl group 20 would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Double-bond carbon and carbonyl carbon would be anticipated to have this effect. Bulky nearby groups for either partner are anticipated to diminish coupling rates, due to steric hindrance. Electron-withdrawing groups adjacent to the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl would be 25 anticipated to make this carbonyl carbon even more reactive with the sulfhydryl partner. Chain extenders may provide sites for degradation, i.e., hydrolysable sites. Examples of hydrolysable chain extenders include, inter alia, alpha-hydroxy acids such as lactic acid and glycolic acid; poly(lactones) 30 such as caprolactone, valerolactone, gamma butyl lactone and p-dioxanone; 20 WO 2004/060346 PCT/US2003/041580 poly(amino acids); poly(anhydrides) such as glutarate and succinate; poly(orthoesters); poly(orthocarbonates) such as trimethylene carbonate; poly(phosphoesters), as well as polymers and copolymers comprising one or more of the units of the monomers lactic acid, glycolic acid, D-lactide, L-lactide, 5 D,L-lactide, glycolide, s-caprolactone, trimethylene carbonate, 1,4-dioxane-2 one or 1,5-dioxepan-2one. Examples of non-degradable chain extenders include, inter alia, succinimide, propionic acid and carboxymethylate. See, for example, PCT WO 99/07417. Examples of enzymatically degradable chain extenders include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly 10 Pro-Lys, which is degraded by plasmin. Gel Strength and Gel Time The compositions of the present invention are formulated to exhibit adequate strength and rapid gel time. The elastic modulus, G', is the preferred measure of gel strength. Preferred compositions for use as tissue 15 sealants can achieve a gel strength of about 10 3 to 108 dynes/cm 2 , and more preferably 104 to 107 dynes/cm 2 . Preferred compositions for use as hemostatic agents or for adhesion prevention have a gel strength of at least 102 to 104 dynes/cm 2 if a soft gel is desired, or 105 to 108 dynes/cm 2 if a harder matrix is desired. 20 The gel time of preferred formulations is less than 60 seconds, more preferably less than 30 seconds, and most preferably less than 15 seconds. The fast gel time ensures maximum material at the site to be treated and sufficient mechanical properties. Druq 25 In addition to the reactive compounds described above, the compositions of the present invention include a drug. As used herein, the term "drug" refers to an organic molecule that exerts biological effects in vivo. In one aspect, the drug is in combination with Compound 1 . In another aspect, the drug is in combination with Compound 2 . Suitable drugs are described below. In one 21 WO 2004/060346 PCT/US2003/041580 aspect, the drug is hydrophobic. In another aspect, the drug is hydrophyllic. One aspect of the invention involves pharmacological alteration of cellular and/ or non-cellular processes involved in the development and/or maintenance of surgical adhesions. Another aspect of this invention involves pharmacological 5 alteration of cellular and/or non-cellular processes involved in the development and/or maintenance of restenosis. Thus, pharmacological agents (i.e., drugs) within the scope of this invention include but are not limited to those which inhibit one or a combination of processes including but not limited to cell division, cell secretion, cell migration, cell adhesion, cytokine, chemokine (or 10 other inflammatory activator) production and/or release, angiogenesis, and/or free radical formation and/or release. Drugs within the scope of this invention may inhibit or affect other processes involved in the scarring process. In addition, an aspect of this invention involves pharmacological alteration of cellular and/or non-cellular processes which increase the 15 development of fibrosis. Thus, pharmacological agents (i.e., drugs) within the scope of this invention include but are not limited to those which increase one or a combination of processes including but not limited to cell division, cell secretion, cell migration, cell adhesion, cytokine, chemokine (or other inflammatory activator) production and/or release, angiogenesis, and/or free 20 radical formation and/or release. Drugs within the scope of this invention may increase or affect other processes involved in the scarring process. Thus, while the non-drug loaded formulation can act as a sealant and/or hemostatic agent and/or adhesion prevention agent, the addition of a drug can effect an increase or decrease in fibrosis, and/or result in tissue 25 augmentation and/or increase or reduction in surgical adhesions depending on the drug mechanism. For example, a drug which decreases fibrosis will be expected to reduce surgical adhesions. Furthermore, the drug-loaded formulation may increase the sealant and/or hemostatic properties of the formulation, especially when the agent acts to increase fibrosis. 30 One aspect of the invention involves pharmacological alteration of cellular and/or non-cellular processes involved in the development and/or 22 WO 2004/060346 PCT/US2003/041580 maintenance of surgical adhesions or restenosis or in more general terms inhibit one or more processes involved in fibrosis. Thus, pharmacological agents within the scope of this invention include but are not limited to those which inhibit one or a combination of processes such as cell division, cell 5 secretion, cell migration, cell adhesion, extracellular matrix production, cytokine (e.g., TNF alpha, IL-1, IL-6), or other inflammatory activator, e.g., chemokines (e.g., MCP-1 or IL-8)) production and/or release, angiogenesis, and/or free radical formation and/or release. Suitable fibrosis, adhesion or stenosis-inhibiting agents may be 10 readily determined based upon the in vitro and in vivo (animal) models such as those provided in Examples 29-33. Numerous fibrosis, adhesion and/or stenosis-inhibiting therapeutic compounds have been identified that are of utility in the invention including: 1. Angiogenesis Inhibitors 15 In one embodiment, the pharmacologically active compound is an angiogenesis inhibitor (e.g., 2-ME (NSC-659853), PI-88 (D-Mannose, 0-6-0 phosphono-Alpha-D-mannopyranosyl-(1-3)-O-Alpha-D-mannopyranosyl-(1-3) O-Alpha-D-mannopyranosyl-(1-3)-O-Alpha-D-mannopyranosyl-(1-2)- hydrogen sulphate [CAS]), thalidomide (1 H-Isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3 20 piperidinyl)- [CAS]), CDC-394, CC-5079, ENMD-0995 (S-3-amino phthalidoglutarimide), AVE-8062A, Vatalanib, SH-268, Halofuginone hydrobromide)) or an analogue or derivative thereof. 2. 5-Lipoxygenase Inhibitors & Antagonists In another embodiment, the pharmacologically active compound 25 is a 5-lipoxygenase inhibitor or antagonist (e.g., licofelone (ML3000), 2-uredo thiophene/2 amino thiophene, 15-deoxy-Prostaglandin J2, Wy-50295 (2 Naphthaleneacetic acid, Alpha-methyl-6-(2-quinolinylmethoxy)-, (S)-[CAS]), ONO-LP-269 (2,11,14-Eicosatrienamide, N-[4-hydroxy-2-(1 H-tetrazol-5-yl)-8 quinolinyl]-, (E,Z,Z)-[CAS]), licofelone (1 H-Pyrrolizine-5-acetic acid, 6-(4 23 WO 2004/060346 PCT/US2003/041580 chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl- [CAS]), CMI-568 (Urea, N butyl-N-hydroxy-N'-[4-[3-(methylsulfonyl)-2-propoxy-5-[tetrahydro-5-(3,4,5 trimethoxyphenyl)-2-furanyl]phenoxy]butyl]-,trans- [CAS]), IP-751 ((3R,4R) (delta6)-THC-DMH-11-oic acid), PF-5901 (Benzenemethanol, Alpha-pentyl-3 5 (2-quinolinylmethoxy)- [CAS]), LY-293111 (Benzoic acid, 2-[3-[3-[(5-ethyl-4' fluoro-2-hydroxy[1,1'-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]- [CAS]), RG 5901-A (Benzenemethanol, Alpha-pentyl-3-(2-quinolinylmethoxy)-, hydrochloride [CAS]), rilopirox (2(1 H)-Pyridinone, 6-[[4-(4 chlorophenoxy)phenoxy]methyl]-1l-hydroxy-4-methyl- [CAS]), L-674636 (Acetic 10 acid, ((4-(4-chlorophenyl)-1l-(4-(2-quinolinylmethoxy)phenyl)butyl)thio)-AS]), 7 [[3-(4-methoxy-tetrahydro-2H-pyran-4-yl)phenyl]methoxy]-4-phenylnaphtho[2,3 c]furan-1 (3H)-one, MK-886 (1H-Indole-2-propanoic acid, 1-[(4 chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-Alpha,Alpha-dimethyl-5-(1 methylethyl)- [CAS]), quiflapon (1H-Indole-2-propanoic acid, 1-[(4 15 chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-Alpha,Alpha-dimethyl-5-(2 quinolinylmethoxy)- [CAS]), quiflapon (1 H-Indole-2-propanoic acid, 1-[(4 chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-Alpha,Alpha-dimethyl-5-(2 quinolinylmethoxy)- [CAS]), docebenone (2,5-Cyclohexadiene-1,4-dione, 2-(12 hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl- [CAS]), zileuton (Urea, N-(1 20 benzo[b]thien-2-ylethyl)-N-hydroxy- [CAS]) ) or an analogue or derivative thereof. 3. Chemokine Receptor Antagonists CCR (1, 3, & 5) In another embodiment, the pharmacologically active compound is a chemokine receptor antagonist (e.g., AMD-3100 (Anormed), ONO-4128 25 (1,4,9-Triazaspiro(5.5)undecane-2,5-dione, 1-butyl-3-(cyclohexylmethyl)-9 ((2,3-dihydro-1,4-benzodioxin-6-yl)methyl- [CAS]), L-381, CT-112 (L-Arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl-L-prolyl- [CAS]), AS 900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIP II, SB 265610, DPC-168, TAK-779 (N, N-Dimethyl-N-[4-[2-(4-methylphenyl)-6,7 24 WO 2004/060346 PCT/US2003/041580 dihydro-5H-benzocyclohepten-8-ylcarboxamido]benyl]tetrahydro-2H-pyran-4 aminium chloride), TAK-220, KRH-1120) or an analogue or derivative thereof. 4. Cell Cycle Inhibitors In another embodiment, the pharmacologically active compound 5 is a cell cycle inhibitor or an analogue or derivative thereof. In related embodiments, the cell-cycle inhibitor is a taxane (e.g., paclitaxel, or an analogue or derivative thereof), an antimetabolite, an alkylating agent, or a vinca alkaloid. In another embodiment, the cell-cycle inhibitor is camptothecin or an analogue or derivative thereof. Other suitable compounds include 10 mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, Peloruside A - a microtubule stabilizing agent, Mitomycin-C, and CDK-2 inhibitors. "Cell Cycle Inhibitor" as used herein refers to any protein, peptide, chemical or other molecule which delays or impairs a dividing cell's ability to progress through the cell cycle and replicate. A wide variety of methods may be 15 utilized to determine the ability of a compound to inhibit the cell cycle including univariate analysis of cellular DNA content and multiparameter analysis. A Cell Cycle Inhibitor may act to inhibit the cell cycle at any of the steps of the biological pathways shown in FIG. 3, as well as at other possible steps in other biological pathways. In addition, it should be understood that while a single cell 20 cycle agent is often referred to, that this in fact should be understood to include two or more cell cycle agents, as more than one cell cycle agent may be utilized within the compositions, methods and/or devices described herein (e.g., two cell-cycle inhibitors may be selected that act on different steps shown in FIG. 3. A wide variety of cell cycle inhibitory agents can be utilized, either 25 with or without a carrier (e.g., a polymer or ointment or vector), within the context of the present invention. Representative examples of such agents include taxanes (e.g., paclitaxel (discussed in more detail below) and docetaxel) (Schiff et al., Nature 277:665-667, 1979; Long and Fairchild, Cancer Research 54:4355-4361, 1994; Ringel and Horwitz, J. Nat'I Cancer Inst. 30 83(4):288-291, 1991; Pazdur et aL, Cancer Treat. Rev. 19(40):351-386, 1993), 25 WO 2004/060346 PCT/US2003/041580 Etanidazole, Nimorazole (B.A. Chabner and D.L. Longo. Cancer Chemotherapy and Biotherapy - Principles and Practice. Lippincott-Raven Publishers, New York, 1996, p.554), perfluorochemicals with hyperbaric oxygen, transfusion, erythropoietin, BW12C, nicotinamide, hydralazine, BSO, 5 WR-2721, ludR, DUdR, etanidazole, WR-2721, BSO, mono-substituted keto aldehyde compounds (L.G. Egyud. Keto-aldehyde-amine addition products and method of making same. U.S. Patent No. 4,066,650, Jan 3, 1978), nitroimidazole (K.C. Agrawal and M. Sakaguchi. Nitroimidazole radiosensitizers for Hypoxic tumor cells and compositions thereof. U.S. Patent No. 4,462,992, 10 Jul. 31, 1984), 5-substituted-4-nitroimidazoles (Adams et al., Int. J. Radiat. Biol. Relat. Stud. Phys., Chem. Med. 40(2):153-61, 1981), SR-2508 (Brown et al., Int. J. Radiat. Oncol., Biol. Phys. 7(6):695-703, 1981), 2H-isoindolediones (J.A. Myers, 2H-Isoindolediones, their synthesis and use as radiosensitizers. U.S. Patent No. 4,494,547, Jan. 22, 1985), chiral [[(2-bromoethyl)-amino]methyl] 15 nitro-1 H-imidazole-1 -ethanol (V.G. Beylin, et al., Process for preparing chiral [[(2-bromoethyl)-amino]methyl]-nitro-1 H-imidazole-1 -ethanol and related compounds. U.S. Patent No. 5,543,527, Aug. 6, 1996; U.S. Patent No. 4,797,397; Jan. 10, 1989; U.S. Patent No. 5,342,959, Aug. 30, 1994), nitroaniline derivatives (W.A. Denny, et al. Nitroaniline derivatives and their use 20 as anti-tumor agents. U.S. Patent No. 5,571,845, Nov. 5, 1996), DNA-affinic hypoxia selective cytotoxins (M.V. Papadopoulou-Rosenzweig. DNA-affinic hypoxia selective cytotoxins. U.S. Patent No. 5,602,142, Feb. 11, 1997), halogenated DNA ligand (R.F. Martin. Halogenated DNA ligand radiosensitizers for cancer therapy. U.S. Patent No. 5,641,764, Jun 24, 1997), 25 1,2,4 benzotriazine oxides (W.W. Lee et al. 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. U.S. Patent No. 5,616,584, Apr. 1, 1997; U.S. Patent No. 5,624,925, Apr. 29, 1997; Process for Preparing 1,2,4 Benzotriazine oxides. U.S. Patent No. 5,175,287, Dec. 29, 1992), nitric oxide (J.B. Mitchell et a!., Use of Nitric oxide releasing compounds as hypoxic 30 cell radiation sensitizers. U.S. Patent No. 5,650,442, Jul. 22, 1997), 2 nitroimidazole derivatives (M.J. Suto et al. 2-Nitroimidazole derivatives useful 26 WO 2004/060346 PCT/US2003/041580 as radiosensitizers for hypoxic tumor cells. U.S. Patent No. 4,797,397, Jan. 10, 1989; T. Suzuki. 2-Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as active ingredient. U.S. Patent No. 5,270,330, Dec. 14, 1993; T. Suzuki et al. 2-Nitroimidazole derivative, 5 production thereof, and radiosensitizer containing the same as active ingredient. U.S. Patent No. 5,270,330, Dec 14, 1993; T. Suzuki. 2 Nitroimidazole derivative, production thereof and radiosensitizer containing the same as active ingredient; Patent No. EP 0 513 351 B1, Jan. 24,1991), fluorine-containing nitroazole derivatives (T. Kagiya. Fluorine-containing 10 nitroazole derivatives and radiosensitizer comprising the same. U.S. Patent No. 4,927,941, May 22, 1990), copper (M.J. Abrams. Copper Radiosensitizers. U.S. Patent No. 5,100,885, Mar. 31, 1992), combination modality cancer therapy (D.H. Picker et al. Combination modality cancer therapy. U.S. Patent No. 4,681,091, Jul. 21, 1987). 5-CIdC or (d)H 4 U or 5-halo-2'-halo-2'-deoxy 15 cytidine or -uridine derivatives (S.B. Greer. Method and Materials for sensitizing neoplastic tissue to radiation. U.S. Patent No. 4,894,364 Jan. 16, 1990), platinum complexes (K.A. Skov. Platinum Complexes with one radiosensitizing ligand. U.S. Patent No. 4,921,963. May 1, 1990; K.A. Skov. Platinum Complexes with one radiosensitizing ligand. Patent No. EP 0 287 317 20 A3), fluorine-containing nitroazole (T. Kagiya, et al. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same. U.S. Patent No. 4,927,941. May 22,1990), benzamide (W.W. Lee. Substituted Benzamide Radiosensitizers. U.S. Patent No. 5,032,617, Jul. 16, 1991), autobiotics (L.G. Egyud. Autobiotics and their use in eliminating nonself cells in vivo. U.S. 25 Patent No. 5,147,652. Sep. 15,1992), benzamide and nicotinamide (W.W. Lee et al. Benzamide and Nictoinamide Radiosensitizers. U.S& Patent No. 5,215,738, Jun 1 1993), acridine-intercalator (M. Papadopoulou-Rosenzweig. Acridine Intercalator based hypoxia selective cytotoxins. U.S. Patent No. 5,294,715, Mar. 15,1994), fluorine-containing nitroimidazole (T. Kagiya et al. 30 Fluorine containing nitroimidazole compounds. U.S. Patent No. 5,304,654, Apr. 19, 1994), hydroxylated texaphyrins (J.L. Sessler et al. Hydroxylated 27 WO 2004/060346 PCT/US2003/041580 texaphrins. U.S. Patent No. 5,457,183, Oct. 10, 1995), hydroxylated compound derivative (T. Suzuki et al. Heterocyclic compound derivative, production thereof and radiosensitizer and antiviral agent containing said derivative as active ingredient. Publication Number 011106775 A (Japan), Oct. 22,1987; T. 5 Suzuki et al. Heterocyclic compound derivative, production thereof and radiosensitizer, antiviral agent and anti cancer agent containing said derivative as active ingredient. Publication Number 01139596 A (Japan), Nov. 25, 1987; S. Sakaguchi et al. Heterocyclic compound derivative, its production and radiosensitizer containing said derivative as active ingredient; Publication 10 Number 63170375 A (Japan), Jan. 7, 1987), fluorine containing 3-nitro-1,2,4 triazole (T. Kagitani et al. Novel fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizer containing same compound. Publication Number 02076861 A (Japan), Mar. 31, 1988), 5-thiotretrazole derivative or its salt (E. Kano et al. Radiosensitizer for Hypoxic cell. Publication Number 61010511 A (Japan), Jun. 15 26, 1984), Nitrothiazole (T .Kagitani et al. Radiation-sensitizing agent. Publication Number 61167616 A (Japan) Jan. 22, 1985), imidazole derivatives (S. Inayma et al. Imidazole derivative. Publication Number 6203767 A (Japan) Aug. 1,1985; Publication Number 62030768 A (Japan) Aug. 1, 1985; Publication Number 62030777 A (Japan) Aug. 1, 1985), 4-nitro-1,2,3-triazole 20 (T. Kagitani et al. Radiosensitizer. Publication Number 62039525 A (Japan), Aug. 15, 1985), 3-nitro-1,2,4-triazole (T. Kagitani et al. Radiosensitizer. Publication Number 62138427 A (Japan), Dec. 12, 1985), Carcinostatic action regulator (H. Amagase. Carcinostatic action regulator. Publication Number 63099017 A (Japan), Nov. 21, 1986), 4,5-dinitroimidazole derivative (S. 25 Inayama. 4,5-Dinitroimidazole derivative. Publication Number 63310873 A (Japan) Jun. 9, 1987), nitrotriazole Compound (T. Kagitanil. Nitrotriazole Compound. Publication Number 07149737 A (Japan) Jun. 22, 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, flurouracil, bleomycin, vincristine, carboplatin, epirubicin, 30 doxorubicin, cyclophosphamide, vindesine, etoposide (I.F. Tannock. Review Article: Treatment of Cancer with Radiation and Drugs. Journal of Clinical 28 WO 2004/060346 PCT/US2003/041580 Oncology 14(12):3156-3174, 1996), camptothecin (Ewend M.G. etal. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Research 56(22):5217-5223, 1996) and paclitaxel (Tishler R.B. et al. Taxol: a novel radiation sensitizer. 5 International Journal of Radiation Oncology and Biological Physics 22(3):613 617, 1992). A number of the above-mentioned cell cycle inhibitors also have a wide variety of analogues and derivatives, including, but not limited to, cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitrosourea, mercaptopurine, 10 methotrexate, flurouracil, epirubicin, doxorubicin, vindesine and etoposide. Analogues and derivatives include (CPA) 2 Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Cis [PtCI 2 (4,7-H-5-methyl-7-oxo] 1,2,4[triazolo[1,5-a]pyrimidine) 2 ] (Navarro et aL., J. Med. Chem. 41(3):332-338, 1998), [Pt(cis-1,4-DACH)(trans 15 CI 2 )(CBDCA)] MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et aL., Pharm. Sci. 3(7):353-356, 1997), Pt(ll) ... Pt(ll) (Pt 2
[NHCHN(C(CH
2
)(CH
3 ))1 4 ) (Navarro et al., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res. 18(3):244-247, 20 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-[Pt(OAc) 2 1 2 (en)] (Kratochwil et al., J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1,2 diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem. 25 62(1):75, 1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et aL., J. Inorg. Biochem. 61(4):291-301, 1996), 5' orientational isomer of cis [Pt(NH 3 )(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. Chem. Soc. 117(43):10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1,2 30 diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol. 121(1):31-8, 1995), (ethylenediamine)platinum(ll) complexes 29 WO 2004/060346 PCT/US2003/041580 (Pasini et al., J. Chem. Soc., Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602, 1994), cis diamminedichloroplatinum(ll) and its analogues cis-1,1 cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediam-mineplatinum(lI) and 5 cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem. 26(4):257-67, 1986; Fan et aL., Cancer Res. 48(11):3135-9, 1988; Heiger Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawa et aL., J. Exp. Clin. Cancer Res. 12(4):233-40, 1993; Murray et al., Biochemistry 31(47):11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1):31-5, 1993), cis 10 amine-cyclohexylamine-dichloroplatinum(ll) (Yoshida et aL., Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et aL., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et aL., J. Am. 15 Chem. Soc. 114(21):8292-3, 1992), platinum(ll) polyamines (Siegmann etaL., Inorg. Met.-Containing Polym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335 61, 1990), cis-(3H)dichloro(ethylenediamine)platinum(lI) (Eastman, Anal. Biochem. 197(2):311-15, 1991), trans-diamminedichloroplatinum(ll) and cis (Pt(NH 3
)
2
(N
3 -cytosine)CI) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 20 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(ll) and 3H-cis-1,2 diaminocyclohexanemalonatoplatinum (II) (Oswald et aL, Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 25 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et aL., Eur. J. Cancer Clin. Oncol. 24(8):1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2):125-34, 1988), platinum(ll), 30 platinum(lV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1):35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(ll) (carboplatin, JM8) and 30 WO 2004/060346 PCT/US2003/041580 ethylenediammine-malonatoplatinum(ll) (JM40) (Begg et al., Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et aL., Int. J. Androl. 10(1); 139-45, 1987), (NPr4)2((PtCL4).cis-(PtCI2-(NH2Me)2)) (Brammer et aL., J. Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic 5 tricarboxylic acid platinum complexes (EPA 185225), cis-dichloro(amino acid)(tert-butylamine)platinum(ll) complexes (Pasini & Bersanetti, lnorg. Chim. Acta 107(4):259-67, 1985); 4-hydroperoxycylcophosphamide (Ballard et aL., Cancer Chemother. Pharmacol. 26(6):397-402,1990), acyclouridine cyclophosphamide derivatives (Zakerinia et aL, Helv. Chim. Acta 73(4):912-15, 10 1990), 1,3,2-dioxa- and -oxazaphosphorinane cyclophosphamide analogues (Yang et al., Tetrahedron 44(20):6305-14, 1988), C5-substituted cyclophosphamide analogues (Spada, University of Rhode Island Dissertation, 1987), tetrahydrooxazine cyclophosphamide analogues (Valente, University of Rochester Dissertation, 1988), phenyl ketone cyclophosphamide analogues 15 (Hales et al., Teratology 39(1):31-7, 1989), phenylketophosphamide cyclophosphamide analogues (Ludeman et aL., J. Med. Chem. 29(5):716-27, 1986), ASTA Z-7557 cyclophosphamide analogues (Evans et al., Int. J. Cancer 34(6):883-90, 1984), 3-(1-oxy-2,2,6,6-tetramethyl-4 piperidinyl)cyclophosphamide (Tsui et aL., J. Med. Chem. 25(9):1106-10, 1982), 20 2-oxobis(2-p3-chloroethylamino)-4-,6-dimethyl-1,3,2-oxazaphosphorinane cyclophosphamide (Carpenter et al., Phosphorus Sulfur 12(3):287-93, 1982), 5 fluoro- and 5-chlorocyclophosphamide (Foster et aL., J. Med. Chem. 24(12):1399-403, 1981), cis- and trans-4-phenylcyclophosphamide (Boyd et aL., J. Med. Chem. 23(4):372-5, 1980), 5-bromocyclophosphamide, 3,5 25 dehydrocyclophosphamide (Ludeman et al., J. Med. Chem. 22(2):151-8, 1979), 4-ethoxycarbonyl cyclophosphamide analogues (Foster, J. Pharm. Sci. 67(5):709-10, 1978), arylaminotetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide cyclophosphamide analogues (Hamacher, Arch. Pharm. (Weinheim, Ger.) 310(5):J,428-34, 1977), NSC-26271 cyclophosphamide analogues 30 (Montgomery & Struck, Cancer Treat. Rep. 60(4):J381-93, 1976), benzo annulated cyclophosphamide analogues (Ludeman & Zon, J. Med. Chem. 31 WO 2004/060346 PCT/US2003/041580 18(12):J1 251-3, 1975), 6-trifluoromethylcyclophosphamide (Farmer & Cox, J. Med. Chem. 18(1 1):J1106-10, 1975), 4-methylcyclophosphamide and 6 methycyclophosphamide analogues (Cox et al., Biochem. Pharmacol. 24(5):J599-606, 1975); FCE 23762 doxorubicin derivative (Quaglia et al, J. Liq. 5 Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et aL., J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl (Rapoport et aL., J. Controlled Release 58(2):153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et aL., Clin. Cancer Res. 4(11):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth. 10 Commun. 28(6):1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et aL., Proc. Nat'l Acad. Sci. U.S.A. 95(4):1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'l Cancer Inst. 89(16):1217-1223, 1997), 4 demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-a-L-lyxo hexopyranosyl)-a-L-lyxo-hexopyranosyl]adriamicinone doxorubicin disaccharide 15 analogue(Monteagudo et al., Carbohydr. Res. 300(1):11-16, 1997), 2 pyrrolinodoxorubicin (Nagy et aL., Proc. Nat'l Acad. Sci. U. S. A. 94(2):652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol. 38(3):210-216, 1996), enaminomalonyl-p-alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin 20 doxorubicin derivatives (Vrudhula etal., J. Med. Chem. 38(8):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J. Cancer 58(1 ):85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et al., Cancer Chemother. Pharmacol. 33(1):10-16, 1993), (6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5 25 diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 1118(1):83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero etal., Biochim. 30 Biophys. Acta 1129(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et aL., J. Med. 32 WO 2004/060346 PCT/US2003/041580 Chem. 34(8):2373-80. 1991), AD198 doxorubicin analogue (Traganos et al., Cancer Res. 51(14):3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et aL., Drug Des. Delivery 6(2):123-9, 1990), 4'-epidoxorubicin (Drzewoski et aL., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et 5 aL., Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et aL., J. Nat' Cancer Inst. 80(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et aL, Vestn. Mosk. Univ., 16(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et aL., Leuk. Res. 10(12):1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin 10 (Giuliani et aL., Proc. Int. Congr. Chemother. 16:285-70-285-77, 1983), 3' deamino-3'-hydroxydoxorubicin (Horton et aL., J. Antibiot. 37(8):853-8, 1984), 4 demethyoxy doxorubicin analogues (Barbieri et aL., Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et aL., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3' 15 deamino-3'-(4-methoxy-1 -piperidinyl) doxorubicin derivatives (4,314,054), 3' deamino-3'-(4-mortholinyl) doxorubicin derivatives (4,301,277), 4' deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et aL., Int. J. Cancer 27(1):5-13, 1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sci. 67(12):1748-52, 1978), SM 5887 (Pharma Japan 1468:20, 1995), MX-2 20 (Pharma Japan 1420:19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4 methoxy-1l-piperidinyl) doxorubicin derivatives (4,314,054), doxorubicin-14 valerate, morpholinodoxorubicin (5,004,606), 3'-deamino-3'-(3"-cyano-4" morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13 25 dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3' deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino 3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives (4,585,859), 3'-deamino 3'-(4-methoxy-1l-piperidinyl) doxorubicin derivatives (4,314,054) and 3-deamino 3-(4-morpholinyl) doxorubicin derivatives (4,301,277); 4,5-dimethylmisonidazole 30 (Born et aL., Biochem. Pharmacol. 43(6):1337-44, 1992), azo and azoxy misonidazole derivatives (Gattavecchia & Tonelli, Int. J. Radiat. BioL Relat. 33 WO 2004/060346 PCT/US2003/041580 Stud. Phys., Chem. Med. 45(5):469-77, 1984); RB90740 (Wardman et al., Br. J. Cancer, 74 Suppl. (27):S70-S74, 1996); 6-bromo and 6-chloro-2,3-dihydro-1,4 benzothiazines nitrosourea derivatives (Rai et aL., Heterocycl. Commun. 2(6):587-592, 1996), diamino acid nitrosourea derivatives (Dulude et al., Bioorg. 5 Med. Chem. Lett. 4(22):2697-700, 1994; Dulude et aL, Bioorg. Med. Chem. 3(2):151-60, 1995), amino acid nitrosourea derivatives (Zheleva et aL., Pharmazie 50(1 ):25-6, 1995), 3',4'-didemethoxy-3',4'-dioxo-4 deoxypodophyllotoxin nitrosourea derivatives (Miyahara et al., Heterocycles 39(1 ):361-9, 1994), ACNU (Matsunaga et al., Immunopharmacology 23(3):199 10 204, 1992), tertiary phosphine oxide nitrosourea derivatives (Guguva et al., Pharmazie 46(8):603, 1991), sulfamerizine and sulfamethizole nitrosourea derivatives (Chiang et aL., Zhonghua Yaozue Zazhi 43(5):401-6, 1991), thymidine nitrosourea analogues (Zhang et al., Cancer Commun. 3(4):119-26, 1991), 1,3-bis(2-chloroethyl)-1l-nitrosourea (August et aL., Cancer Res. 15 51(6):1586-90, 1991), 2,2,6,6-tetramethyl-1l-oxopiperidiunium nitrosourea derivatives (U.S.S.R. 1261253), 2- and 4-deoxy sugar nitrosourea derivatives (4,902,791), nitroxyl nitrosourea derivatives (U.S.S.R. 1336489), fotemustine (Boutin et aL., Eur. J. Cancer Clin. Oncol. 25(9):1311-16, 1989), pyrimidine (11) nitrosourea derivatives (Wei et al., Chung-hua Yao Hsueh Tsa Chih 41(1 ):19 20 26, 1989), CGP 6809 (Schieweck et al., Cancer Chemother. Pharmacol. 23(6):341-7, 1989), B-3839 (Prajda et aL., In Vivo 2(2):151-4, 1988), 5 halogenocytosine nitrosourea derivatives (Chiang & Tseng, T'ai-wan Yao Hsueh Tsa Chih 38(1):37-43, 1986), 1-(2-chloroethyl)-3-isobutyl-3-(P-maltosyl) 1-nitrosourea (Fujimoto & Ogawa, J. Pharmacobio-Dyn. 10(7):341-5, 1987), 25 sulfur-containing nitrosoureas (Tang et aL, Yaoxue Xuebao 21(7):502-9, 1986), sucrose, 6-((((2-chloroethyl)nitrosoamino-)carbonyl)amino)-6-deoxysucrose (NS-1C) and 6'-((((2-chloroethyl)nitrosoamino)carbonyl)amino)-6'-deoxysucrose (NS-1 D) nitrosourea derivatives (Tanoh et al., Chemotherapy (Tokyo) 33(11):969-77, 1985), CNCC, RFCNU and chlorozotocin (Mena et aL., 30 Chemotherapy (Basel) 32(2):131-7, 1986), CNUA (Edanami et al., Chemotherapy (Tokyo) 33(5):455-61, 1985), 1-(2-chloroethyl)-3-isobutyl-3-(p 34 WO 2004/060346 PCT/US2003/041580 maltosyl)-1l-nitrosourea (Fujimoto & Ogawa, Jpn. J. Cancer Res. (Gann) 76(7):651-6, 1985), choline-like nitrosoalkylureas (Belyaev et aL., Izv. Akad. NAUK SSSR, Ser. Khim. 3:553-7, 1985), sucrose nitrosourea derivatives (JP 84219300), sulfa drug nitrosourea analogues (Chiang et al., Proc. Nat'l Sci. 5 Counc., Repub. China, Part A 8(1):18-22, 1984), DONU (Asanuma et aL., J. Jpn. Soc. Cancer Ther. 17(8):2035-43, 1982), N,N'-bis (N-(2-chloroethyl)-N nitrosocarbamoyl)cystamine (CNCC) (Blazsek et al., Toxicol. Appl. Pharmacol. 74(2):250-7, 1984), dimethylnitrosourea (Krutova et al., Izv. Akad. NAUK SSSR, Ser. BioL. 3:439-45,1984), GANU (Sava & Giraldi, Cancer Chemother. 10 Pharmacol. 10(3):167-9, 1983), CCNU (Capelli et aL, Med., Bio/., Environ. 11(1):111-16, 1983), 5-aminomethyl-2'-deoxyuridine nitrosourea analogues (Shiau, Shih Ta Hsueh Pao (Taipei) 27:681-9, 1982), TA-077 (Fujimoto & Ogawa, Cancer Chemother. Pharmacol. 9(3):134-9, 1982), gentianose nitrosourea derivatives (JP 82 80396), CNCC, RFCNU, RPCNU AND 15 chlorozotocin (CZT) (Marzin et al., INSERM Symp., 19(Nitrosoureas Cancer Treat.):165-74, 1981), thiocolchicine nitrosourea analogues (George, Shih Ta Hsueh Pao (Taipei) 25:355-62, 1980), 2-chloroethyl-nitrosourea (Zeller & Eisenbrand, Oncology 38(1 ):39-42, 1981), ACNU, (1-(4-amino-2-methyl-5 pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride) (Shibuya et 20 aL., Gan To Kagaku Ryoho 7(8):1393-401, 1980), N-deacetylmethyl thiocolchicine nitrosourea analogues (Lin et aL, J. Med. Chem. 23(12):1440-2, 1980), pyridine and piperidine nitrosourea derivatives (Crider et aL., J. Med. Chem. 23(8):848-51, 1980), methyl-CCNU (Zimber & Perk, Refu. Vet. 35(1):28, 1978), phensuzimide nitrosourea derivatives (Crider et al., J. Med. Chem. 25 23(3):324-6, 1980), ergoline nitrosourea derivatives (Crider et aL., J. Med. Chem. 22(1):32-5, 1979), glucopyranose nitrosourea derivatives (JP 78 95917), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (Farmer et aL., J. Med. Chem. 21(6):514-20, 1978), 4-(3-(2-chloroethyl)-3-nitrosoureid-o)-cis cyclohexanecarboxylic acid (Drewinko et aL., Cancer Treat. Rep. 61(8):J1513 30 18,1977), RPCNU (ICIG 1163) (Larnicol et aL., Biomedicine 26(3):J176-81, 1977), IOB-252 (Sorodoc et al., Rev. Roum. Med. Virol. 28(1):J55-61, 1977), 35 WO 2004/060346 PCT/US2003/041580 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (Siebert & Eisenbrand, Mutat. Res. 42(1):J45-50, 1977), 1-tetrahydroxycyclopentyl-3-nitroso-3-(2-chloroethyl)-urea (4,039,578), d-1-1-(P-chloroethyl)-3-(2-oxo-3-hexahydroazepinyl)-1-nitrosourea (3,859,277) and gentianose nitrosourea derivatives (JP 57080396); 6-S 5 aminoacyloxymethyl mercaptopurine derivatives (Harada et aL., Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 18(11):1492-7, 1995), 7,8-polymethyleneimidazo-1,3,2 diazaphosphorines (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg. Biochem. 56(4):249-64, 1994), methyl-D 10 glucopyranoside mercaptopurine derivatives (Da Silva et aL., Eur. J. Med. Chem. 29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et aL., Khim.-Farm. Zh. 15(8):65-7, 1981); indoline ring and a modified ornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 45(7):1146-1150, 1997), alkyl-substituted benzene ring C bearing 15 methotrexate derivatives (Matsuoka et aL., Chem. Pharm. Bull. 44(12):2287 2293, 1996), benzoxazine or benzothiazine moiety-bearing methotrexate derivatives (Matsuoka et al., J. Med. Chem. 40(1):105-111, 1997), 10 deazaaminopterin analogues (DeGraw et aL., J. Med. Chem. 40(3):370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate 20 analogues (Piper et al., J. Med. Chem. 40(3):377-384, 1997), indoline moiety bearing methotrexate derivatives (Matsuoka et aL., Chem. Pharm. Bull. 44(7):1332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et aL, World Meet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), L-threo (2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid-containing 25 methotrexate analogues (Hart et al., J. Med. Chem. 39(1):56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et aL., J. Heterocycl. Chem. 32(1):243-8, 1995), N-(a-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou, threo-4 30 fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem. Pharmacol. 42(12):2400-3, 1991), 1,y-methano methotrexate analogues 36 WO 2004/060346 PCT/US2003/041580 (Rosowsky et al., Pteridines 2(3):133-9, 1991), 10-deazaaminopterin (10 EDAM) analogue (Braakhuis et aL., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027-30, 1989), y-tetrazole methotrexate analogue (Kalman et aL., Chem. BioL. Pteridines, Proc. Int. Symp. Pteridines Folic Acid 5 Deriv., 1154-7, 1989), N-(L-a-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et aL., J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), y-fluoromethotrexate (McGuire et aL., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives 10 (Kumar et al., Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), a- and y-substituted methotrexate analogues (Tsushima et aL., Tetrahedron 44(17):5375-87, 1988), 5-methyl-5 deaza methotrexate analogues (4,725,687), N8-acyl-Nca-(4-amino-4 deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. Med. Chem. 15 31(7):1332-7, 1988), 8-deaza methotrexate analogues (Kuehl et al., Cancer Res. 48(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky et al., J. Med. Chem. 30(8):1463-9, 1987), polymeric platinol methotrexate derivative (Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv. Biomed. Polym.):311 24, 1987), methotrexate-y-dimyristoylphophatidylethanolamine (Kinsky et aL., 20 Biochim. Biophys. Acta 917(2):211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et aL., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-y-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid 25 Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webber et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp et aL., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. 30 Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-containing methotrexate analogues (McGuire 37 WO 2004/060346 PCT/US2003/041580 et al., Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol. 122(Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper et al., J. Med. Chem. 29(6):1080-7, 1986), quinazoline methotrexate analogue 5 (Mastropaolo et al., J. Med. Chem. 29(1):155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), y-tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1):45-9, 10 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim. Ther. 19(3):267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate derivates (Forsch & Rosowsky, J. Org. Chem. 15 49(7):1305-9, 1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res. 43(10):4648-52, 1983), poly-y-glutamyl methotrexate analogues (Piper & Montgomery, Adv. Exp. Med. Biol., 163(Folyl Antifolyl Polyglutamates):95-100, 1983), 3',5'-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10):1448 52, 1983), diazoketone and chloromethylketone methotrexate analogues 20 (Gangjee et al., J. Pharm. Sci. 71(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate homologs (Piper et aL., J. Med. Chem. 25(7):877-80, 1982), lectin derivatives of methotrexate (Lin et aL., JNCI 66(3):523-8, 1981), polyglutamate methotrexate derivatives (Galivan, MoL. Pharmacol. 17(1 ):105 10, 1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):J955-8, 25 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem. 20(10):J1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 17(12):J1308-11, 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190-3, 1973), deaza amethopterin 30 analogues (Montgomery et aL., Ann. N.Y. Acad. Sci. 186:J227-34, 1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid 38 WO 2004/060346 PCT/US2003/041580 methotrexate analogues (EPA 0142220); N3-alkylated analogues of 5 fluorouracil (Kozai et aL, J. Chem. Soc., Perkin Trans. 1(19):3145-3146, 1998), 5-fluorouracil derivatives with 1,4-oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside 5 analogues (Li, Anticancer Res. 17(1A):21-27, 1997), cis- and trans-5-fluoro-5,6 dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem. 70(4):1162-9, 1992), A-OT-fluorouracil (Zhang et aL., Zongguo Yiyao Gongye Zazhi 20(11):513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine 10 and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun. 3(9):478-81, 1980; Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), uracil-1 -(2-tetrahydrofuryl)-5 fluorouracil (Anal et al., Oncology 45(3):144-7, 1988), 1-(2'-deoxy-2'-fluoro-P3-D 15 arabinofuranosyl)-5-fluorouracil (Suzuko et al., Mol. Pharmacol. 31(3):301-6, 1987), doxifluridine (Matuura et al., Oyo Yakuri 29(5):803-31, 1985), 5'-deoxy-5 fluorouridine (Bollag & Hartmann, Eur. J. Cancer 16(4):427-32, 1980), 1-acetyl 3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28(1 ):49-66, 1979), 5 fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)-5 20 fluorouracil (JP 53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680); 4'-epidoxorubicin (Lanius, Adv. Chemother. Gastrointest. Cancer, (Int. Symp.), 159-67, 1984); N-substituted deacetylvinblastine amide (vindesine) sulfates (Conrad et al., J. Med. Chem. 22(4):391-400, 1979); and Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7):1003-1008, 1998), 25 pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 413-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), y-lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahedron Lett. 30 34(45):7313-16, 1993), etoposide A-ring analogues (Kadow et al., Bioorg. Med. Chem. Lett. 2(1):17-22, 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et 39 WO 2004/060346 PCT/US2003/041580 al., Bioorg. Med. Chem. Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al., J. Med. Chem. 32(7):1418-20, 1989). Within one preferred embodiment of the invention, the cell cycle 5 inhibitor is paclitaxel, a compound which disrupts mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof. Briefly, paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325, 1971) which has been obtained from the harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae and 10 Endophytic Fungus of the Pacific Yew (Stierle et al., Science 60:214-216, 1993). "Paclitaxel" (which should be understood herein to include formulations, prodrugs, analogues and derivatives such as, for example, TAXOL® (Bristol Myers Squibb Company, New York, NY), TAXOTERE® (Aventis Pharmaceuticals, France), docetaxel, 10-desacetyl analogues of paclitaxel and 15 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see, e.g., Schiff et al., Nature 277:665-667, 1979; Long and Fairchild, Cancer Research 54:4355-4361, 1994; Ringel and Horwitz, J. Nat'I Cancer Inst. 83(4):288-291, 1991; Pazdur et al., Cancer Treat. Rev. 19(4):351-386, 1993; WO 94/07882; 20 WO 94/07881; WO 94/07880; WO 94/07876; WO 93/23555; WO 93/10076; WO 94/00156; WO 93/24476; EP 590267; WO 94/20089; U.S. Patent Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850; 5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 25 5,440,056; 4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184; Tetrahedron Letters 35(52):9709-9712, 1994; J. Med. Chem. 35:4230-4237, 1992; J. Med. Chem. 34:992-998, 1991; J. Natural Prod. 57(10):1404-1410, 1994; J. Natural Prod. 57(11):1580-1583, 1994; J. Am. Chem. Soc. 110:6558 6560, 1988), or obtained from a variety of commercial sources, including for 30 example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia). 40 WO 2004/060346 PCT/US2003/041580 Representative examples of paclitaxel derivatives or analogues include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol, 10 deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy and carbonate 5 derivatives of taxol, taxol 2',7-di(sodium 1,2-benzenedicarboxylate, 10 desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives, 10 desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives ), (2'-and/or 7-0 carbonate derivatives), asymmetric synthesis of taxol side chain, fluoro taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine II, 9-deoxotaxol, 7-deoxy-9 10 deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol, Derivatives containing hydrogen or acetyl group and a hydroxy and tert-butoxycarbonylamino, sulfonated 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol derivatives, succinyltaxol, 2'-y-aminobutyryltaxol formate, 2'-acetyl taxol, 7-acetyl taxol, 7 glycine carbamate taxol, 2'-OH-7-PEG(5000) carbamate taxol, 2'-benzoyl and 15 2',7-dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol; 2',7 diacetyltaxol; 2'succinyltaxol; 2'-(beta-alanyl)-taxol); 2'gamma aminobutyryltaxol formate; ethylene glycol derivatives of 2'-succinyltaxol; 2' glutaryltaxol; 2'-(N,N-dimethylglycyl) taxol; 2'-(2-(N,N dimethylamino)propionyl)taxol; 2'orthocarboxybenzoyl taxol; 2'aliphatic 20 carboxylic acid derivatives of taxol, Prodrugs {2'(N,N diethylaminopropionyl)taxol, 2'(N,N-dimethylglycyl)taxol, 7(N,N dimethylglycyl)taxol, 2',7-di-(N,N-dimethylglycyl)taxol, 7(N,N diethylaminopropionyl)taxol, 2',7-di(N,N-diethylaminopropionyl)taxol, 2'-(L glycyl)taxol, 7-(L-glycyl)taxol, 2',7-di(L-glycyl)taxol, 2'-(L-alanyl)taxol, 7-(L 25 alanyl)taxol, 2',7-di(L-alanyl)taxol, 2'-(L-leucyl)taxol, 7-(L-leucyl)taxol, 2',7-di(L leucyl)taxol, 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol, 2',7-di(L-isoleucyl)taxol, 2'-(L-valyl)taxol, 7-(L-valyl)taxol, 2'7-di(L-valyl)taxol, 2'-(L-phenylalanyl)taxol, 7 (L-phenylalanyl)taxol, 2',7-di(L-phenylalanyl)taxol, 2'-(L-prolyl)taxol, 7-(L prolyl)taxol, 2',7-di(L-prolyl)taxol, 2'-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2',7-di(L 30 lysyl)taxol, 2'-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2',7-di(L-glutamyl)taxol, 2' (L-arginyl)taxol, 7-(L-arginyl)taxol, 2',7-di(L-arginyl)taxol}, Taxol analogues with 41 WO 2004/060346 PCT/US2003/041580 modified phenylisoserine side chains, taxotere, (N-debenzoy-N-tert (butoxycaronyl)-10-deacetyltaxol, and taxanes (e.g., baccatin Ill, cephalomannine, 10-deacetylbaccatin III, brevifoliol, yunantaxusin and taxusin); and other taxane analogues and derivatives, including 14-beta-hydroxy-10 5 deacetybaccatin III, debenzoyl-2-acyl paclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxy and carbonate paclitaxel derivatives, sulfonated 2' acryloyltaxol; sulfonated 2'-O-acyl acid paclitaxel derivatives, 18-site-substituted paclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxy ether paclitaxel derivatives, sulfenamide taxane derivatives, brominated paclitaxel 10 analogues, Girard taxane derivatives, nitrophenyl paclitaxel, 10-deacetylated substituted paclitaxel derivatives, 14- beta -hydroxy-10 deacetylbaccatin III taxane derivatives, C7 taxane derivatives, C10 taxane derivatives, 2-debenzoyl 2-acyl taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel derivatives, taxane and baccatin III analogues bearing new C2 and C4 functional groups, n-acyl 15 paclitaxel analogues, 10-deacetylbaccatin III and 7-protected-10 deacetylbaccatin Ill derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl-4-acyl paclitaxel analogues, orthro-ester paclitaxel analogues, 2-aroyl-4-acyl paclitaxel analogues and 1-deoxy paclitaxel and 20 1-deoxy paclitaxel analogues. In one aspect, the Cell Cycle Inhibitor is a taxane having the formula (Cl): HCC H3 OH HC CH, HC A o 0H o oH where the gray-highlighted portions may be substituted and the non-highlighted 25 portion is the taxane core. A side-chain (labeled "A" in the diagram ) is 42 WO 2004/060346 PCT/US2003/041580 desirably present in order for the compound to have good activity as a Cell Cycle Inhibitor. Examples of compounds having this structure include paclitaxel (Merck Index entry 7117), docetaxol (TAXOTERE, Merck Index entry 3458), and 3'-desphenyl-3'-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)- 0 5 deacetyltaxol. In one aspect, suitable taxanes such as paclitaxel and its analogues and derivatives are disclosed in U.S. Patent No. 5,440,056 as having the structure (C2): R2 X R3 CH3 H3 CH3 H3C"' RIO - O R50 R40 (02) 10 wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors; R 1 is selected from paclitaxel or taxotere side chains or alkanoyl of the formula (03) O
R
7 KNH O R8 OR9
OR
9 (C3) wherein R 7 is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy 15 (substituted or unsubstituted); R 8 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta naphthyl; and R 9 is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, 20 nitro, and -OSO 3 H, and/or may refer to groups containing such substitutions; R 2 is selected from hydrogen or oxygen-containing groups, such as hydroxyl, 43 WO 2004/060346 PCT/US2003/041580 alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; R 3 is selected from hydrogen or oxygen-containing groups, such as hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy, and may further be a silyl containing group or a sulphur containing group; R 4 is selected from acyl, 5 alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R 5 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R 6 is selected from hydrogen or oxygen-containing groups, such as hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy. In one aspect, the paclitaxel analogues and derivatives useful as 10 Cell Cycle Inhibitors in the present invention are disclosed in PCT International Patent Application No. WO 93/10076. As disclosed in this publication, the analogue or derivative should have a side chain attached to the taxane nucleus at C 13 , as shown in the structure below (formula C4), in order to confer antitumor activity to the taxane. 10 7 13 5 1 4 2 15 (C4) WO 93/10076 discloses that the taxane nucleus may be substituted at any position with the exception of the existing methyl groups. The substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached to carbons 20 labeled 2, 4, 9, 10. As well, an oxetane ring may be attached at carbons 4 and 5. As well, an oxirane ring may be attached to the carbon labeled 4. In one aspect, the taxane-based Cell Cycle Inhibitor useful in the present invention is disclosed in U.S. Patent No. 5,440,056, which discloses 9 deoxo taxanes. These are compounds lacking an oxo group at the carbon 25 labeled 9 in the taxane structure shown above (formula C4). The taxane ring 44 WO 2004/060346 PCT/US2003/041580 may be substituted at the carbons labeled 1, 7 and 10 (independently) with H, OH, O-R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, it may be substituted at carbons labeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups. The side chain of formula (C3) may be 5 substituted at R 7 and R 8 (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N. R 9 may be substituted with H, or a substituted or unsubstituted alkanoyl group. Taxanes in general, and paclitaxel is particular, is considered to function as a Cell Cycle Inhibitor by acting as an anti-microtuble agent, and 10 more specifically as a stabilizer. These compounds have been shown useful in the treatment of proliferative disorders, including: non-small cell (NSC) lung; small cell lung; breast; prostate; cervical; endometrial; head and neck cancers. In another aspect, the Cell Cycle Inhibitor is a Vinca Alkaloid. Vinca alkaloids have the following general structure. They are indole 15 dihydroindole dimers. R,
R
4 -N R4-N ' 6 indole I R7 N H / 00 H3C - I p. dihydroindole HoH HC-0 N H O-R 3 I OH
O-R
2 As disclosed in U.S. Patent Nos. 4,841,045 and 5,030,620, Ri can be a formyl or methyl group or alternately H. R, could also be an alkyl group or an aldehyde-substituted alkyl (e.g., CH 2 CHO). R 2 is typically a CH 3 or NH 2 20 group. However it can be alternately substituted with a lower alkyl ester or the ester linking to the dihydroindole core may be substituted with C(O)-R where R is NH 2 , an amino acid ester or a peptide ester. R 3 is typically C(O)CHa, CH 3 or H. Alternately, a protein fragment may be linked by a bifunctional group such 45 WO 2004/060346 PCT/US2003/041580 as maleoyl amino acid. R 3 could also be substituted to form an alkyl ester which may be further substituted. R 4 may be -CH 2 - or a single bond. R 5 and
R
6 may be H, OH or a lower alkyl, typically -CH 2
CH
3 . Alternatively R 6 and R 7 may together form an oxetane ring. R 7 may alternately be H. Further 5 substitutions include molecules wherein methyl groups are substituted with other alkyl groups, and whereby unsaturated rings may be derivatized by the addition of a side group such as an alkane, alkene, alkyne, halogen, ester, amide or amino group. Exemplary Vinca Alkaloids are vinblastine, vincristine, vincristine 10 sulfate, vindesine, and vinorelbine, having the structures: Rs R4 N CH3
H
3 C-O N H O-R3 O . OH O0- 2 R, R 2
R
3
R
4
R
5 Vinblastine: CH 3
CH
3
C(O)CH
3 OH CH 2 Vincristine: CH 2 0 CH 3
C(O)CH
3 OH CH 2 Vindesine: CH 3
NH
2 H OH CH 2 Vinorelbine: CH 3
CH
3
CH
3 H single bond Analogues typically require the side group (shaded area) in order to have activity. These compounds are thought to act as Cell Cycle Inhibitors by functioning as anti-microtubole agents, and more specifically to inhibit 15 polymerization. These compounds have been shown useful in treating proliferative disorders, including NSC lung; small cell lung; breast; prostate; brain; head and neck; retinoblastoma; bladder; and penile cancers; and soft tissue sarcoma. 46 WO 2004/060346 PCT/US2003/041580 In another aspect, the Cell Cycle Inhibitor is Camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.
R
2 R3 O R, N X R4 N O H3C-" OH 5 In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. R 1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C 1
-
3 alkane. R 2 is typically H or an amino containing group such as (CH 3
)
2
NHCH
2 , but may be other groups e.g.,
NO
2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent No. 5,552,156) or a short 10 alkane containing these groups. R 3 is typically H or a short alkyl such as C 2
H
5 .
R
4 is typically H but may be other groups, e.g., a methylenedioxy group with R 1 . Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11 -methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10 15 hydroxycamptothecin. Exemplary compounds have the structures:
R
2 R, 0 R, N X E N O
H
3 C OH R, R 2
R
3 Camptothecin: H H H Topotecan: OH (CH 3
)
2
NHCH
2 H SN-38: OH H C 2
H
5 X: O for most analogs, NH for 21-lactam analogs Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity. These compounds are useful to as Cell Cycle Inhibitors, 47 WO 2004/060346 PCT/US2003/041580 where they function as Topoisomerase I Inhibitors and/or DNA cleavage agents. They have been shown useful in the treatment of proliferative disorders, including, for example, NSC lung; small cell lung; and cervical cancers. 5 In another aspect, the Cell Cycle Inhibitor is a Podophyllotoxin, or a derivative or an analoguethereof. Exemplary compounds of this type are Etoposide or Teniposide, which have the following structures: 0 HO 0o ... R o Etoposide CH 3 Teniposide s / c0 O H C H , These compounds are thought to function as Cell Cycle Inhibitors 10 by being Topoisomerase 11 Inhibitors and/or by DNA cleaving agents. They have been shown useful as antiproliferative agents in, e.g., small cell lung, prostate, and brain cancers, and in retinoblastoma. In another aspect, the Cell Cycle Inhibitor is an Anthracycline. Anthracyclines have the following general structure, where the R groups may 15 be a variety of organic groups: 0 R, R, OH R, R O R 3
O-R
2 According to U.S. Patent No. 5,594,158, suitable R groups are:
R
1 is CH 3 or CH 2 OH; R 2 is daunosamine or H; R 3 and R 4 are independently one of OH, NO 2 , NH 2 , F, CI, Br, I, CN, H or groups derived from these; R5-7 are all H 48 WO 2004/060346 PCT/US2003/041580 or R 5 and R 6 are H and R 7 and R 8 are alkyl or halogen, or vice versa: R 7 and
R
8 are H and R 5 and R 6 are alkyl or halogen. According to U.S. Patent No. 5,843,903, R 2 may be a conjugated peptide. According to U.S. Patent Nos. 4,215,062 and 4,296,105, R 5 may be 5 OH or an ether linked alkyl group. R 1 may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2
CH(CH
2
-X)C(O)-R
1 , wherein X is H or an alkyl group (see, e.g., U.S. Patent No. 4,215,062). R 2 may alternately be a group linked by the functional group =N-NHC(O)-Y, where Y is 10 a group such as a phenyl or substituted phenyl ring. Alternately R 3 may have the following structure:
H
3 C NH R, I K10 in which R 9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R 3 . R 10 may be H or form a secondary amine with a group such 15 as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent No. 5,843,903). Alternately, R 10 io may be derived from an amino acid, having the structure C(O)CH(NHRy 1
)(R
1 2 ), in which RII is H, or forms a C3-4 membered alkylene with
R
12 . R 12 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl 20 or methylthio (see U.S. Patent No. 4,296,105). Exemplary Anthracyclines are Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Pirarubicin, Zorubicin, and Carubicin. Suitable compounds can have the structures: 49 WO 2004/060346 PCT/US2003/041580 Doxorubicin: OCH CH20H OH out ofng plane 00 Epirubicin: OCH= CH20H OH in ring plane (4' epimeral[dorambicin) Daunarubicina OCH CHe OH out of ring plane ,,OH Piaubcn , 0 OH A Zorubicin OH =N-NHC()CH B DCarublcin OCH CHO OH o ring plane EpbMenogaril, Nogalamycin, Aclacinomycin A,CHH O livomycin A, Chromomycin A3, andplane (4. nlgrn.r d-arblein dPlicamycin having the structures:bl H CH OH o ofrn plane PiblnH3 OHC OH A Zororbicin OCH, =N.NMC(O)CeH, B Ce...obln OHO CH0 B
KC>--,-
Menogaril, Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin A 3 , and Plicamycin having the structures:
CM
0 OH O: H O H O H NHt OHHc-CNO~ H3 N Anhramycin 0 "" 0 HOo"' CI-3 N NHH 0H 0 R2 H OH OH R R, RR R Menogaril H OCH 3 HI OH C m cNogalamyc ln0-sugar COC 5 0 CO N OCH3 oH NHHH ". .a 0 OH 3 C1 Mitoxantrone 0 CH ORz CH3 3
R
H CH3
OCH
3 OH 0-OH,
C
0 O H O H 0 O f 0 OH OH Aacinomycin A H(CHw MaC H C 0 O3 R,O C HO R, R, Rn R 4 0 Olivomycin A COCH(CH,), CHn COCH 0 H H 0 0 o Chromomycin A. COCH 3
CH
3
COCH
3
CH
3 5 Plicamycin H H H CH, 50 WO 2004/060346 PCT/US2003/041580 These compounds are thought to function as Cell Cycle Inhibitors by being Topoisomerase Inhibitors and/or by DNA cleaving agents. They have been shown useful in the treatment of proliferative disorders, including small cell lung; breast; endometrial; head and neck; retinoblastoma; liver; bile duct; 5 islet cell; and bladder cancers; and soft tissue sarcoma. In another aspect, the Cell Cycle Inhibitor is a Platinum compound. In general, suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic structure: ZI R X R2 Z2 10 wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R 1 and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(ll) complexes Z 1 and Z 2 are non-existent. For Pt(IV) Z 1 and Z 2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. 15 See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189. Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type: 51 WO 2004/060346 PCT/US2003/041580 Z, Z, X "_R, X IR 2 Pt Pt Yf AY
Z
2
Z
2 Z, Z, Z1 X I J R 1 X I A IX Pt Pt Pt , YA Y R 2
Z
2
Z
2
Z
2 Z, Z, X ,R2 R2 I _X Pt Pt
Z
2
Z
2 z2Pt* R3 Y-I >-ZI x Exemplary Platinum compound are Cisplatin, Carboplatin, Oxaliplatin, and Miboplatin having the structures:
NH
3
NH
3 O O Pt CI-Pt-NH 3
I
N H3 1i 0 CI 0 Cisplatin Carboplatin 0 0 O /NH 2 o JqH 2 Pt PtH 0 NH 0 HN O 0 Oxaliplatin Miboplatin 5 These compounds are thought to function as Cell Cycle Inhibitors by binding to DNA, i.e., acting as alkylating agents of DNA. These compounds have been shown useful in the treatment of cell proliferative disorders, including, e.g., NSC lung; small cell lung; breast; cervical; brain; head and neck; 52 WO 2004/060346 PCT/US2003/041580 esophageal; retinoblastom; liver; bile duct; bladder; penile; and vulvar cancers; and soft tissue sarcoma. In another aspect, the Cell Cycle Inhibitor is a Nitrosourea. Nitrosourease have the following general structure (CS), where typical R groups 5 are shown below. o R R R N NHR N O (CS) R Group:
H
2 C CI0 OH Carmustine OH O-CH 3 OH Ranimustine Lomustine OH OH O
OH
3 NH 2 OH H 3 C N NH /O cH 3 OHOH N O
OH
3 OH 0 0 N CH 3 OH Fotemustine Nimustine Chlorozotocin Streptozocin Other suitable R groups include cyclic alkanes, alkanes, halogen substituted groups, sugars, aryl and heteroaryl groups, phosphonyl and sulfonyl 10 groups. As disclosed in U.S. Patent No. 4,367,239, R may suitably be CH 2 C(X)(Y)(Z), wherein X and Y may be the same or different members of the following groups: phenyl, cyclyhexyl, or a phenyl or cyclohexyl group substituted with groups such as halogen, lower alkyl (C 1 -4), trifluore methyl, cyano, phenyl, cyclohexyl, lower alkyloxy (C1- 4 ). Z has the following structure: 15 -alkylene-N-R 1
R
2 , where R 1 and R 2 may be the same or different members of the following group: lower alkyl (C1- 4 ) and benzyl, or together R 1 and R 2 may form a saturated 5 or 6 membered heterocyclic such as pyrrolidine, piperidine, morfoline, thiomorfoline, N-lower alkyl piperazine, where the heterocyclic may be optionally substituted with lower alkyl groups. 53 WO 2004/060346 PCT/US2003/041580 As disclosed in U.S. Patent No. 6,096,923, R and R' of formula (C5) may be the same or different, where each may be a substituted or unsubstituted hydrocarbon having 1-10 carbons. Substitutions may include hydrocarbyl, halo, ester, amide, carboxylic acid, ether, thioether and alcohol 5 groups. As disclosed in U.S. Patent No. 4,472,379, R of formula (C5) may be an amide bond and a pyranose structure (e.g., Methyl 2'-[N-[N-(2-chloroethyl) N-nitroso-carbamoyl]-glycyl]amino-2'-deoxy-a-D-glucopyranoside). As disclosed in U.S. Patent No. 4,150,146, R of formula (C5) may be an alkyl group of 2 to 6 carbons and may be substituted with an ester, sulfonyl, or 10 hydroxyl group. It may also be substituted with a carboxylica acid or CONH 2 group. Exemplary Nitrosoureas are BCNU (Carmustine), Methyl-CCNU (Semustine), CCNU (Lomustine), Ranimustine, Nimustine, Chlorozotocin, Fotemustine, Streptozocin, and Streptozocin, having the structures: 0 NH R Group: 0 N o -CI Carmustine
H
2 . OH OH 0 OH OH 0OH 3 OH OH Ranimustine Lomustine 0 HCOH N NH Nimustine Chlorozotocin CH, /O CH 3 O Fotemustine 15 These nitrosourea compounds are thought to function as Cell Cycle Inhibitor by binding to DNA, that is, by functioning as DNA alkylating agents. These Cell Cycle Inhibitors have been shown useful in treating cell 54 WO 2004/060346 PCT/US2003/041580 proliferative disorders such as, for example, islet cell; small cell lung; melanoma; and brain cancers. In another aspect, the Cell Cycle Inhibitor is a Nitroimidazole, where exemplary Nitroimidazoles are Metronidazole, Benznidazole, 5 Etanidazole, and Misonidazole, having the structures: R, R3 R 3 Ri
R
2 R3 Metronidazole OH CH 3
NO
2 Benznidazole C(O)NHCH 2 -benzyl NO 2 H Etanidazole CONHCH2CH2OH NO 2 H Suitable nitroimidazole compounds are disclosed in, e.g., U.S. Patent Nos. 4,371,540 and 4,462,992. In another aspect, the Cell Cycle Inhibitor is a Folic acid 10 antagonist, such as Methotrexate or derivatives or analogues thereof, including Edatrexate, Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex, and Pteropterin. Methotrexate analogues have the following general structure:
R
1 1 R N R, R4
R
6 R2
R
3
R
3 ' R 10 Ry R The identity of the R group may be selected from organic groups, particularly 15 those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582. For example, R 1 may be N, R 2 may be N or C(CH 3 ), R 3 and R 3 ' may H or alkyl, e.g.,
CH
3 , R 4 may be a single bond or NR, where R is H or alkyl group. R 5
,
6
,
8 may be H, OCH 3 , or alternately they can be halogens or hydro groups. R 7 is a side chain of the general structure: 55 WO 2004/060346 PCT/US2003/041580 0 NH /o HO 0 0 OH wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2 + salt. R 9 and R 10 can be NH 2 or may be alkyl substituted. 5 Exemplary folic acid antagonist compounds have the structures:
R
6 R R4 R NH2 R3 R, R7 R, R R, R 2 R, R 4 Rs R, R, Rs Methatratle NH 2 N N H N(C~H,) H H A (n=1) H Edatrexae NH, N N H N(CH2CH,) H H A(n=l) H Trimetrexate NH 2 N C(CHa) H NH H OCH a
OCH
a OCH, Plaroplerin NH, N N H N(CH,) H H A (n=3) H Denopterin OH N N cH, N(cH,) H H A (n=1) H Pirltrexlm NH, N C(CH,) H single OCH, H H OCH, H bond Ao HO I II , Y= Z I -. N CH, 7 SN HOOC NHN. H Tomudex These compounds are thought to function as Cell Cycle Inhibitors by serving as antimetabolites of folic acid. They have been shown useful in the 10 treatment of cell proliferative disorders including, for example, soft tissue sarcoma, small cell lung, breast, brain, head and neck, bladder, and penile cancers. In another aspect, the Cell Cycle Inhibitor is a Cytidine analogue, such as Cytarabine or derivatives or analogues thereof, including Enocitabine, 15 FMdC ((E(-2'-deoxy-2'-(fluoromethylene)cytidine), Gemcitabine, 5-Azacitidine, Ancitabine, and 6-Azauridine. Exemplary compounds have the structures: 56 WO 2004/060346 PCT/US2003/041580 HNR HO ON OH R 2 R, R 2
R
3
R
4 Cytarabine H OH H CH Enocitabine C(O)(CH) 20
CH
3 OH H CH Gemcitabine H F F CH Azacitidine H H OH N FMdC H CH 2 F H CH NH 0 N HN 'N HO N HO N O 0 OH H OH OH Ancitabine 6-Azauridine These compounds are thought to function as Cell Cycle Inhibitors as acting as antimetabolites of pyrimidine. These compounds have been 5 shown useful in the treatment of cell proliferative disorders including, for example, pancreatic, breast, cervical, NSC lung, and bile duct cancers. In another aspect, the Cell Cycle Inhibitor is a Pyrimidine analogue. In one aspect, the Pyrimidine analogues have the general structure:
R
6 R7 R, N R,
R
4 0 0
R
3
R
2 ' 10 wherein positions 2', 3' and 5' on the sugar ring (R 2 , R 3 and R 4 , respectively) can be H, hydroxyl, phosphoryl (see, e.g., U.S. Patent No. 4,086,417) or ester (see, e.g., U.S. Patent No. 3,894,000). Esters can be of alkyl, cycloalkyl, aryl or 57 WO 2004/060346 PCT/US2003/041580 heterocyclo/aryl types. The 2' carbon can be hydroxylated at either R 2 or R 2 , the other group is H. Alternately, the 2' carbon can be substituted with halogens e.g., fluoro or difluoro cytidines such as Gemcytabine. Alternately, the sugar can be substituted for another heterocyclic group such as a furyl 5 group or for an alkane, an alkyl ether or an amide linked alkane such as
C(O)NH(CH
2
)
5
CH
3 . The 2 ° amine can be substituted with an aliphatic acyl (R 1 ) linked with an amide (see, e.g., U.S. Patent No. 3,991,045) or urethane (see, e.g., U.S. Patent No. 3,894,000) bond. It can also be further substituted to form a quaternary ammonium salt. R 5 in the pyrimidine ring may be N or CR, where 10 R is H, halogen containing groups, or alkyl (see, e.g., U.S. Patent No. 4,086,417). R 6 and R 7 can together can form an oxo group or R 6 = -NH-R 1 and
R
7 = H. R 8 is H or R 7 and R 8 together can form a double bond or R 8 can be X, where X is: CN 00 e 0 N0 15 Specific pyrimidine analogues are disclosed in U.S. Patent No. 3,894,000 (see, e.g., 2'-O-palmityl-ara-cytidine, 3'-O-benzoyl-ara-cytidine, and more than 10 other examples); U.S. Patent No. 3,991,045 (see, e.g., N4-acyl-1 j3-D-arabinofuranosylcytosine, and numerous acyl groups derivatives as listed therein, such as palmitoyl. 20 In another aspect, the Cell Cycle Inhibitor is a Fluoro-pyrimidine Analog, such as 5-Fluorouracil, or an analogue or derivative thereof, including Carmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine. Exemplary compounds have the structures: 58 WO 2004/060346 PCT/US2003/041580 0 F R R, R2 5-Fluorouracil H H Carmofur C(O)NH(CH 2
),CH
3 H Doxifluridine A 1 H Floxuridine A z H Emitefur CHOCH 2
CH
3 B Tegafur C H A, no Ho 0 o C B 00 Co Other suitable Fluoropyrimidine Analogues include 5-FudR (5 fluoro-deoxyuridine), or an analogue or derivative thereof, including 5 iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine 5 triphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds have the structures: 0 R NH HO OO 0 OH 5-Fluoro-2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridine: R = Br 5-lodoo-2'-deoxyuridine: R = I These compounds are thought to function as Cell Cycle Inhibitors by serving as antimetabolites of pyrimidine. 10 In another aspect, the Cell Cycle Inhibitor is a Purine Analogue. Purine analogues have the following general structure: 59 WO 2004/060346 PCT/US2003/041580 R2 R N
R
3 wherein X is typically carbon; R 1 is H, halogen, amine or a substituted phenyl;
R
2 is H, a primary, secondary or tertiary amine, a sulfur containing group, typically -SH, an alkane, a cyclic alkane, a heterocyclic or a sugar; R 3 is H, a 5 sugar (typically a furanose or pyranose structure), a substituted sugar or a cyclic or heterocyclic alkane or aryl group. See, e.g., U.S. Patent No. 5,602,140 for compounds of this type. In the case of pentostatin, X-R2 is -CH 2 CH(OH)-. In this case a second carbon atom is inserted in the ring between X and the adjacent nitrogen 10 atom. The X-N double bond becomes a single bond. U.S. Patent No. 5,446,139 describes suitable purine analogues of the type shown in the following formula:
R
3 /BN R, N R rJA R7
R
6
R
2 R 8
R
Y O 0 y wherein N signifies nitrogen and V, W, X, Z can be either carbon or nitrogen 15 with the following provisos. Ring A may have 0 to 3 nitrogen atoms in its structure. If two nitrogens are present in ring A, one must be in the W position. If only one is present, it must not be in the Q position. V and Q must not be simultaneously nitrogen. Z and Q must not be simultaneously nitrogen. If Z is nitrogen, R 3 is not present. Furthermore, R1- 3 are independently one of H, 20 halogen, C1-.
7 alkyl, C01.7 alkenyl, hydroxyl, mercapto, Cj-7 alkylthio, C1.7 alkoxy, 60 WO 2004/060346 PCT/US2003/041580
C
2
-
7 alkenyloxy, aryl oxy, nitro, primary, secondary or tertiary amine containing group. R 5 -8 are H or up to two of the positions may contain independently one of OH, halogen, cyano, azido, substituted amino, R 5 and R 7 can together form a double bond. Y is H, a C1- 7 alkylcarbonyl, or a mono- di or tri phosphate. 5 Exemplary suitable purine analogues include 6-Mercaptopurine, Thiguanosine, Thiamiprine, Cladribine, Fludaribine, Tubercidin, Puromycin, Pentoxyfilline; where these compounds may optionally be phosphorylated. Exemplary compounds have the structures: RN R , R 2 R A: : 6-Mercaptopurine H SH H o Thloguanosine NH 2 SH B ON ON Thiamiprine NH A H Ba: B aO Cladribine C1 NH 2B o Fludarabine F NH 2 B Puromycin H N(CH z)2 B on Tubercidin H NH B 1 B 4 : "N
CH
3 O N
H
3 C N 0 0 OH 3 10 Pentoxyfilline These compounds are thought to function as Cell Cycle Inhibitors by serving as antimetabolites of purine. In another aspect, the Cell Cycle Inhibitor is a Nitrogen Mustard. Many suitable Nitrogen Mustards are known and are suitably used as a Cell 15 Cycle Inhibitor in the present invention. Suitable Nitrogen Mustards are also known as cyclophosphamides. A preferred Nitrogen Mustard has the general structure: 61 WO 2004/060346 PCT/US2003/041580 R, A N CI (i) Where A is: 0-oP/ 1 O N R2
R
3 or -CH 3 or other alkane, or chloronated alkane, typically CH 2
CH(CH
3 )CI, or a 5 polycyclic group such as B, or a substituted phenyl such as C or a heterocyclic group such as D. 0
H
3 C H H HO H
HOOC
NH
2 (iii) H N H O (iv) 10 Suitable Nitrogen Mustards are disclosed in U.S. Patent No. 3,808,297, wherein A is: ON R2 R3
R
1
-
2 are H or CH 2
CH
2 CI; R 3 is H or oxygen-containing groups such as 15 hydroperoxy; and R 4 can be alkyl, aryl, heterocyclic. 62 WO 2004/060346 PCT/US2003/041580 The cyclic moiety need not be intact. See, e.g., U.S. Patent Nos. 5,472,956, 4,908,356, 4,841,085 that describe the following type of structure: RR., R O O Cl
R
4 RNR2
R
3
R
2 wherein R 1 is H or CH 2
CH
2 CI, and R 2 -6 are various substituent groups. 5 Exemplary Nitrogen Mustards include methylchloroethamine, and analogues or derivatives thereof, including methylchloroethamine oxide hydrohchloride, Novembichin, and Mannomustine (a halogenated sugar). Exemplary compounds have the structures: CI CI HCI R CH3 Mechlorethanime CH 3 Mechlorethanime Oxide HCI Novembichin CH,CH(CH3)C 10 The Nitrogen Mustard may be Cyclophosphamide, Ifosfamide, Perfosfamide, or Torofosfamide, where these compounds have the structures: R, 0 N C N R2
R
3 Ri R2 R3 Cyclophosphamide H CH 2
CH
2 cI H Ifosfamide CH 2
CH
2 CI H H Perfosfamide CH 2 CH2Cl H OOH Torofosfamide CH 2
CH
2 Cl CH 2
CH
2 CI H The Nitrogen Mustard may be Estramustine, or an analogue or derivative thereof, including Phenesterine, Prednimustine, and Estramustine 63 WO 2004/060346 PCT/US2003/041580 P0 4 . Thus, suitable Nitrogen Mustard type Cell Cycle Inhibitors of the present invention have the structures: ci 0 0 H3C H H RR H R Estramustine OH Phenesterine C(CH 3
)(CH
2
)
3
CH(CH
3
)
2 ci 5 The Nitrogen Mustard may be Chlorambucil, or an analogue or derivative thereof, including Melphalan and Chlormaphazine. Thus, suitable Nitrogen Mustard type Cell Cycle Inhibitors of the present invention have the structures N t R, o O HR2 H CHC CHo R, R 2
R
3 Chlorambucd CH2COOH H H Melphalan COOH NH2 H Chlornaphazine H together forms a beOH Prednimustinene ring 510 The Nitrogen Mustard may be Churacil mustardcil, whihor an analogue ors the derivative thereof, including Melphalan and Chlormaphazine. Thus, suitable Nitrogen Mustard type Cell Cycle Inhibitors of the present invention have the structure: 64 R N Cl
R
2
R
3 CI R R 2
R
3 Chlorambucil CH 2 COOH H H Melphalan COOH NH 2 H Chlornaphazine H together forms a benzene ring 10 The Nitrogen Mustard may be uracil mustard, which has the structure: 64 WO 2004/060346 PCT/US2003/041580 H N H The Nitrogen Mustards are thought to function as cell cycle inhibitors by serving as alkylating agents for DNA. The cell cycle inhibitor of the present invention may be a 5 hydroxyurea. Hydroxyureas have the following general structure: O
R
3 O-X / N R2 R, Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R 1 is: S R9 Ra 3 10 and R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether. Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein R 1 is a cycloalkenyl group, for example N-[3-[5-(4 fluorophenylthio)-furyl]-2-cyclopenten-1 -yl]N-hydroxyurea; R 2 is H or an alkyl 15 group having 1 to 4 carbons and R 3 is H; X is H or a cation. Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein R, is a phenyl group substituted with on or more fluorine atoms; R 2 is a cyclopropyl group; and R 3 and X is H. Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent 20 No. 5,066,658, wherein R 2 and R 3 together with the adjacent nitrogen form: 65 WO 2004/060346 PCT/US2003/041580
(CH
2 )n Y N S(CH2)m wherein m is 1 or 2, n is 0-2 and Y is an alkyl group. In one aspect, the hydroxy urea has the structure: 0 /0H H2N NH Hydroxyurea 5 Hydroxyureas are thought to function as Cell Cycle Inhibitors by serving to inhibit DNA synthesis. In another aspect, the Cell Cycle Inhibitor is a Belomycin, such as Bleomycin A 2 , which have the structures: 0 HO N N o NH ;H0 NH CH 2 HO CH 3 Bleomycin O N N HO ~ H R HO OH 0 In another aspect, the Cell Cycle minahibitor is a Mytomicin, such asmine 09 H OH Dleomycin 0 H, 10 Bleomycin A 2 : R = (CH 3
)
2
S+(CH
2
)
3
NH
Belomycins are thought to function as Cell Cycle Inhibitors by cleaving DNA. They have been shown useful in the treatment of cell proliferative disorder such as, e.g., penile cancer. In another aspect, the Cell Cycle Inhibitor is a Mytomicin, such as 15 Mitomycin C, or an analogue or derivative thereof, such as Porphyromycin. Suitable compounds have the structures: 66 WO 2004/060346 PCT/US2003/041580 0 0O
NH
2 H 2 N NH, I I OCH3 H C N N-R O R Mitomycin C H Porphyromycin
CH
3 (N-methyl Mitomycin C) These compounds are thought to function as Cell Cycle Inhibitors by serving as DNA alkylating agents. In another aspect, the Cell Cycle Inhibitor is an Alkyl Sulfonate, 5 such as Busulfan, or an analogue or derivative thereof, such as Treosulfan, Improsulfan, Piposulfan, and Pipobroman. Exemplary compounds have the structures: O o
H
3 C-S-0O O-S-CH 3 II v R'- v II 0 0 R Busulfan single bond Improsulfan -CH 2
-NH-CH
2 Piposulfan o--N 0 0/-/ 4 0 B N N Br B, 0 Pipobroman 10 These compounds are thought to function as Cell Cycle Inhibitors by serving as DNA alkylating agents. In another aspect, the Cell Cycle Inhibitor is a Benzamide. In yet another aspect, the Cell Cycle Inhibitor is a Nicotinamide. These compounds have the basic structure: 67 WO 2004/060346 PCT/US2003/041580 R2e A X
R
3 wherein X is either O or S; A is commonly NH 2 or it can be OH or an alkoxy group; B is N or C-R 4 , where R 4 is H or an ether-linked hydroxylated alkane such as OCH 2
CH
2 OH, the alkane may be linear or branched and may contain 5 one or more hydroxyl groups. Alternately, B may be N-R 5 in which case the double bond in the ring involving B is a single bond. R 5 may be H, and alkyl or an aryl group (see, e.g., U.S. Patent No. 4,258,052); R 2 is H, OR 6 , SR 6 or
NHR
6 , where R 6 is an alkyl group; and R 3 is H, a lower alkyl, an ether linked lower alkyl such as -O-Me or -O-Ethyl (see, e.g., U.S. Patent No. 5,215,738). 10 Suitable Benzamide compounds have the structures: x Y
NH
2 Benzamides X=OorS Y = H, OR, CH 3 , acetoxy Z= H, OR, SR, NHR R = alkyl group where additional compounds are disclosed in U.S. Patent No. 5,215,738, (listing some 32 compounds). Suitable Nicotinamide compounds have the structures: x z NH2 Nicotinamides X=OorS Z = H, OR, SR, NHR 15 R = alkyl group 68 WO 2004/060346 PCT/US2003/041580 where additional compounds are disclosed in U.S. Patent No. 5,215,738 (listing some 58 compounds, e.g., 5-OH nicotinamide, 5-aminonicotinamide, 5-(2,3 dihydroxypropoxy) nicotinamide), and compounds having the structures: x x x RA B A A R R Nicotinamides X = O orS (only O is described) A = OH, NH 2 , alkoxy B=O R = alkyl or aryl group 5 and U.S. Patent No. 4,258,052 (listing some 46 compounds, e.g., 1-methyl-6 keto-1,6-dihydronicotinic acid). In one aspect, the Cell Cycle Inhibitor is a Tetrazine compound, such as Temozolomide, or an analogue or derivative thereof, including Dacarbazine. Suitable compounds have the structures:
NH
2 0 0 NH N NH, CH N N H N=N-N NN
CH
3 0 10 Temozolomide Dacarbazine Another suitable Tetrazine Compound is Procarbazine, including HCI and HBr salts, having the structure:
H
3 C NH-NH 0 N CH3 N
H
Procarbazine
CH
3 In another aspect, the Cell Cycle Inhibitor is Actinomycin D, or 15 other members of this family, including Dactinomycin, Actinomycin C 1 , 69 WO 2004/060346 PCT/US2003/041580 Actinomycin C2, Actinomycin C3, and Actinomycin F 1 . Suitable compounds have the structures: 0
H
3 c NH 2 0 R, R2 R, Actinomycin D (Cl) D-Va( D-Val single bond Actinomycin C. D-Val D-Alloisoleucine 0 Actinomycin C 3 D-Alloisoleucine D-Alloisoleucine 0 In another aspect, the Cell Cycle Inhibitor is an Aziridine 5 compound, such as Benzodepa, or an analogue or derivative thereof, including Meturedepa, Uredepa, and Carboquone. Suitable compounds have the structures: O RgN-P-NH O R, 12 O
N
2 R2 R 0 , R R, % O' NH 2 Benzodepa phenyl H 0 0 ICH Meturedepa CH 3
CH
3 Carboquone Uredepa CH 3 H In another aspect, the Cell Cycle Inhibitor is a Halogenated Sugar, 10 such as Mitolactol, or an analogue or derivative thereof, including Mitobronitol and Mannomustine. Suitable compounds have the structures:
OH
2 Br CH 2 r CH 2
NH
2
CHCH
2 CI H- -OH HO-- H HO- -H HO- -H HO- -H HO- -H HO -- H H--OH H--OH H--OH H--OH H--OH
CH
2 ABr CH 2 Br CH 2
NH
2 CH2CI Mitolactol Mitobronitol Mannomustine 70 WO 2004/060346 PCT/US2003/041580 In another aspect, the Cell Cycle Inhibitor is a Diazo compound, such as Azaserine, or an analogue or derivative thereof, including 6-diazo-5 oxo-L-norleucine and 5-diazouracil (also a pyrimidine analog). Suitable compounds have the structures: 0 NN_-_ R 1
R
2 NOH 0 NH 2 Ri
R
2 Azaserine O single bond 6-diazo-5-oxo 5 L-norleucine single bond CH 2 Other compounds that may serve as Cell Cycle Inhibitors according to the present invention are Pazelliptine; Wortmannin; Metoclopramide; RSU; Buthionine sulfoxime; Tumeric; Curcumin; AG337, a thymidylate synthase inhibitor; Levamisole; Lentinan, a polysaccharide; 10 Razoxane, an EDTA analog; Indomethacin; Chlorpromazine; cc and p interferon; MnBOPP; Gadolinium texaphyrin; 4-amino-1,8-naphthalimide; Staurosporine derivative of CGP; and SR-2508. Thus, in one aspect, the Cell Cycle Inhibitor is a DNA alkylating agent. In another aspect, the Cell Cycle Inhibitor is an anti-microtubule agent. 15 In another aspect, the Cell Cycle Inhibitor is a Topoisomerase inhibitor. In another aspect, the Cell Cycle Inhibitor is a DNA cleaving agent. In another aspect, the Cell Cycle Inhibitor is an antimetabolite. In another aspect, the Cell Cycle Inhibitor functions by inhibiting adenosine deaminase (e.g., as a purine analog). In another aspect, the Cell Cycle Inhibitor functions by inhibiting 20 purine ring synthesis and/or as a nucleotide interconversion inhibitor (e.g., as a purine analogue such as mercaptopurine). In another aspect, the Cell Cycle Inhibitor functions by inhibiting dihydrofolate reduction and/or as a thymidine monophosphate block (e.g., methotrexate). In another aspect, the Cell Cycle Inhibitor functions by causing DNA damage (e.g., Bleomycin). In another 25 aspect, the Cell Cycle Inhibitor functions as a DNA intercalation agent and/or 71 WO 2004/060346 PCT/US2003/041580 RNA synthesis inhibition (e.g., Doxorubicin). In another aspect, the Cell Cycle Inhibitor functions by inhibiting pyrimidine synthesis (e.g., N-phosphonoacetyl L-Aspartate). In another aspect, the Cell Cycle Inhibitor functions by inhibiting ribonucleotides (e.g., hydroxyurea). In another aspect, the Cell Cycle Inhibitor 5 functions by inhibiting thymidine monophosphate (e.g., 5-fluorouracil). In another aspect, the Cell Cycle Inhibitor functions by inhibiting DNA synthesis (e.g., Cytarabine). In another aspect, the Cell Cycle Inhibitor functions by causing DNA adduct formation (e.g., platinum compounds). In another aspect, the Cell Cycle Inhibitor functions by inhibiting protein synthesis (e.g., L 10 Asparginase). In another aspect, the Cell Cycle Inhibitor functions by inhibiting microtubule function (e.g., taxanes). In another aspect, the Cell Cycle Inhibitors acts at one or more of the steps in the biological pathway shown in FIG. 3. Additional Cell Cycle Inhibitors useful in the present invention, as well as a discussion of their mechanisms of action, may be found in Hardman 15 J.G., Limbird L.E. Molinoff R.B., Ruddon R. W., Gilman A.G. editors, Chemotherapy of Neoplastic Diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics Ninth Edition, McGraw-Hill Health Professions Division, New York, 1996, pages 1225-1287. See also U.S. Patent Nos. 3,387,001; 3,808,297; 3,894,000; 3,991,045; 4,012,390; 4,057,548; 20 4,086,417; 4,144,237; 4,150,146; 4,210,584; 4,215,062; 4,250,189; 4,258,052; 4,259,242; 4,296,105; 4,299,778; 4,367,239; 4,374,414; 4,375,432; 4,472,379; 4,588,831; 4,639,456; 4,767,855; 4,828,831; 4,841,045; 4,841,085; 4,908,356; 4,923,876; 5,030,620; 5,034,320; 5,047,528; 5,066,658; 5,166,149; 5,190,929; 5,215,738; 5,292,731; 5,380,897; 5,382,582; 5,409,915; 5,440,056; 5,446,139; 25 5,472,956; 5,527,905; 5,552,156; 5,594,158; 5,602,140; 5,665,768; 5,843,903; 6,080,874; 6,096,923; and RE030561. Numerous polypeptides, proteins and peptides, as well as nucleic acids that encode such proteins, can also be used therapeutically as cell cycle inhibitors. This is accomplished by delivery by a suitable vector or gene 30 delivery vehicle which encodes a cell cycle inhibitor (Walther & Stein, Drugs 60(2):249-71, Aug 2000; Kim et al., Archives of Pharmacal Res. 24(1):1-15, 72 WO 2004/060346 PCT/US2003/041580 Feb 2001; and Anwer et al., Critical Reviews in Therapeutic Drug Carrier Systems 17(4):377-424, 2000. Genes encoding proteins that modulate cell cycle include the INK4 family of genes (US 5,889,169; US 6,033,847), ARF-p19 (US 5,723,313), p 2 1 wAFI/cIP1 and p 2 7 KIP1 (WO 95/13375; WO 98/35022), 5 p27
K
P
1 (WO 97/38091), p 5 7
KP
2 (US 6,025,480), ATM/ATR (WO 99/04266), Gadd 45 (US 5,858,679), Mytl (US 5,744,349), Weel (WO 99/49061) smad 3 and smad 4 (US 6,100,032), 14-3-3a (WO 99/31240), GSK3p (Stambolic, V. and Woodgett, J. R., Biochem Journal 303: 701-704, 1994), HDAC-1 (Furukawa, Y. et aL., Cytogenet. Cell Genet. 73: 130-133, 1996; Taunton, J. et 10 aL., Science 272: 408-411, 1996), PTEN (WO 99/02704), p53 (U.S. Patent No. 5,532,220), p 33 INGl (U.S. Patent No. 5.986.078), Retinoblastoma (EPO 390530), and NF-1 (WO 92/00387). A wide variety of gene delivery vehicles may be utilized to deliver and express the proteins described herein, including for example, viral vectors such as 15 retroviral vectors (e.g., U.S. Patent Nos. 5,591,624, 5,716,832, 5,817,491, 5,856,185, 5,888,502, 6,013,517, and 6,133,029; as well as subclasses of retroviral vectors such as lentiviral vectors (e.g., PCT Publication Nos. WO 00/66759, WO 00/00600, WO 99/24465, WO 98/51810, WO 99/51754, WO 99/31251, WO 99/30742, and WO 99/15641)), alphavirus based vector systems 20 (e.g., U.S. Patent Nos. 5,789,245, 5,814,482, 5,843,723, and 6,015,686), adeno associated virus-based system (e.g., U.S. Patent Nos. 6,221,646, 6,180,613, 6,165,781, 6,156,303, 6,153,436, 6,093,570, 6,040,183, 5,989,540, 5,856,152, and 5,587,308) and adenovirus-based systems (e.g., U.S. Patent Nos. 6,210,939, 6,210,922, 6,203,975, 6,194,191, 6,140,087, 6,113,913, 6,080,569, 6,063,622, 25 6,040,174, 6,033,908, 6,033,885, 6,020,191, 6,020,172, 5,994,128, and 5,994,106), herpesvirus based or 'amplicon" systems (e.g., U.S. Patent Nos. 5,928,913, 5,501,979, 5,830,727, 5,661,033, 4,996,152 and 5,965,441) and, "naked DNA" based systems (e.g., U.S. Patent Nos. 5,580,859 and 5,910,488) (all of which are, as noted above, incorporated by reference in their entirety). 30 Within one aspect of the invention, ribozymes or antisense sequences (as well as gene therapy vehicles which can deliver such sequences) 73 WO 2004/060346 PCT/US2003/041580 can be utilized as cell cycle inhibitors. One representative example of such inhibitors is disclosed in PCT Publication No. WO 00/32765 (which, as noted above, is incorporated by reference in its entirety). 5. Cyclin Dependent Protein Kinase Inhibitors 5 In another embodiment, the pharmacologically active compound is a cyclin dependent protein kinase inhibitor (e.g., R-roscovitine, CYC-101, CYC-103, CYC-400, MX-7065, alvocidib (4H-1-Benzopyran-4-one, 2-(2 chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1 -methyl-4-piperidinyl)-, cis-(-) [CAS]), SU-9516, AG-12275, PD-0166285, CGP-79807, fascaplysin, GW-8510 10 (Benzenesulfonamide, 4-[[(Z)-(6,7-dihydro-7-oxo-8H-pyrrolo[2,3-g]benzothiazol 8-ylidene)methyl]amino]-N-(3-hydroxy-2,2-dimethylpropyl)- [CAS]), GW 491619, Indirubin 3' monoxime, GW8510) or an analogue or derivative thereof. 6. EGF (Epidermal Growth Factor) Receptor Kinase Inhibitors In another embodiment, the pharmacologically active compound 15 is an EGF (epidermal growth factor) kinase inhibitor (e.g., erlotinib (4 Quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-, monohydrochloride [CAS]), VIATRIS (Viatris GMBH & Co., Germany), erbstatin, BIBX-1382, gefitinib (4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7 methoxy-6-(3-(4-morpholinyl)propoxy) [CAS]) ) or an analogue or derivative 20 thereof. 7. Elastase Inhibitors In another embodiment, the pharmacologically active compound is an elastase inhibitor (e.g., ONO-6818, sivelestat sodium hydrate (Glycine, N [2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sul Ifonyl]amino]benzoyl]- [CAS]), 25 erdosteine (Acetic acid, [[2-oxo-2-[(tetrahydro-2-oxo-3-thienyl)amino]ethyl]thio] [CAS]), MDL-100948A, MDL-104238 (N-[4-(4-morpholinylcarbonyl)benzoyl]-L valyl-N'-[3,3,4,4,4-pentafluoro-1 -(1 -methylethyl)-2-oxobutyl]-L-2-azetamide), MDL-27324 (L-Prolinamide, N-[[5-(dimethylamino)-1 -naphthalenyl]sulfonyl]-L 74 WO 2004/060346 PCT/US2003/041580 alanyl-L-alanyl-N-[3,3,3-trifluoro-1l-(1-methylethyl)-2-oxopropyl]-, (S)- [CAS]), SR-26831 (Thieno[3,2-c]pyridinium, 5-[(2-chlorophenyl)methyl]-2-(2,2-dimethyl 1-oxopropoxy)-4,5,6,7-tetrahydro-5-hydroxy- [CAS]), Win-68794, Win-63110, SSR-69071 (2-(9(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2 5 yloxymethyl)-4-(1 -methylethyl)-6-methyoxy-1,2-benzisothiazol-3(2H)-one-1,1 dioxide), (N(Alpha)-(1-adamantylsulfonyl)N(epsilon)-succinyl-L-lysyl-L-prolyl-L valinal), Ro-31-3537 (NAlpha-(1-adamantanesulphonyl)-N-(4-carboxybenzoyl) L-lysyl-alanyl-L-valinal), R-665, FCE-28204, ((6R,7R)-2-(Benzoyloxy)-7 methoxy-3-methyl-4-pivaloyl-3-cephem 1,1-dioxide), 1,2-Benzisothiazol-3(2H) 10 one, 2-(2,4-dinitrophenyl)-, 1,1-dioxide [CAS], L-658758 (L-Proline, 1-[[3 [(acetyloxy)methyl]-7-methoxy-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-en-2 yl]carbonyl]-, S,S-dioxide, (6R-cis)- [CAS]), L-659286 (Pyrrolidine, 1-[[7 methoxy-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3 yl)thio]methyl]-5-thia-1l-azabicyclo[4.2.0]oct-2-en-2-yl]carbonyl]-, S,S-dioxide, 15 (6R-cis)- [CAS]), L-680833 (Benzeneacetic acid, 4-[[3,3-diethyl-1-[[[1-(4 methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-, [S-(R*,S*)]- [CAS]) ) or an analogue or derivative thereof. 8. Factor Xa Inhibitors In another embodiment, the pharmacologically active compound 20 is a factor Xa inhibitor (e.g., CY-222, fondaparinux sodium (Alpha-D Glucopyranoside, methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-Alpha-D glucopyranosyl-(1 -4)-O-R-D-glucopyranuronosyl-(1 -4)-O-2-deoxy-3,6-di-O sulfo-2-(sulfoamino)-Alpha-D-glucopyranosyl-(1-4)-O-2-O-sulfo-Alpha-L idopyranuronosyl-(1-4)-2-deoxy-2-(sulfoamino)-, 6-(hydrogen sulfate) [CAS]), 25 danaparoid sodium) or an analogue or derivative thereof. 9. Farnesyltransferase Inhibitors In another embodiment, the pharmacologically active compound is a farnesyltransferase inhibitor (e.g., dichlorobenzoprim (2,4-diamino-5-[4 (3,4-dichlorobenzylamino)-3-nitrophenyl]-6-ethylpyrimidine), B-581, B-956 (N 75 WO 2004/060346 PCT/US2003/041580 [8(R)-Amino-2(S)-benzyl-5(S)-isopropyl-9-sulfanyl-3(Z),6(E)-nonadienoyl]-L methionine), OSI-754, perillyl alcohol (1-Cyclohexene-l-methanol, 4-(1 methylethenyl)- [CAS], RPR-114334, lonafarnib (1-Piperidinecarboxamide, 4-[2 [4-[(1 R)-3,10-dibromo-8-chloro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2 5 b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl]- [CAS]), Sch-48755, Sch-226374, (7,8 Dichloro-5H-dibenzo[b,e][1,4]diazepin-11-yl )-pyridin-3-ylmethylamine, J 104126, L-639749, L-731734 (Pentanamide, 2-[[2-[(2-amino-3 mercaptopropyl)amino]-3-methylpentyl]amino]-3-methyl-N-(tetrahydro-2-oxo-3 furanyl)-, [3S-[3R*[2R*[2R*(S*),3S*],3R*]]]- [CAS]), L-744832 (Butanoic acid, 2 10 ((2-((2-((2-amino-3-mercaptopropyl)amino)-3-methylpentyl)oxy)-1 -oxo-3 phenylpropyl)amino)-4-(methylsulfonyl)-, 1-methylethyl ester, (2S (1(R*(R*)),2R*(S*),3R*))- [CAS]), L-745631 (1-Piperazinepropanethiol, 1 amino-2-(2-methoxyethyl)-4-(1-naphthalenylcarbonyl)-, (IfR,2S)- [CAS]), N acetyl-N-naphthylmethyl-2(S)-[(1-(4-cyanobenzyl)-1 H-imidazol-5 15 yl)acetyl]amino-3(S)-methylpentamine, (2AIpha)-2-hydroxy-24,25 dihydroxylanost-8-en-3-one, BMS-316810, UCF-1-C (2,4-Decadienamide, N-(5 hydroxy-5-(7-((2-hydroxy-5-oxo-1l-cyclopenten--yl)amino-oxo-1,3,5 heptatrienyl)-2-oxo-7-oxabicyclo(4.1.0)hept-3-en-3-yl)-2,4,6-trimethyl-, (lS (1Alpha,3(2E,4E,6S*),5Alpha,5(1E,3E,5E),6Alpha))- [CAS]), UCF-116-B) or an 20 analogue or derivative thereof. 10. Fibrinogen Antagonists In another embodiment, the pharmacologically active compound is a fibrinogen antagonist (e.g., 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8, tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2 25 yl]carbonyl]-amino]propionic acid, streptokinase (Kinase (enzyme-activating), strepto- [CAS]), urokinase (Kinase (enzyme-activating), uro- [CAS]), plasminogen activator, pamiteplase, monteplase, heberkinase, anistreplase, alteplase, pro-urokinase, picotamide (1,3-Benzenedicarboxamide, 4-methoxy N,N'-bis(3-pyridinylmethyl)- [CAS]) ) or an analogue or derivative thereof. 76 WO 2004/060346 PCT/US2003/041580 11. Guanylate Cyclase Stimulants In another embodiment, the pharmacologically active compound is a guanylate cyclase stimulant (e.g., isosorbide-5-mononitrate (D-Glucitol, 1,4:3,6-dianhydro-, 5-nitrate [CAS]) ) or an analogue or derivative thereof. 5 12. Heat Shock Protein 90 Antagonists In another embodiment, the pharmacologically active compound is a heat shock protein 90 antagonist (e.g., geldanamycin; NSC-33050 (17 Allylaminogeldanamycin), rifabutin (Rifamycin XIV, 1',4-didehydro-1l-deoxy-1,4 dihydro-5'-(2-methylpropyl)-1l-oxo-[CAS]), 17AAG), or an analogue or derivative 10 thereof. 13. HMGCoA Reductase Inhibitors In another embodiment, the pharmacologically active compound is an HMGCoA reductase inhibitor (e.g., BCP-671, BB-476, fluvastatin (6 Heptenoic acid, 7-[3-(4-fluorophenyl)-1l-(1-methylethyl)-1 H-indol-2-yl]-3,5 15 dihydroxy-, monosodium salt, [R*,S*-(E)]-(±)- [CAS]), dalvastatin (2H-Pyran-2 one, 6-(2-(2-(2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-l-cyclohexen-1 yl)ethenyl)tetrahydro)-4-hydroxy-, (4AIpha,6R(E))-(+/-)- [CAS]), glenvastatin (2H-Pyran-2-one, 6-[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3 pyridinyl]ethenyl]tetrahydro-4-hydroxy-, [4R-[4Alpha,6R(E)]]- [CAS]), S-2468, N 20 (1-oxododecyl)-4Alpha,10-dimethyl-8-aza-trans-decal-31-ol, atorvastatin calcium (1 H-Pyrrole-1 -heptanoic acid, 2-(4-fluorophenyl)-R,delta-dihydroxy-5 (1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, calcium salt [R-(R*,R*)] [CAS]), CP-83101 (6,8-Nonadienoic acid, 3,5-dihydroxy-9,9-diphenyl-, methyl ester, [R*,S*-(E)]-(+/-)- [CAS]), pravastatin (1-Naphthaleneheptanoic acid, 25 1,2,6,7,8,8a-hexahydro-R,delta,6-trihydroxy-2-methyl-8-(2-methyl-1l-oxobutoxy) , monosodium salt, [1S-[1Alpha(BS*,deltaS*),2Alpha,6Alpha,8R(R*),8aAlpha]] [CAS]), U-20685, pitavastatin (6-Heptenoic acid, 7-[2-cyclopropyl-4-(4 fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-, calcium salt (2:1), [S-[R*,S*-(E)]] [CAS]), N-((1 -methylpropyl)carbonyl)-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H 77 WO 2004/060346 PCT/US2003/041580 pyran-2-yl)ethyl]-perhydro-isoquinoline, dihydromevinolin (Butanoic acid, 2 methyl-, 1,2,3,4,4a,7,8,8a-octahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6 oxo-2H-pyran-2-yl)ethyl]-1 -naphthalenylester[1Alpha(R*),3Alpha,4aAlpha, 7f1,81(2S*,4S*),8a1]]- [CAS]), HBS-107, dihydromevinolin (Butanoic acid, 2 5 methyl-, 1,2,3,4,4a,7,8,8a-octahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6 oxo-2H-pyran-2-yl)ethyl]-1l-naphthalenyl ester[1Alpha(R*),3Alpha,4aAlpha,7, 81(2S*,4S*),8aR]]- [CAS]), L-669262 (Butanoic acid, 2,2-dimethyl-, 1,2,6,7,8,8a-hexahydro-3,7-dimethyl-6-oxo-8-[2-(tetrahydro-4-hydroxy-6-oxo 2H-pyran-2-yl)ethyl]-1 -naphthalenyl[1S-[1AIpha,71,81(2S*,4S*),8aR]]- [CAS]), 10 simvastatin (Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl 8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1l-naphthalenyl ester, [1S-[1AIpha,3Alpha,71,8(2S*,4S*),8aR]]- [CAS]), rosuvastatin calcium (6 Heptenoic acid, 7-(4-(4-fluorophenyl)-6-(1-methylethyl)-2 (methyl(methylsulfonyl)amino)-5-pyrimdinyl)-3,5-dihydroxy- calcium salt (2:1) 15 (S-(R*, S*-(E))) [CAS]), meglutol (2-hydroxy-2-methyl-1,3-propandicarboxylic acid), lovastatin (Butanoic acid, 2-methyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl 8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1.alpha.(R*),3Apha,7R,8R(2S*,4S*),8af]]- [CAS])) or an analogue or derivative thereof. 20 14. Hydroorotate Dehydrogenase Inhibitors In another embodiment, the pharmacologically active compound is a hydroorotate dehydrogenase inhibitor (e.g., leflunomide (4 Isoxazolecarboxamide, 5-methyl-N-[4-(trifluoromethyl)phenyl]- [CAS]), laflunimus (2-Propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl 25 4(trifluoromethyl)phenyl)-, (Z)-[CAS]) ) or an analogue or derivative thereof. 15. IKK2 Inhibitors In another embodiment, the pharmacologically active compound is an IKK2 inhibitor (e.g., MLN-120B, SPC-839) or an analogue or derivative thereof. 78 WO 2004/060346 PCT/US2003/041580 16. IL-1, ICE, and IRAK Antagonists In another embodiment, the pharmacologically active compound is an IL-1, ICE ((aryl)acyloxymethyl ketone) & IRAK antagonist (e.g., VX-765 (Vertex Pharmaceuticals, Cambridge, MA), VX-740 (Vertex Pharmaceuticals), 5 E-5090 (2-Propenoic acid, 3-(5-ethyl-4-hydroxy-3-methoxy- 1 -naphthalenyl)-2 methyl-, (Z)- [CAS]), CH-164, CH-172, CH-490, AMG-719, iguratimod (N-[3 (Formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl] methanesulfonamide), AV94-88, pralnacasan (6H-Pyridazino(1,2-a)(1,2)diazepine-1-carboxamide, N ((2R,3S)-2-ethoxytetrahydro-5-oxo-3-furanyl)octahydro-9-((1 10 isoquinolinylcarbonyl)amino)-6,10-dioxo-, (1S,9S)- [CAS]), (2S-cis)-5 [Benzyloxycarbonylamino-1,2,4,5,6,7-hexahydro-4-(oxoazepino[3,2, -hi]indole 2-carbonyl)-amino]-4-oxobutanoic acid, AVE-9488, ESONARIMOD (Taisho Pharmaceutical Co., Ltd., Japan) (Benzenebutanoic acid, Alpha [(acetylthio)methyl]-4-methyl-Gamma-oxo- [CAS]), pralnacasan (6H 15 Pyridazino(1,2-a)(1,2)diazepine-1 -carboxamide, N-((2R,3S)-2-ethoxytetrahydro 5-oxo-3-furanyl)octahydro-9-((1-isoquinolinylcarbonyl)amino)-6,10-dioxo-, (1S,9S)- [CAS]), tranexamic acid (Cyclohexanecarboxylic acid, 4 (aminomethyl)-, trans- [CAS]), Win-72052, Tomazarit (Ro-31-3948) (Propanoic acid, 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methyl-[CAS]),
PD
20 163594, SDZ-224-015 (L-Alaninamide N-((phenylmethoxy)carbonyl)-L-valyl-N ((1 S)-3-((2,6-dichlorobenzoyl)oxy)-1-(2-ethoxy-2-oxoethyl)-2-oxopropyl) [CAS]), L-709049 (L-Alaninamide, N-acetyl-L-tyrosyl-L-valyl-N-(2-carboxy-1 formylethyl)-, (S)- [CAS]), TA-383 (1 H-Imidazole, 2-(4-chlorophenyl)-4,5 dihydro-4,5-diphenyl-, monohydrochloride, cis- [CAS]), El-1507-1 (6a,12a 25 Epoxybenz[a]anthracen-1,12(2H,7H)-dione, 3,4-dihydro-3,7-dihydroxy-8 methoxy-3-methyl- [CAS]), Ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2 (1,2,4-triazol-1 -yl methyl)quinoline-3-carboxylate, El-1941-1, TJ-114, anakinra (Interleukin 1 receptor antagonist (human isoform x reduced), N2-L-methionyl [CAS]) ) or an analogue or derivative thereof. 79 WO 2004/060346 PCT/US2003/041580 17. IL-4 Agonists In another embodiment, the pharmacologically active compound is an IL-4 agonist (e.g., glatiramir acetate (L-Glutamic acid, polymer with L alanine, L-lysine and L-tyrosine, acetate (salt) [CAS])) or an analogue or 5 derivative thereof. 18. Immunomodulatory Agents In another embodiment, the pharmacologically active compound is an immunomodulatory agent (e.g. Biolimus, leflunamide, ABT-578, methylsulfamic acid 3-(2-methoxyphenoxy)-2 10 [[(methylamino)sulfonyl]oxy]propyl ester, sirolimus, CCI-779 (Rapamycin 42-(3 hydroxy-2-(hydroxymethyl)-2-methylpropanoate) [CAS]), LF-15-0195, NPC15669 (L-Leucine, N-[[(2,7-dimethyl-9H-fluoren-9-yl)methoxy]carbonyl] [CAS]), NPC-15670 (L-Leucine, N-[[(4,5-dimethyl-9H-fluoren-9 yl)methoxy]carbonyl]- [CAS]), NPC-16570 (4-[2-(Fluoren-9-yl)ethyloxy 15 carbonyl]aminobenzoic acid), sufosfamide (Ethanol, 2-[[3-(2 chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-yl]amino]-, methanesulfonate (ester), P-oxide [CAS]), tresperimus (2-[N-[4-(3 Aminopropylamino)butyl]carbamoyloxy]-N-(6-guanidinohexyl)acetamide), 4-[2 (Fluoren-9-yl)ethoxycarbonylamino]-benzo-hydroxamic acid, laquinimod, PBI 20 1411, azathioprine (6-[(1-Methyl-4-nitro-1 H-imidazol-5-yl)thio]-1 H-purine), PB0032, beclometasone, MDL-28842 (9H-Purin-6-amine, 9-(5-deoxy-5-fluoro I-D-threo-pent-4-enofuranosyl)-, (Z)- [CAS]), FK-788, AVE-1726, ZK-90695, ZK-90695, Ro-54864, didemnin-B, Illinois (Didemnin A, N-[1-(2-hydroxy-1 oxopropyl)-L-prolyl]-, (S)- [CAS]), SDZ-62-826 (Ethanaminium, 2-[[hydroxy[[1 25 [(octadecyloxy)carbonyl]-3-piperidinyl]methoxy]phosphinyl]oxy]-N,N,N-trimethyl , inner salt [CAS]), argyrin B ((4S,7S,13R,22R)-13-Ethyl-4-(1 H-indol-3 ylmethyl)-7-(4-methoxy-1 H-indol-3-ylmethyl)1 8,22-dimethyl-16-methyl-ene-24 thia-3,6,9,12,15,18,21,26-octaazabicyclo[21.2.1 ]-hexacosa-1 (25),23(26)-diene 2,5,8,11,14,17,20-heptaone [CAS]), everolimus (Rapamycin, 42-O-(2 30 hydroxyethyl)- [CAS]), SAR-943, L-687795, 6-[(4-Chlorophenyl)sulfinyl]-2,3 80 WO 2004/060346 PCT/US2003/041580 dihydro-2-(4-methoxy-phenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, 91Y78 (1 H-Imidazo[4,5-c]pyridin-4-amine, 1-1f-D-ribofuranosyl- [CAS]), auranofin (Gold, (1-thio-rl-D-glucopyranose 2,3,4,6-tetraacetato-S)(triethylphosphine) [CAS]), 27-0-Demethylrapamycin, tipredane (Androsta-1,4-dien-3-one, 17 5 (ethylthio)-9-fluoro-11-hydroxy-17-(methylthio)-, (11 11, 17Alpha)- [CAS]), AI-402, LY-178002 (4-Thiazolidinone, 5-[[3,5-bis(1,1-dimethylethyl)-4 hydroxyphenyl]methylene]-[CAS]), SM-8849 (2-Thiazolamine, 4-[1-(2 fluoro[1 ,1'-biphenyl]-4-yl)ethyl]-N-methyl- [CAS]), piceatannol, resveratrol, triamcinolone acetonide (Pregna-1,4-diene-3,20-dione, 9-fluoro-11,21 10 dihydroxy-16,17-[(1 -methylethylidene)bis(oxy)]-, (1113,16Alpha)- [CAS]), ciclosporin (Cyclosporin A- [CAS]), tacrolimus (15,19-Epoxy-3H-pyrido(2,1 c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy 3-(2-(4-hyd roxy-3-methoxycyclohexyl)- 1 -methylethenyl)-1 4,16-dimethoxy 15 4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S (3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*)) - [CAS]), gusperimus (Heptanamide, 7-[(aminoiminomethyl)amino]-N-[2-[[4-[(3 aminopropyl)amino]butyl]amino]-1l-hydroxy-2-oxoethyl]-, (+/-)- [CAS]), tixocortol pivalate (Pregn-4-ene-3,20-dione, 21-[(2,2-dimethyl-1 -oxopropyl)thio]-1 1,17 20 dihydroxy-, (1113)- [CAS]), alefacept (1-92 LFA-3 (Antigen) (human) fusion protein with immunoglobulin G1 (human hinge-CH2-CH3 Gammal-chain), dimmer), halobetasol propionate (Pregna-1,4-diene-3,20-dione, 21-chloro-6,9 difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)-, (6Alpha,1113,1613)- [CAS]), iloprost trometamol (Pentanoic acid, 5-[hexahydro-5-hydroxy-4-(3-hydroxy-4 25 methyl-1 -octen-6-ynyl)-2(1H)-pentalenylidene]- [CAS]), beraprost (1H Cyclopenta[b]benzofuran-5-butanoic acid, 2,3,3a,8b-tetrahydro-2-hydroxy-l1-(3 hydroxy-4-methyl-1l-octen-6-ynyl)- [CAS]), rimexolone (Androsta-1,4-dien-3 one,11 -hydroxy-16,17-dimethyl-17-(1 -oxopropyl)-, (11 B,16Alpha, 1713)- [CAS]), dexamethasone (Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16 30 methyl-, (111,16Alpha)- [CAS]), sulindac (cis-5-fluoro-2-methyl-1l-[(p methylsulfinyl)benzylidene]indene-3-acetic acid), proglumetacin (1 H-Indole-3 81 WO 2004/060346 PCT/US2003/041580 acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, 2-(4-(3-((4 (benzoylamino)-5-(dipropylamino)-1,5-dioxopentyl)oxy)propyl)- 1 piperazinyl)ethylester, (+/-)- [CAS]), alclometasone dipropionate (Pregna-1,4 diene-3,20-dione, 7-chloro-11 -hydroxy-1 6-methyl-17,21 -bis(1 -oxopropoxy)-, 5 (7Alpha, 11 f, 1 6AIpha)- [CAS]), pimecrolimus (15,19-Epoxy-3H-pyrido(2,1 c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 3-(2-(4-chloro-3 methoxycyclohexyl)-1l-methyletheny)-8-ethyl 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy 14,16-dimethoxy-4,10,12,18-tetramethyl-, (3S 10 (3R*(E(1S*,3S*,4R*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*)) - [CAS]), hydrocortisone-17-butyrate (Pregn-4-ene-3,20-dione, 11,21-dihydroxy 17-(1-oxobutoxy)-, (11 R)- [CAS]), mitoxantrone (9,10-Anthracenedione, 1,4 dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]- [CAS]), mizoribine (1H-Imidazole-4-carboxamide, 5-hydroxy-l-Il-D-ribofuranosyl- [CAS]), 15 prednicarbate (Pregna-1,4-diene-3,20-dione, 17-[(ethoxycarbonyl)oxy]-1 1 hydroxy-21-(1-oxopropoxy)-, (11 1)- [CAS]), Iobenzarit (Benzoic acid, 2-[(2 carboxyphenyl)amino]-4-chloro- [CAS]), glucametacin (D-Glucose, 2-[[[1-(4 chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl]acetyl]amino]-2-deoxy [CAS]), fluocortolone monohydrate ((6AIpha)-fluoro-16AIpha-methylpregna-1,4 20 dien-11121,21-diol-3,20-dione), fluocortin butyl (Pregna-1,4-dien-21-oic acid, 6 fluoro-11 -hydroxy-16-methyl-3,20-dioxo-, butyl ester, (6Alpha, 11 R, 1 6Alpha) '[CAS]), difluprednate (Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-6,9-difluoro 11-hydroxy-17-(1 -oxobutoxy)-, (6Alpha,111 )- [CAS]), diflorasone diacetate (Pregna-1,4-diene-3,20-dione, 17,21-bis(acetyloxy)-6,9-difluoro-11-hydroxy-16 25 methyl-, (6Alpha,11 1,16f)- [CAS]), dexamethasone valerate (Pregna-1,4 diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16-methyl-17-[(1-oxopentyl)oxy]-, (111,16Alpha)- [CAS]), methylprednisolone, deprodone propionate (Pregna 1,4-diene-3,20-dione, 11-hydroxy-17-(1-oxopropoxy)-, (11 .beta.)- [CAS]), bucillamine (L-Cysteine, N-(2-mercapto-2-methyl-1 -oxopropyl)- [CAS]), 30 amcinonide (Benzeneacetic acid, 2-amino-3-benzoyl-, monosodium salt, monohydrate [CAS]), acemetacin (1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl) 82 WO 2004/060346 PCT/US2003/041580 5-methoxy-2-methyl-, carboxymethyl ester [CAS]) ) or an analogue or derivative thereof. Further, analogues of rapamycin include tacrolimus and derivatives thereof (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772). Further representative 5 examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, 10 WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179. Representative U.S. patents include U.S. Patent Nos. 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 15 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091,389. The structures of sirolimus, everolimus, and tacrolimus are provided below: 20 Name Code Name Company Structure Everolimus SAR-943 Novartis See below Sirolimus AY-22989 Wyeth See below Rapamune NSC-226080 Rapamycin Tacrolimus FK506 Fujusawa See below 83 WO 2004/060346 PCT/US2003/041580 0 o oc" Everolimus 0 Tacrolimus 5 0 0 a 0 a Sirolimus 19. Inosine monophosphate dehydrogenase inhibitors In another embodiment, the pharmacologically active compound 10 is an inosine monophosphate dehydrogenase inhibitor (e.g., Mycophenolate Mofetil (4-Hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo 84 WO 2004/060346 PCT/US2003/041580 5-isobenzofuranyl)-4-methyl-, 2-(4-morpholinyl)ethyl ester, (E)- [CAS]), ribavirin (1 H-1,2,4-Triazole-3-carboxamide, 1-1l-D-ribofuranosyl- [CAS]), tiazofurin (4 Thiazolecarboxamide, 2-f-D-ribofuranosyl- [CAS]), viramidine, aminothiadiazole, thiophenfurin, tiazofurin) or an analogue or derivative thereof. 5 Additional representative examples are included in U.S. Patent Nos. 5,536,747; 5,807;876; 5,932,600; 6,054,472, 6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518291; 6541496; 6,596,747; 6,617,323; and 6,624,184, U.S. Publication Nos. 2002/0040022A1, 2002/0052513A1, 2002/0055483A1, 2002/0068346A1, 2002/0111378A1, 10 2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1, 2002/0173491A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, 2003/0144300A1, 2003/0166201A1, 2003/0181497A1, 2003/0186974A1, 2003/0186989A1, and 2003/0195202A1, and PCT 15 Publication Nos. WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO 0056331A1, WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 02/51814A1, WO 02/57287A2, WO 02/57425A2, WO 02/60875A1, WO 02/60896A1, WO 02/60898A1, WO 20 02/68058A2, WO 03/20298A1, WO 03/37349A1, WO 03/39548A1, WO 03/45901A2, WO 03/47512A2, WO 03/53958A1, WO 03/55447A2, WO 03/59269A2, WO 03/63573A2, WO 03/87071A1, WO 90/01545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1, and WO 99/55663A1. 20. Leukotriene Inhibitors 25 In another embodiment, the pharmacologically active compound is a leukotreine inhibitor (e.g., DTI-0026, ONO-4057(Benzenepropanoic acid, 2 (4-carboxybutoxy)-6-[[6-(4-methoxyphenyl)-5-hexenyl]oxy]-, (E)- [CAS]), ONO LB-448, pirodomast 1,8-Naphthyridin-2(1 H)-one, 4-hydroxy-1l-phenyl-3-(1 pyrrolidinyl)- [CAS], Sch-40120 (Benzo[b][1,8]naphthyridin-5(7H)-one, 10-(3 30 chlorophenyl)-6,8,9,10-tetrahydro- [CAS]), L-656224 (4-Benzofuranol, 7-chloro 85 WO 2004/060346 PCT/US2003/041580 2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl- [CAS]), MAFP (methyl arachidonyl fluorophosphonate), ontazolast (2-Benzoxazolamine, N-[2 cyclohexyl-1 -(2-pyridinyl)ethyl]-5-methyl-, (S)- [CAS]), amelubant (Carbamic acid, ((4-((3-((4-(1-(4-hydroxyphenyl)-l 5 methylethyl)phenoxy)methyl)phenyl)methoxy) phenyl)iminomethyl)- ethyl ester [CAS]), SB-201993 (Benzoic acid, 3-[[[[6-[(1 E)-2-carboxyethenyl]-5-[[8-(4 methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]-[CAS]), LY-203647 (Ethanone, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1 H-tetrazol-5-yl)butyl]-2H-tetrazol 5-yl]butoxy]phenyl]- [CAS]), LY-210073, LY-223982 (Benzenepropanoic acid, 5 10 (3-carboxybenzoyl)-2-[[6-(4-methoxyphenyl)-5-hexenyl]oxy]-, (E)- [CAS]), LY 293111 (Benzoic acid, 2-[3-[3-[(5-ethyl-4'-fluoro-2-hydroxy[1,1'-biphenyl]-4 yl)oxy]propoxy]-2-propylphenoxy]- [CAS]), SM-9064 (Pyrrolidine, 1-[4,11 dihydroxy-13-(4-methoxyphenyl)-1l-oxo-5,7,9-tridecatrienyl]-, (E,E,E)- [CAS]), T 0757 (2,6-Octadienamide, N-(4-hydroxy-3,5-dimethylphenyl)-3,7-dimethyl-, 15 (2E)- [CAS]) ) or an analogue or derivative thereof. 21. MCP-1 Antagonists In another embodiment, the pharmacologically active compound is a MCP-1 antagonist (e.g., nitronaproxen (2-Napthaleneacetic acid, 6 methoxy-Alpha-methyl 4-(nitrooxy)butyl ester (AlphaS)- [CAS]), Bindarit (2-(1 20 benzylindazol-3-ylmethoxy)-2-methylpropanoic acid), 1-alpha-25 dihydroxy vitamin D 3 ) or an analogue or derivative thereof. 22. MMP Inhibitors In another embodiment, the pharmacologically active compound is a MMP inhibitor (e.g., D-9120, doxycycline (2-Naphthacenecarboxamide, 4 25 (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy 6-methyl-1,11-dioxo- [4S-(4Alpha,4aAlpha,5Alpha,5aAlpha,6Alpha,12aAlpha)] [CAS]), BB-2827, BB-1101 (2S-allyl-Nl-hydroxy-3R-isobutyl-N4-(1S methylcarbamoyl-2-phenylethyl)-succinamide), BB-2983, solimastat (N'-[2,2 Dimethyl-1 (S)-[N-(2-pyridyl)carbamoyl]propyl]-N4-hydroxy-2(R)-isobutyl-3(S) 86 WO 2004/060346 PCT/US2003/041580 methoxysuccinamide), BATIMASTAT (Butanediamide, N4-hydroxy-Nl1-[2 (methylamino)-2-oxo- 1-(phenyl m ethyl)ethyl]-2-(2-methylpropyl)-3-[(2 thienylthio)methyl]-, [2R-[1 (S*),2R*,3S*]]-[CAS]; British Biotech, UK), CH-138, CH-5902, D-1927, D-5410, EF-13 (Gamma-linolenic acid lithium salt),CMT-3 5 (2-Naphthacenecarboxamide, 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a tetrahydroxy-1,11-dioxo-, (4aS,5aR, 12aS)- [CAS]), MARIMASTAT (N-[2,2 Dimethyl-1 (S)-(N-methylcarbamoyl)propyl]-N,3(S)-dihyd roxy-2(R) isobutylsuccinamide, British Biotech, UK), TIMP'S,ONO-4817, rebimastat (L Valinamide, N-((2S)-2-mercapto-1l-oxo-4-(3,4,4-trimethyl-2,5-dioxo-1 10 imidazolidinyl)butyl)-L-leucyl-N,3-dimethyl- [CAS]), PS-508, CH-715, nimesulide (Methanesulfonamide, N-(4-nitro-2-phenoxyphenyl)- [CAS]), hexahydro-2-[2(R) [1 (RS)-(hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]-N-(2,2,6,6-etramethyl-4 piperidinyl)-3(S)-pyridazine carboxamide, Rs-113-080, Ro-1130830, Cipemastat (1-Piperidinebutanamide, RI-(cyclopentylmethyl)-N-hydroxy 15 Gamma-oxo-Alpha-[(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)methyl] ,(AlphaR, lRR)- [CAS]), 5-(4'-biphenyl)-5-[N-(4-nitrophenyl)piperazinyl]barbituric acid, 6-methoxy-1,2,3,4-tetrahydro-norharman-1l-carboxylic acid, Ro-31-4724 (L-Alanine, N-[2-[2-(hydroxyamino)-2-oxoethyl]-4-methyl-1l-oxopentyl]-L-leucyl-, ethyl ester[CAS]), prinomastat (3-Thiomorpholinecarboxamide, N-hydroxy-2,2 20 dimethyl-4-((4-(4-pyridinyloxy) phenyl)sulfonyl)-, (3R)- [CAS]), AG-3433 (1H Pyrrole-3-propanic acid, 1-(4'-cyano[1, 1'-biphenyl]-4-yl)-b-[[[(3S)-tetrahydro-4,4 dimethyl-2-oxo-3-furanyl]amino]carbonyl]-, phenylmethyl ester, (bS)- [CAS]), PNU-142769 (2H-Isoindole-2-butanamide, 1,3-dihydro-N-hydroxy-Alpha-[(3S) 3-(2-methylpropyl)-2-oxo-1l-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-, (AlphaR) 25 [CAS]), (S)-1-[2-[[[(4,5-Dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino] carbonyl]amino]-I -oxo-3-(pentafluorophenyl)propyl]-4-(2-pyridinyl)piperazine, SU-5402 (I H-Pyrrole-3-propanoic acid, 2-[(1,2-dihydro-2-oxo-3H-indol-3 ylidene)methyl]-4-methyl- [CAS]), SC-77964, PNU-171829, CGS-27023A, N hydroxy-2(R)-[(4-methoxybenzene-sulfonyl)(4-picolyl)amino]-2-(2 30 tetrahydrofuranyl)-acetamide, L-758354 ((1,1'-Biphenyl)-4-hexanoic acid, Alpha-butyl-Gamma-(((2,2-dimethyl-1 87 WO 2004/060346 PCT/US2003/041580 ((methylamino)carbonyl)propyl)amino)carbonyl)-4'-fluoro-, (AlphaS (AlphaR*,GammaS*(R*)))- [CAS]), GI-155704A, CPA-926 or an analogue or derivative thereof. Additional representative examples are included in U.S. Patent Nos. 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 5 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 10 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 15 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 20 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 25 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 30 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 88 WO 2004/060346 PCT/US2003/041580 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,691,381; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 5 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 10 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; and 6,087,359. 23. NF kappa B Inhibitors In another embodiment, the pharmacologically active compound is a NF kappa B inhibitor (e.g., Celgene (SP100030, SP100207, SP100393), 15 AVE-0545, Oxi-104 (Benzamide, 4-amino-3-chloro-N-(2-(diethylamino)ethyl) [CAS]), dexlipotam, INDRA, R-flurbiprofen ([1,1'-Biphenyl]-4-acetic acid, 2 fluoro-Alpha-methyl), SP100030 (2-chloro-N-[3,5-di(trifluoromethyl)phenyl]-4 (trifluoromethyl)pyrimidine-5-carboxamide), AVE-0545, VIATRIS, AVE-0547, Bay 11-7082, Bay 11-7085, 15 deoxy-prostaylandin J2, bortezomib (Boronic 20 acid, [(1 R)-3-methyl-1l-[[(2S)-l-oxo-3-phenyl-2 [(pyrazinylcarbonyl)amino]propyl]amino]butyl]- [CAS]) or an analogue or derivative thereof. 24. NO Agonists In another embodiment, the pharmacologically active compound 25 is a NO antagonist (e.g., NCX-4016 (Benzoic acid, 2-(acetyloxy)-, 3 ((nitrooxy)methyl)phenyl ester [CAS]), NCX-2216, L-arginine or an analogue or derivative thereof. 89 WO 2004/060346 PCT/US2003/041580 25. P38 MAP Kinase Inhibitors In another embodiment, the pharmacologically active compound is a P38 MAP kinase inhibitor (e.g., VX-745 (Vertex Pharmaceuticals, Inc., Cambridge, MA), GW-2286, SK86002, CGP-52411, BIRB-798, SB220025, RO 5 320-1195, RWJ-67657, RWJ-68354, SCIO-469, SCIO-323, AMG-548, CMC 146, SD-31145, CC-8866, Ro-320-1195, Roche (3853,4507, 6145, 8464,0945, 6257, 3391, 3470, 1151634,5274, 5161, 4194, 1195), BIX 983 (Boehringer Ingelheim), PD-98059 (4H-1-Benzopyran-4-one, 2-(2-amino-3-methoxyphenyl) [CAS]), CGH-2466, doramapimod, SB-203580 (Pyridine, 4-[5-(4-fluorophenyl) 10 2-[4-(methylsulfinyl)phenyl]-1lH-imidazol-4-yl]- [CAS]), SB-220025 ((5-(2-Amino 4-pyrimidinyl)-4-(4-fluorophenyl)-1 -(4-piperidinyl)imidazole)), SB-281832, PD169316, SB202190 or an analogue or derivative thereof. Additional representative examples are included in U.S. Patent Nos. 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874; 15 and 6,630,485, U.S. Publication Nos. 2001/0044538A1; 2002/0013354A1; 2002/0049220A1; 2002/0103245A1; 2002/0151491A1; 2002/0156114A1; 2003/0018051A1; 2003/0073832A1; 2003/0130257A1; 2003/0130273A1; 2003/0130319A1; 2003/0139388A1; 2003/0139462A1; 2003/0149031A1; 2003/0166647A1; and 2003/0181411A1; and PCT Publication Nos. WO 20 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941A2, WO 03/063799A2, WO 25 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 99/01449A1, and WO 99/58523A1. 26. Phosphodiesterase Inhibitors In another embodiment, the pharmacologically active compound is a phosphodiesterase inhibitor (e.g., CDP-840 (Pyridine, 4-[(2R)-2-[3 30 (cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]- [CAS]), CH-3697, CT-2820, 90 WO 2004/060346 PCT/US2003/041580 D-22888 (Imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7 methyl-5-propyl-[CAS]), D-4418 (8-Methoxyquinoline-5-[N-(2,5-dichloropyridin 3-yl)]carboxamide), 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichloro-4 pyridyl) ethanone oxime, D-4396, ONO-6126, CDC-998, CDC-801, V-11294A 5 (3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride), S,S'-methylene-bis(2-(8-cyclopropyl-3-propyl-6-(4 pyridylmethylamino)-2-thio-3H-purine)) tetrahyrochloride, Rolipram (2 Pyrrolidinone, 4-[3-(cyclopentyloxy)-4-methoxyphenyl]- [CAS]), CP-293121, CP 353164 (5-(3-Cyclopentyloxy-4-methoxyphenyl)pyridine-2-carboxamide), 10 oxagrelate (6-Phthalazinecarboxylic acid, 3,4-dihydro-l-(hydroxymethyl)-5,7 dimethyl-4-oxo-, ethyl ester [CAS]), PD-168787, ibudilast (1-Propanone, 2 methyl-1 -[2-(1 -methylethyl)pyrazolo[1,5-a]pyridin-3-yl]- [CAS]), oxagrelate (6 Phthalazinecarboxylic acid, 3,4-dihydro-l-(hydroxymethyl)-5,7-dimethyl-4-oxo-, ethyl ester [CAS]), griseolic acid (Alpha-L-talo-Oct-4-enofuranuronic acid, 1-(6 15 amino-9H-purin-9-yl)-3,6-anhydro-6-C-carboxy-1,5-dideoxy- [CAS]), KW-4490, KS-506, T-440, roflumilast (Benzamide, 3-(cyclopropylmethoxy)-N-(3,5 dichloro-4-pyridinyl)-4-(difluoromethoxy)- [CAS]), rolipram, milrinone, triflusinal (Benzoic acid, 2-(acetyloxy)-4-(trifluoromethyl)- [CAS]), anagrelide hydrochloride (Imidazo[2,1-b]quinazolin-2(3H)-one, 6,7-dichloro-1,5-dihydro-, 20 monohydrochloride [CAS]), cilostazol (2(1H)-Quinolinone, 6-[4-(1-cyclohexyl 1 H-tetrazol-5-yl)butoxy]-3,4-dihydro-[CAS]), propentofylline (1 H-Purine-2,6 dione, 3,7-dihydro-3-methyl-l-(5-oxohexyl)-7-propyl- [CAS]), sildenafil citrate (Piperazine, 1-((3-(4,7-dihyd ro-1 -methyl-7-oxo-3-propyl- 1 H-pyrazolo(4,3 d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl, 2-hydroxy-1,2,3 25 propanetricarboxylate- (1:1) [CAS]), tadalafil (Pyrazino(1',2':1,6)pyrido(3,4 b)indolel,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl , (6R-trans) [CAS]), vardenafil (Piperazine, 1-(3-(1,4-dihydro-5-methyl(-4-oxo-7 propylimidazo(5,1 -f)(1,2,4)-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethyl [CAS]), milrinone ([3,4'-Bipyridine]-5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo 30 [CAS]), enoximone (2H-Imidazol-2-one, 1,3-dihydro-4-methyl-5-[4 (methylthio)benzoyl]- [CAS]), theophylline (1H-Purine-2,6-dione, 3,7-dihydro 91 WO 2004/060346 PCT/US2003/041580 1,3-dimethyl- [CAS]), ibudilast (1-Propanone, 2-methyl-1-[2-(1 methylethyl)pyrazolo[1,5-a]pyridin-3-yl]- [CAS]), aminophylline (1 H-Purine-2,6 dione, 3,7-dihydro-1,3-dimethyl-, compd. with 1,2-ethanediamine (2:1)- [CAS]), acebrophylline (7H-Purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6 5 dioxo-,compd. with trans-4-[[(2-amino-3,5 dibromophenyl)methyl]amino]cyclohexanol (1:1) [CAS]), plafibride (Propanamide, 2-(4-chlorophenoxy)-2-methyl-N-[[(4 morpholinylmethyl)amino]carbonyl]- [CAS]), loprinone hydrochloride (3 Pyridinecarbonitrile, 1,2-dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-, 10 monohydrochloride- [CAS]), fosfosal (Benzoic acid, 2-(phosphonooxy)- [CAS]), amrinone ([3,4'-Bipyridin]-6(1H)-one, 5-amino- [CAS]) or an analogue or derivative thereof. 27. TGF beta Inhibitors In another embodiment, the pharmacologically active compound 15 is a TGF beta Inhibitor (e.g., mannose-6-phosphate, LF-984, tamoxifen (Ethanamine, 2-[4-(1,2-diphenyl-1l-butenyl)phenoxy]-N,N-dimethyl-, (Z)- [CAS]), tranilast or an analogue or derivative thereof. 28. Thromboxane A2 Antagonists In another embodiment, the pharmacologically active compound 20 is a thromboxane A2 antagonist (e.g., CGS-22652 (3-Pyridineheptanoic acid, .gamma.-[4-[[(4-chlorophenyl)sulfonyl]amino]butyl]-, (.+-.)- [CAS]), ozagrel (2 Propenoic acid, 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-, (E)- [CAS]), argatroban (2-Piperidinecarboxylic acid, 1-[5-[(aminoiminomethyl)amino]-1l-oxo-2-[[(1,2,3,4 tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-[CAS]), 25 ramatroban (9H-Carbazole-9-propanoic acid, 3-[[(4 fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-, (R)- [CAS]), torasemide (3 Pyridinesulfonamide, N-[[(1-methylethyl)amino]carbonyl]-4-[(3 methylphenyl)amino]- [CAS]), gamma linoleic acid ((Z,Z,Z)-6,9,12 Octadecatrienoic acid [CAS]), seratrodast (Benzeneheptanoic acid, zeta-(2,4,5 92 WO 2004/060346 PCT/US2003/041580 trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-, (+/-)- [CAS]) or an analogue or derivative thereof. 29. TNFa Antagonists / TACE Inhibitors In another embodiment, the pharmacologically active compound 5 is a TNFa Antagonist / TACE Inhibitor (e.g., Celgene (CC10037, CC-11049, CC-10004, CC10083), E-5531 (2-Deoxy-6-0-[2-deoxy-3-0-[3(R)-[5(Z) dodecenoyloxy]-decyl]-6-0-methyl-2-(3-oxotetradecanamido)-4-O-phosphono I-D-glucopyranosyl]-3-0-[3(R)-hydroxydecyl]-2-(3-oxotetradecanamido)-Alpha D-glucopyranose-1-O-phosphate), AZD-4717, glycophosphopeptical, UR-12715 10 (Benzoic acid, 2-hydroxy-5-[[4-[3-[4-(2-methyl-1 H-imidazol[4,5-c]pyridin-1 yl]methyl]-1 -piperidinyl]-3-oxo-1 -phenyl-1 -propenyl]phenyl]azo] (Z) [CAS]), PMS-601, AM-87, xyloadenosine (9H-Purin-6-amine, 9-1-D-xylofuranosyl [CAS]), RDP-58, RDP-59, BB2275, benzydamine, E-3330 (Undecanoic acid, 2 [(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1 -yl)methylene]-, (E) 15 [CAS]), N-[D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl]-L-3-(2' naphthyl)alanyl-L-alanine, 2-aminoethyl amide, CP-564959, MLN-608, SPC 839, ENMD-0997, Sch-23863 ((2-[10,11-Dihydro-5-ethoxy-5H-dibenzo [a,d] cyclohepten-S-yl]-N, N-dimethyl-ethanamine), SH-636, PKF-241-466, PKF-242 484, TNF-484A, cilomilast (Cis-4-cyano-4-[3-(cyclopentyloxy)-4 20 methoxyphenyl]cyclohexane-l-carboxylic acid), GW-3333, GW-4459, BMS 561392, AM-87, cloricromene (Acetic acid, [[8-chloro-3-[2-(diethylamino)ethyl] 4-methyl-2-oxo-2H-1-benzopyran-7-yl]oxy]-, ethyl ester [CAS]), thalidomide (1 H-Isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl)- [CAS]), vesnarinone (Piperazine, 1-(3,4-dimethoxybenzoyl)-4-(1,2,3,4-tetrahydro-2-oxo-6-quinolinyl) 25 [CAS]), infliximab, lentinan, etanercept (1-235-Tumor necrosis factor receptor (human) fusion protein with 236-467-immunoglobulin G1 (human gammal chain Fc fragment) [CAS]), diacerein (2-Anthracenecarboxylic acid, 4,5 bis(acetyloxy)-9,10-dihydro-9,10-dioxo- [CAS]) or an analogue or derivative thereof. 93 WO 2004/060346 PCT/US2003/041580 30. Tyrosine Kinase Inhibitors In another embodiment, the pharmacologically active compound is a tyrosine kinase inhibitor (e.g., SKI-606, ER-068224, SD-208, N-(6 Benzothiazolyl)-4-(2-(1-piperazinyl)pyrid-5-yl)-2-pyrimidineamine, celastrol 5 (24,25,26-Trinoroleana-1(10),3,5,7-tetraen-29-oic acid, 3-hydroxy-9,13 dimethyl-2-oxo-, (9.beta.,13Alpha,141,20Alpha)- [CAS]), CP-127374 (Geldanamycin, 17-demethoxy-17-(2-propenylamino)- [CAS]), CP-564959, PD 171026, CGP-52411 (1H-lsoindole-1,3(2H)-dione, 4,5-bis(phenylamino) [CAS]), CGP-53716 (Benzamide, N-[4-methyl-3-[[4-(3-pyridinyl)-2 10 pyrimidinyl]amino]phenyl]- [CAS]), imatinib (4-((Methyl-1 -piperazinyl)methyl)-N [4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate), NVP-AAK980-NX, KF-250706 (13-Chloro,5(R),6(S)-epoxy 14,16-dihydroxy- 11-(hydroyimino)-3(R)-methyl-3,4,5,6,11,12-hexahydro-1 H-2 benzoxacyclotetradecin-1 -one), 5-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4 15 oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethyl] 2,4-oxazolidinedione, genistein or an analogue or derivative thereof. 31. Vitronectin Inhibitors In another embodiment, the pharmacologically active compound is a vitronectin inhibitor (e.g., O-[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4 20 [(1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono]-8-benz(e)azulenyl]-N [(phenylmethoxy)carbonyl]-DL-homoserine 2,3-dihydroxypropyl ester, (2S) Benzoylcarbonylamino-3-[2-((4S)-(3-(4,5-dihydro-1 H-imidazol-2-ylamino) propyl)-2,5-dioxo-imidazolidin-1 -yl)-acetylamino]-propionate, Sch-221153, S 836, SC-68448 (fl-[[2-2-[[[3-[(aminoiminomethyl)amino] 25 phenyl]carbonyl]amino]acetyl]amino]-3,5-dichlorobenzenepropanoic acid), SD 7784, S-247 or an analogue or derivative thereof. 32. Fibroblast Growth Factor Inhibitors In another embodiment, the pharmacologically active compound is a fibroblast growth factor inhibitor (e.g., CT-052923 ([(2H-benzo[d]1,3 94 WO 2004/060346 PCT/US2003/041580 dioxalan-5-methyl)amino][4-(6,7-dimethoxyquinazolin-4-yl)piperazinyl]methane 1-thione) or an analogue or derivative thereof. 33. Protein Kinase Inhibitors In another embodiment, the pharmacologically active compound 5 is a protein kinase inhibitor (e.g., KP-0201448, NPC15437 (Hexanamide, 2,6 diamino-N-[[1-(1-oxotridecyl)-2-piperidinyl]methyl]- [CAS]), fasudil (1 H-1,4 Diazepine, hexahydro-1l-(5-isoquinolinylsulfonyl)- [CAS]), midostaurin (Benzamide, N-(2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1 -oxo-9,13 epoxy-1 H,9H-diindolo[1,2,3-gh:3',2',1'-Im]pyrrolo[3,4-j][1,7]benzodiazonin-11 10 yl)-N-methyl-, (9AIpha,10,11,13Alpha)- [CAS]),fasudil (1H-1,4-Diazepine, hexahydro-1 -(5-isoquinolinylsulfonyl)- [CAS]) or an analogue or derivative thereof. 34. PDGF Receptor Kinase Inhibitors In another embodiment, the pharmacologically active compound 15 is a PDGF receptor kinase inhibitor (e.g., RPR-127963E or an analogue or derivative thereof. 35. Endothelial Growth Factor Receptor Kinase Inhibitors In another embodiment, the pharmacologically active compound is an endothelial growth factor receptor kinase inhibitor (e.g., CEP-7055, SU 20 0879 ((E)-3-(3,5-di-tert-Butyl-4-hydroxyphenyl)-2 (aminothiocarbonyl)acrylonitrile), BIBF-1000 or an analogue or derivative thereof. 36. Retinoic Acid Receptor Antagonists In another embodiment, the pharmacologically active compound 25 is a retinoic acid receptor antagonist (e.g., etarotene (Ro-15-1570) (Naphthalene, 6-[2-[4-(ethylsulfonyl)phenyl]-1l-methylethenyl]-1,2,3,4 tetrahydro-1,1,4,4-tetramethyl-, (E)- [CAS]), (2E,4E)-3-Methyl-5-(2-((E)-2-(2,6,6 95 WO 2004/060346 PCT/US2003/041580 trimethyl-1-cyclohexen-1-yl)ethenyl)-I -cyclohexen-1-yl)-2,4-pentadienoic acid, tocoretinate (Retinoic acid, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12 trimethyltridecyl)-2H-1-benzopyran-6-yl ester, [2R*(4R*,8R*)]-(±)- [CAS]), aliretinoin (Retinoic acid, cis-9, trans-13- [CAS]), bexarotene (Benzoic acid, 4 5 (1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl)- [CAS]) or an analogue or derivative thereof. 37. Platelet Derived Growth Factor Receptor Kinase Inhibitors In another embodiment, the pharmacologically active compound is a platelet derived growth factor receptor kinase inhibitor (e.g., leflunomide (4 10 Isoxazolecarboxamide, 5-methyl-N-[4-(trifluoromethyl)phenyl]- [CAS]) or an analogue or derivative thereof. 38. Fibronogin Antagonists In another embodiment, the pharmacologically active compound is a fibrinogin antagonist (e.g., picotamide (1,3-Benzenedicarboxamide, 4 15 methoxy-N,N'-bis(3-pyridinylmethyl)- [CAS]) or an analogue or derivative thereof. 39. Antimycotic Agents In another embodiment, the pharmacologically active compound is an antimycotic agent (e.g., miconazole, sulconizole, parthenolide, rosconitine, 20 nystatin, isoconazole, fluconazole, ketoconasole, imidazole, itraconazole, terpinafine, elonazole, bifonazole, clotrimazole, conazole, terconazole (Piperazine, 1-[4-[[2-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3 dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)-, cis- [CAS]), isoconazole (1-[2 (2-6-dichlorobenzyloxy)-2-(2-,4-dichlorophenyl)ethyl]), griseofulvin 25 (Spiro[benzofuran-2(3H),l'-[2]cyclohexane]-3,4'-dione, 7-chloro-2',4,6-trimeth oxy-6'methyl-, (1 'S-trans)- [CAS]), bifonazole (1 H-Imidazole, 1-([1,1'-biphenyl] 4-ylphenylmethyl)- [CAS]), econazole nitrate (1-[2-[(4-chlorophenyl)methoxy]-2 (2,4-dichlorophenyl)ethyl]-I H-imidazole nitrate), croconazole (1 H-Imidazole, 1 96 WO 2004/060346 PCT/US2003/041580 [1-[2-[(3-chlorophenyl)methoxy]phenyl]ethenyl]- [CAS]), sertaconazole (1 H Imidazole, 1-[2-[(7-chlorobenzo[b]thien-3-yl)methoxy]-2-(2,4 dichlorophenyl)ethyl]- [CAS]), omoconazole (1 H-Imidazole, 1-[2-[2-(4 chlorophenoxy)ethoxy]-2-(2,4-dichlorophenyl)-1l-methylethenyl]-, (Z)- [CAS]), 5 flutrimazole (1H-Imidazole, 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl] [CAS]), fluconazole (1H-1,2,4-Triazole-1 -ethanol, Alpha-(2,4-difluorophenyl) Alpha-(1 H-1,2,4-triazol-1-ylmethyl)- [CAS]), neticonazole (1 H-Imidazole, 1-[2 (methylthio)-I-[2-(pentyloxy)phenyl]ethenyl]-, monohydrochloride, (E)- [CAS]), butoconazole (I H-Imidazole, 1-[4-(4-chlorophenyl)-2-[(2,6 10 dichlorophenyl)thio]butyl]-, (+/-)-[CAS]), clotrimazole (1-[(2 chlorophenyl)diphenylmethyl]-I H-imidazole) or an analogue or derivative thereof. 40. Bisphosphonates In another embodiment, the pharmacologically active compound 15 is a bisphosphonate (e.g., clodronate, alendronate, pamidronate, zoledronate, etidronate) or an analogue or derivative thereof. 41. Phospholipase Al Inhibitors In another embodiment, the pharmacologically active compound is a phospholipase Al inhibitor (e.g., loteprednol etabonate (Androsta-1,4 20 diene-17-carboxylic acid, 17-[(ethoxycarbonyl)oxy]-I 1-hydroxy-3-oxo-, chloromethyl ester, (11 I,1 7Alpha)- [CAS] or an analogue or derivative thereof. 42. Histamine H1/H2/H3 Receptor Antagonists In another embodiment, the pharmacologically active compound is a histamine H1/H2/H3 receptor antagonist (e.g., ranitidine (1,1 25 Ethenediamine, N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl] N'-methyl-2-nitro- [CAS]), niperotidine (N-[2-[[5 [(dimethylamino)methyl]furfuryl]thio]ethyl]-2-nitro-N'-piperonyl-1, 1 ethenediamine), famotidine (Propanimidamide, 3-[[[2 97 WO 2004/060346 PCT/US2003/041580 [(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)- [CAS]), roxitadine acetate HCI (Acetamide, 2-(acetyloxy)-N-[3-[3-(1 piperidinylmethyl)phenoxy]propyl]-, monohydrochloride [CAS]), lafutidine (Acetamide, 2-[(2-furanylmethyl)sulfinyl]-N-[4-[[4-(1-piperidinylmethyl)-2 5 pyridinyl]oxy]-2-butenyl]-, (Z)- [CAS]), nizatadine (1,1-Ethenediamine, N-[2-[[[2 [(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro- [CAS]), ebrotidine (Benzenesulfonamide, N-[[[2-[[[2-[(aminoiminomethyl)amino]-4 thiazoly]methyl]thio]ethyl]amino]methylene]-4-bromo- [CAS]), rupatadine (5H Benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3 10 pyridinyl)methyl]-4-piperidinylidene]-, trihydrochloride- [CAS]), fexofenadine HCI (Benzeneacetic acid, 4-[1-hydroxy-4-[4(hydroxydiphenylmethyl)-l piperidinyl]butyl]-Alpha,Alpha-dimethyl-, hydrochloride [CAS]) or an analogue or derivative thereof. 43. Macrolide Antibiotics 15 In another embodiment, the pharmacologically active compound is a macrolide antibiotic (e.g., dirithromycin (Erythromycin, 9-deoxo-11 deoxy-9,11 -[imino[2-(2-methoxyethoxy)ethylidene]oxy]-, [9S(R)]- [CAS]), flurithromycin ethylsuccinate (Erythromycin, 8-fluoro-mono(ethyl butanedioate) (ester)- [CAS]), erythromycin stinoprate (Erythromycin, 2'-propanoate, compd. 20 with N-acetyl-L-cysteine (1:1) [CAS]), clarithromycin (Erythromycin, 6-O-methyl [CAS]), azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin-A), telithromycin (3-De((2,6-dideoxy-3-C-methyl-3-O-methyl-Alpha-L-ribo hexopyranosyl)oxy)-1 1,12-dideoxy-6-O-methyl-3-oxo-12,11 -(oxycarbonyl((4-(4 (3-pyridinyl)-1 H-imidazol-1 -yl)butyl)imino))- [CAS]), roxithromycin 25 (Erythromycin, 9-[O-[(2-methoxyethoxy)methyl]oxime] [CAS]), rokitamycin (Leucomycin V, 4B-butanoate 3B-propanoate [CASI), RV-11 I (erythromycin monopropionate mercaptosuccinate), midecamycin acetate (Leucomycin V, 3B,9-diacetate 3,4B-dipropanoate [CAS]), midecamycin (Leucomycin V, 3,4B dipropanoate [CAS]), josamycin (Leucomycin V, 3-acetate 4B-(3 30 methylbutanoate) [CAS]) or an analogue or derivative thereof. 98 WO 2004/060346 PCT/US2003/041580 44. GPIIb Ilia Receptor Antagonists In another embodiment, the pharmacologically active compound is an GPIIb lia receptor antagonist (e.g., tirofiban hydrochloride (L-Tyrosine, N (butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-, monohydrochloride- [CAS]), 5 eptifibatide (L-Cysteinamide, N6-(aminoiminomethyl)-N2-(3-mercapto-1 oxopropyl)-L-lysylglycyl-L-Alpha-aspartyl-L-tryptophyl-L-prolyl -, cyclic(1->6) disulfide [CAS]) or an analogue or derivative thereof. 45. Endothelin Receptor Antagonists In another embodiment, the pharmacologically active compound 10 is an endothelin receptor antagonist (e.g., bosentan (Benzenesulfonamide, 4 (1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2' bipyrimidin]-4-yl]- [CAS]) or an analogue or derivative thereof. 46. Peroxisome Proliferator-Activated Receptor Agonists In another embodiment, the pharmacologically active compound 15 is a peroxisome proliferators-activated receptor agonist (e.g., gemfibrozil (Pentanoic acid, 5-(2,5-dimethylphenoxy)-2,2-dimethyl- [CAS]), fenofibrate (Propanoic acid, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester [CAS]), ciprofibrate (Propanoic acid, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2 methyl- [CAS]), rosiglitazone maleate (2,4-Thiazolidinedione, 5-((4-(2-(methyl 20 2-pyridinylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1) [CAS]), pioglitazone hydrochloride (2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2 pyridinyl)ethoxy]phenyl]methyl]-, monohydrochloride (+/-)- [CAS]), etofylline clofibrate (Propanoic acid, 2-(4-chlorophenoxy)-2-methyl-, 2-(1,2,3,6-tetrahydro 1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl ester [CAS]), etofibrate (3 25 Pyridinecarboxylic acid, 2-[2-(4-chlorophenoxy)-2-methyl-1 -oxopropoxy]ethyl ester [CAS]), clinofibrate (Butanoic acid, 2,2'-[cyclohexylidenebis(4,1 phenyleneoxy)]bis[2-methyl-][CAS]), bezafibrate (Propanoic acid, 2-[4-[2-[(4 chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl- [CAS]), binifibrate (3 99 WO 2004/060346 PCT/US2003/041580 Pyridinecarboxylic acid, 2-[2-(4-chlorophenoxy)-2-methyl-1l-oxopropoxy]-1,3 propanediyl ester [CAS]) or an analogue or derivative thereof. 47. Estrogen Receptor Agents In another embodiment, the pharmacologically active compound 5 is an estrogen receptor agent (e.g., estradiol, 17-p-estradiol) or an analogue or derivative thereof. 48. Somatostatin Analogues In another embodiment, the pharmacologically active compound is somatostatin or a somatostatin analogue (e.g., angiopeptin, lanretide, 10 octreotide) or an analogue or derivative thereof. 49. JNK (Jun Kinase) Inhibitors In another embodiment, the pharmacologically active compound is a JNK Kinase inhibitor (e.g., Celgene (SP600125, SPC105, SPC23105), AS-602801 (Serono)) or an analogue or derivative thereof. 15 50. Melanocortin Analogues In another embodiment, the pharmacologically active compound is a melanocortin analogue (e.g., HP228) or an analogue or derivative thereof. 51. RAF Kinase Inhibitors In yet another embodiment, the pharmacologically active 20 compound is a raf kinase inhibitor (e.g., BAY-43-9006 (N-(4-chloro-3 (trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea) or analogue or derivative thereof. 100 WO 2004/060346 PCT/US2003/041580 52. Lysylhydroxylase Inhibitors In another embodiment, the pharmacologically active compound is a lysylhydroxylase inhibitor (e.g., minoxidil), or an analogue or derivative thereof. 5 53. IKK 1/2 inhibitors In another embodiment, the pharmacologically active compound is an IKK 1/2 inhibitor (e.g., BMS-345541, SPC839) or an analogue or derivative thereof. In addition to incorporation of a fibrosis-inhibiting agent into or 10 onto the formulation, another biologically active agent can be incorporated into or onto the formulation, for example an anti-inflammatory (e.g., dexamethazone or asprin), antithrombotic agents (e.g., heparin, heparin complexes, hydrophobic heparin derivatives, aspirin or dipyridamole), and/or an antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, 15 amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir). In one aspect of the invention the pharmacologically active compound is capable of altering cellular and/or non-cellular processes involved in the development and/or maintenance of one or more processes involved in fibrosis or adhesions between tissues or between tissues and a medical device. 20 Fibrosis inducing compositions may be useful, for example, as tissue sealants, for effecting tissue adhesion, and for tissue augmentation and repair. Thus, pharmacological agents within the scope of this invention include but are not limited to those which increase one or a combination of processes such as cell division, cell secretion, cell migration, cell adhesion, extracellular matrix 25 production, cytokine (e.g., TNF alpha, IL-1, or IL-6), or other inflammatory activator (e.g., chemokines (e.g., MCP-1, IL-8)) production and/or release, angiogenesis, and/or free radical formation and/or release. Suitable fibrosis-inducing agents may be readily determined based upon the in vitro and in vivo (animal) models such as those provided in 30 Examples 34-36. 101 WO 2004/060346 PCT/US2003/041580 Numerous therapeutic compounds have been identified that are of utility in the invention. In one aspect, the fibrosis or adhesion-inducing agent is silk. Silk refers to a fibrous protein, and may be obtained from a number of sources, 5 typically spiders and silkworms. Typical silks contain about 75% of actual fiber, referred to as fibroin, and about 25% sericin, which is a gummy protein that holds the filaments together. Silk filaments are generally very fine and long - as much as 300-900 meters long. There are several species of domesticated silkworm that are used in commercial silk production, however, Bombyx mori is 10 the most common, and most silk comes from this source. Other suitable silkworms include Philosamia cynthia ricini, Antheraea yamamai, Antheraea pernyi, and Antheraea mylitta. Spider silk is relatively more difficult to obtain, however, recombinant techniques hold promise as a means to obtain spider silk at economical prices (see, e.g., U.S. Patent Nos. 6,268,169; 5,994,099; 15 5,989,894; and 5,728,810, which are exemplary only). Biotechnology has allowed researchers to develop other sources for silk production, including animals (e.g., goats) and vegetables (e.g., potatoes). Silk from any of these sources may be used in the present invention. A commercially available silk protein is available from Croda, Inc., 20 of Parsippany, N.J., and is sold under the trade names CROSILK LIQUID (silk amino acids), CROSILK 10,000 (hydrolyzed silk), CROSILK POWDER (powdered silk), and CROSILKQUAT (cocodiammonium hydroxypropyl silk amino acid). Another example of a commercially available silk protein is SERICIN, available from Pentapharm, LTD, a division of Kordia, BV, of the 25 Netherlands. Further details of such silk protein mixtures can be found in U.S. Patent. No. 4,906,460, to Kim, et al., assigned to Sorenco. Silk useful in the present invention includes natural (raw) silk, hydrolyzed silk, and modified silk, i.e., silk that has undergone a chemical, mechanical, or vapor treatment, e.g., acid treatment or acylation (see, e.g., U.S. Patent No. 5,747,015). 30 Raw silk is typically twisted into a strand sufficiently strong for weaving or knitting. Four different types of silk thread may be produced by this 102 WO 2004/060346 PCT/US2003/041580 procedure: organzine, crepe, tram and thrown singles. Organzine is a thread made by giving the raw silk a preliminary twist in one direction and then twisting two of these threads together in the opposite direction. Crepe is similar to organzine but is twisted to a much greater extent. Twisting in only one direction 5 two or more raw silk threads makes tram. Thrown singles are individual raw silk threads that are twisted in only one direction. Any of these types of silk threads may be used in the present invention. The silk used in the present invention may be in any suitable form that allows the silk to be joined with the medical implant, e.g., the silk may be in 10 thread or powder-based forms. Furthermore, the silk may have any molecular weight, where various molecular weights are typically obtained by the hydrolysis of natural silk, where the extent and harshness of the hydrolysis conditions determines the product molecular weight. For example, the silk may have an average (number or weight) molecular weight of 200 to 5,000. See, 15 e.g., JP-B-59-29199 (examined Japanese patent publication) for a description of conditions that may be used to hydrolyze silk. A discussion of silk may be found in the following documents, which are exemplary only: Hinman, M.B., et al. "Synthetic spider silk: a modular fibre" Trends in Biotechnology, 2000, 18(9) 374-379; Vollrath, F. and 20 Knight, D.P. "Liquid crystalline spinning of spider silk" Nature, 2001, 410(6828) 541-548; and Hayashi, C.Y., et al. "Hypotheses that correlate the sequence, structure, and mechanical properties of spider silk proteins" Int. J. Biol. Macromolecules, 1999, 24(2-3), 265-270; and U.S. Patent No. 6,427,933. Other representative examples of fibrosis and adhesion-inducing 25 agents include irritants (e.g., talc, talcum powder, copper, metallic beryllium (or its oxides), quartz dust, silica, crystalline silicates), polymers (e.g., polylysine, polyurethanes, poly(ethylene terephthalate), PTFE, poly(alkylcyanoactylates), and poly(ethylene-co-vinylacetate)); vinyl chloride and polymers of vinyl chloride; peptides with high lysine content; bleomycin and analogues and 30 derivatives thereof; growth factors and inflammatory cytokines involved in angiogenesis, fibroblast migration, fibroblast proliferation, ECM synthesis and 103 WO 2004/060346 PCT/US2003/041580 tissue remodeling, such as Epidermal Growth Factor (EGF) Family, Transforming Growth Factor-a (TGF- ca), Transforming Growth Factor-P3 (TGF 9-1, TGF-9-2, TGF-9-3, Platelet-derived Growth Factor (PDGF), Fibroblast Growth Factor (acidic - aFGF; and basic - bFGF), Fibroblast stimulating factor 5 1, Activins, Vascular Endothelial Growth Factor (including VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, Placental Growth Factor - PIGF), Angiopoietins, Insulin-like Growth Factors (IGF), Hepatocyte Growth Factor (HGF), Connective Tissue Growth Factor (CTGF), Myeloid Colony-stimulating Factors (CSFs), Monocyte chemotactic protein, Granulocyte-Macrophage Colony-stimulating 10 Factors (GM-CSF), Granulocyte Colony-stimulating Factor (G-CSF), Macrophage Colony-stimulating Factor (M-CSF), Erythropoietin, Interleukins (particularly IL-1, IL-8, IL-6), Tumor Necrosis Factor-a (TNF9), Nerve Growth Factor (NGF), Interferon-a, Interferon-p, histamine, endothelin-1, angiotensin II, growth hormone (GH), and synthetic peptides, analogues or derivatives of 15 these factors are also suitable for release from specific implants and devices to be described later. Other examples include CTGF (connective tissue growth factor); inflammatory microcrystals (e.g., crystalline minerals such as crystalline silicates); Monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, endothelin-1, angiotensin II, bovine collagen, bromocriptine, 20 methylsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, Thioacetamide, Fibrosin, ethanol, naturally occurring or synthetic peptides containing the Arg-Gly-Asp (RGD) sequence, generally at one or both termini, described, e.g., in U.S. Patent No. 5,997,895, and tissue adhesives, such as cyanoacrylate and crosslinked poly(ethylene glycol) - methylated 25 collagen compositions, such as CT3 (Cohesion Technolgies, Palo Alto, CA). Other examples of fibrosis-inducing agents include bone morphogenic proteins (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16). Of these BMP's, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of 30 particular utility. Bone morphogenic proteins are described, for example, in U.S. Patent Nos. 4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 104 WO 2004/060346 PCT/US2003/041580 6,432,919; and 6,534,268 and Wozney, J.M., et al. (1988) Science: 242(4885); 1528-1534. Other representative examples of fibrosis-inducing agents include components of extracellular matrix (e.g., fibronectin, fibrin, fibrinogen, collagen, 5 including fibrillar and non-fibrillar collagen, adhesive glycoproteins, proteoglycans (e.g., heparin sulphate, chondroitin sulphate, dermatan sulphate), hyaluronan, Secreted Protein Acidic and Rich in Cysteine (SPARC), Thrombospondins, Tenacin, and Cell Adhesion Molecules (including integrins, vitronectin, fibronectin, laminin, hyaluronic acid, elastin, bitronectin), and 10 proteins found in basement membranes, and fibrosin). Within various embodiments of the invention, a composition which promotes fibrosis (and/or restenosis) also includes a compound which acts to stimulate cellular proliferation. Representative examples of agents that stimulate cellular proliferation include, e.g., dexamethasone, isotretinoin, 17-3 15 estradiol, diethylstibesterol, cyclosporin A and all-trans retinoic acid (ATRA) and analogues and derivatives thereof. Other examples of agents that stimulate cellular proliferation include: Sphingosine 1-phosphate receptor agonist (e.g., FTY-720 (1,3-Propanediol, 2-amino-2-(2-(4-octylphenyl)ethyl)-,hydrochloride [CAS]; Immunostimulants, such as Imupedone (Methanone, [5-amino-2-(4 20 methyl-l-piperidinyl)phenyl](4-chlorophenyl)- [CAS]), DiaPep227; and Nerve Growth Factor Agonist, such as, e.g., NG-012 (5H,9H,13H,21H,25H, Dibenzo[k,u][1,5,9,15,19] pentaoxacyclotetracosin-5,9,13,21,25-pentone, 7,8,11,12,15,16,23,24,27,28-decahydro-2,4,18,20-tetrahydroxy-1 1 (hydroxymethyl)-7,15,23,27-tetramethyl- [CAS]), NG-121, SS-701 (2,2':6',2" 25 Terpyridine, 4'-(4-methylphenyl)-, trihydrochloride [CAS]), AMPAlex (Piperidine, 1-(6-quinoxalinylcarbonyl)- [CAS]), RGH-2716 (8-[4,4-bis(4-fluorophenyl)butyl] 3-(1,1-dimethylethyl)-4-methylene-1 -oxa-3,8-diaza-spiro[4.5] decan-2-one [CAS]), TDN-345 (1-Oxa-3,8-diazaspiro[4.5]decan-2-one, 8-[4,4-bis(4 fluorophenyl)butyl]-3-(1,1-dimethylethyl)-4-methylene- [CAS]). 30 Within various embodiments of the invention, a stent graft is coated on one aspect with a composition which promotes fibrosis (and/or 105 WO 2004/060346 PCT/US2003/041580 restenosis), as well as being coated with a composition or compound which prevents thrombosis on another aspect of the device. Representative examples of agents that inhibit thrombosis include heparin, aspirin, dipyridamole, as well as analogues and derivatives thereof. 5 In another embodiment of the invention, the drug is a hydrophobic drug. The term "hydrophobic drug" refers to drugs that are insoluble or sparingly or poorly soluble in water. As used herein, such drugs will have a solubility below 10 mg/ml, usually below 1 mg/ml, sometimes below 0.01 mg/ml, and sometimes below 0.001 mg/ml. Exemplary hydrophobic drugs include 10 certain steroids, such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone; dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, and the like; certain peptides, such as cyclosporin cyclic peptide, retinoids, such as all-cis retinoic acid, 13-trans retinoic acid, and other vitamin A and beta carotene 15 derivatives; vitamins D, E, and K and water insoluble precursors and derivatives thereof; prostaglandins and leukotrienes and their activators and inhibitors including prostacyclin (epoprostanol), and prostaglandins; tetrahydrocannabinol; lung surfactant lipids; lipid soluble antioxidants; hydrophobic antibiotics and chemotherapeutic drugs such as amphotericin B 20 and adriamycin and the like. In one aspect, the hydrophobic drug is selected from the following classes of compounds: chemotherapeutic, antibiotic, antimicrotubule, anti-inflammatory, and antiproliferative compounds. In a preferred aspect, the hydrophobic drug is selected from paclitaxel, hydrophobic paclitaxel derivatives and hydrophobic paclitaxel analogs. In another preferred 25 aspect, the hydrophobic drug is paclitaxel. The hydrophobic drug may be combined directly with Compound 1 and/or Compound 2 . Alternatively, the hydrophobic drug may be combined with a secondary carrier, e.g., a micelle, where the secondary carrier assists in solubilization and/or delivery of the drug. The drug/secondary carrier mixture is 30 then combined directly with Compound 1 and/or Compound 2 , and/or added separately to the mixture of Compound 1 and Compound 2 . The secondary 106 WO 2004/060346 PCT/US2003/041580 carrier is particularly useful in those instances where the drug is hydrophobic and does not readily dissolve in water. In one embodiment (e.g., in which the drug is hydrophobig), the drug is associated with a secondary carrier. Optionally, this drug/carrier combination is present in an aqueous buffer 5 solution that is combined with Compound 1 and/or Compound 2 and/or the reaction product thereof. Suitable secondary carriers are described herein. However, a preferred secondary carrier is described in PCT International Publication No. WO 02/072150 and U.S. Patent Application No. 10/251,659. Optional Composition Constituents 10 In addition to the reactive compounds and the drug, the compositions of the present invention may also contain other compounds, which may be included in one or both of the components of the two-component compositions, or may be separately administered. In one embodiment, these compounds may become covalently incorporated into the matrix itself by 15 becoming crosslinked to one or both of the reactive compounds after they are mixed together. In another embodiment, (e.g., if the compound was unreactive with either of the reactive compounds), the compound may be administered in such a way that it becomes physically or ionically associated with the matrix forming compounds after mixing, and thus becomes part of the matrix itself. 20 Additional compounds that may be added into the instant compositions include glycosaminoglycans and proteins. Suitable glycosaminoglycans include, inter alia, hyaluronic acid, chitin, chitosan, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin, and derivatives thereof. In another embodiment, proteins can be added for a variety 25 of purposes. For example, collagen may improve biocompatibility of the matrix, including the potential colonization by cells, promotion of wound healing, etc. Collagen and any amino group-containing proteins would also contribute to the structural integrity of the matrix by becoming crosslinked thereto along with the other matrix components. In particular, if PEG-succinimidyl esters are used, 30 the amide bonds formed with collagen will be more stable to hydrolytic 107 WO 2004/060346 PCT/US2003/041580 degradation than the bonds formed by the reaction of succinimidyl esters and sulfhydryls. Suitable proteins include, inter alia, collagen, fibronectin, gelatin and albumin, as well as peptide fragments thereof. Particularly preferred is 5 collagen, which may be in the form of afibrillar, microfibrillar or fibrillar collagen. Types I and Ill collagen isolated from bovine corium or human placenta, or prepared by recombinant DNA methods, are suitable. See PCT WO 90/05755 for a description of suitable collagens and collagen derivatives. It should be understood that when adding collagen to the composition, it is important to 10 adjust the concentration of the other composition components to avoid precipitation. Additional constituents which may be added to the composition include antibiotics, growth factors, hemostatic proteins (such as thrombin, fibrin, fibrinogen, blood factors, etc.), cells, genes, DNA, etc. 15 In one aspect, the compositions of the present invention include one or more preservatives or bacteriostatic agents, present in an effective amount to preserve the composition and/or inhibit bacterial growth in the composition, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propyl hydroxybenzoate, erythromycin, 20 chlorocresol, benzalkonium chlorides, and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. In one aspect, the compositions of the present invention include one or more bactericidal (also known as bacteriacidal) agents. 25 In one aspect, the compositions of the present invention include one or more antioxidant, present in an effective amount. Examples of the antioxidant include sulfites and ascorbic acid. In one aspect, the compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which will be present 30 in an effective amount to impart observable coloration to the composition, e.g., the gel. Examples of coloring agents include dyes suitable for food such as 108 WO 2004/060346 PCT/US2003/041580 those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. Optional Composition Properties and Packaqing 5 In one aspect, the compositions of the present invention are sterile. Many pharmaceuticals are manufactured to be sterile and this criterion is defined by the USP XXII <1211> where the term "USP" refers to U.S. Pharmacopeia (see www.usp.org, Rockville, MD). Sterilization in this embodiment may be accomplished by a number of means accepted in the 10 industry and listed in the USP XXII <1211>, including gas sterilization, ionizing radiation or, when appropriate, filtration. Sterilization may be maintained by what is termed asceptic processing, defined also in USP XXII <1211>. Acceptable gases used for gas sterilization include ethylene oxide. Acceptable radiation types used for ionizing radiation methods include gamma, for instance 15 from a cobalt 60 source and electron beam. A typical dose of gamma radiation is 2.5 MRad. Filtration may be accomplished using a filter with suitable pore size, for example 0.22 pm and of a suitable material, for instance Teflon. In another aspect, the compositions of the present invention are contained in a container that allows them to be used for their intended purpose, 20 i.e., as a pharmaceutical composition. Properties of the container that are important are a volume of empty space to allow for the addition of a constitution medium, such as water or other aqueous medium, e.g., saline, acceptable light transmission characteristics in order to prevent light energy from damaging the composition in the container (refer to USP XXII <661>), an acceptable limit of 25 extractables within the container material (refer to USP XXII), an acceptable barrier capacity for moisture (refer to USP XXII <671>) or oxygen. In the case of oxygen penetration, this may be controlled by including in the container, a positive pressure of an inert gas, such as high purity nitrogen, or a noble gas, such as argon. 109 WO 2004/060346 PCT/US2003/041580 Typical materials used to make containers for pharmaceuticals include USP Type I through III and Type NP glass (refer to USP XXII <661>), polyethylene, polytetrafluoroethylene (e.g., TEFLON from E. I. DuPont De Nemours and Company, Wilmington, DE), silicone, and gray-butyl rubber. For 5 parenterals, USP Types I to III glass and polyethylene are preferred. Incorporation of biologically active agents into the compositions Biologically active agents can be incorporated directly into the composition or they can be incorporated into a secondary carrier. Accordingly, a secondary carrier is another optional constituent of the compositions of the 10 present invention. For direct incorporation of the biologically active agent, the agent may or may not contain electrophilic or nucleophilic group or groups that can react with either the activated functional groups of the synthetic polymer of the composition. The biologically active agents can be incorporated into the composition before the components of the composition are brought together to 15 produce the crosslinked composition or after the components of the composition are brought together to form the crosslinked composition. The biologically active agent can be admixed with either of the starting components, admixed with both of the starting components, admixed with the admix of both starting components, admixed with either or both of the starting components at 20 the time of application or incorporated into the composition at a time after the starting components have been mixed or reacted with each other. A combination of these methods may also be used to incorporate the biologically active agent into the composition. The presence of the appropriate electrophilic or nucleophilic groups on the biologically active agent will allow the biologically 25 active agent to be incorporated into the final composition via chemical bonds. The absence of the appropriate electrophilic or nucleophilic groups on the biologically active agent will allow the biologically active agent to be incorporated into the final composition via physical entrapment, electrostatic interactions, hydrogen bonding, hydrophobic interactions, Van Der Waals 30 interactions or a combination of these interactive forces. A single biologically 110 WO 2004/060346 PCT/US2003/041580 active agent may be directly incorporated into the composition or a combination of biologically active agents may be incorporated into the composition using any of the possible approaches described above. For the incorporation of the biologically active agent into the 5 composition via the use of a secondary carrier, which is a preferred embodiment when the drug is hydrophobic, the biologically active agent can be incorporated into the secondary carrier by covalent linking to the secondary carrier, physical entrapment, adsorption, electrostatic interactions, hydrophobic interactions, partitioning effects, precipitation in the secondary carrier or a 10 combination of these interactions. This biologically active agent/secondary carrier composition can then be incorporated directly into the composition (either with Compound 1 or with Compound 2 or with both Compound 1 and Compound 2 ) or they can be used as a separate component of the composition. The secondary carriers that can be used to incorporate these 15 biologically active agents may be in the form of particulates, microparticles, nanoparticles, nanocrystals, microspheres, nanospheres, liposomes, micelles, emulsions, microemulsions, dispersions, inclusion complexes, non-ionic surfactant vesicles (NISV), niosomes, proniosomes, cochleates, immunostimulating complexes (ISCOMs) and association complexes. In one 20 embodiment, the microparticles, nanoparticles or microspheres can be prepared using polymers and copolymers that include one or more of the residue units from the following monomers: D-lactide, L-lactide, D,L-lactide, glycolide, s-caprolactone, trimethylene carbonate, 1,4-dioxane-2-one, or 1,5 dioxepan-2one. In another embodiment, the microparticles, nanoparticles, or 25 microspheres can be prepared using block copolymers of the for A-B, A-B-A or B-A-B where A is a poly(alkylene oxide) (e.g., poly(ethylene glycol), poly(propylene glycol), copolymers of ethylene oxide and propylene oxide, or mono-alkyl ethers thereof) and be is a degradable polyester, for example polymers and copolymers comprising one or more of the residue units of the 30 monomers D-lactide, L-lactide, D,L-lactide, glycolide, e-caprolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2-one). Micelles 111 WO 2004/060346 PCT/US2003/041580 can be prepared using small molecule surfactants (e.g., SDS) or polymeric compositions (e.g., PLURONIC F127 or PLURONIC F68 (both available from BASF Corporation, Mount Olive, NJ), block copolymers of the form A-B, A-B-A or B-A-B, where A is a poly(alkylene oxide) e.g., poly(ethylene glycol), 5 poly(propylene glycol), copolymers of ethylene oxide and propylene oxide, or mono-alkyl ethers thereof) and B is a degradable polyester, for example polymers and copolymers comprising one or more of the residue units of the monomers D-lactide, L-lactide, D,L-lactide, glycolide, s-caprolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2-one). Albumin, 10 alginate, gelatin, starch, collagen, chitosan, poly(anhydrides), poly(orthoesters), poly(phosphazines) can also be used to prepare these secondary carriers. Liposome compositions can include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine as well as any of the commercially available lipids (for example, lipids available from Avanti Polar Lipids). Non-polymeric 15 compounds such as sucrose derivatives (e.g., sucrose acetate isobutyrate, sucrose oleate); sterols such as cholesterol, stigmasterol, P3-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; 012 -024 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C18 -C 36 mono-, di- and triacylglycerides such 20 as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose 25 distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C16 -C18 fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids such as stearic anhydride; 30 phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof; 112 WO 2004/060346 PCT/US2003/041580 sphingosine and derivatives thereof; spingomyelins such as stearyl, palmitoyl, and tricosanyl spingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols, calcium phosphate can also be used as part of the secondary carrier composition. 5 In one embodiment, one or more additives can be added to the drug component, the PEG components or the secondary carriers in order to modulate the pH or the composition and/or release of the drug from the composition. These additives can include neutral, positively or negatively charged lipids, fatty acids, amino-containing molecules or bile salts. Specific 10 examples of additives that can be used include histidine, spermidine, 1,2 dipalmitoyl-sn-glycero-3-phosphoethanolamine, 3-ethylphosphocholine chloride, palmitic acid or cholic acid. The biologically active agent/secondary carrier composition can be admixed with either of the starting components, admixed with both of the 15 starting components, admixed with the admix of both starting components, admixed with either or both of the starting components at the time of application or incorporated into the composition at a time after the starting components have been mixed or reacted with each other. A combination of these methods may also be used to incorporate the biologically active agent/secondary carrier 20 into the composition. The biologically active agent/secondary carrier composition can contain groups that may or may not be able to react with the electrophilic or nucleophilic groups of the starting components. In one embodiment, the secondary carrier does not contain electrophilic or nucleophilic groups that can 25 react with the starting polymer components, in which case the secondary carrier/biologically active agent is retained within the final composition through physical entrapment, hydrophobic, hydrogen bonding, Van der Waals interactions, electrostatic interactions or a combination of these interactive forces. 30 In another embodiment, the biologically active agent/secondary carrier composition may contain functional groups that can react with either the 113 WO 2004/060346 PCT/US2003/041580 electrophilic or nucleophilic groups of the starting components. Under these circumstances, the biologically active agent/secondary carrier composition is retained in the final composition via covalent bonds. Other interactions such as physical entrapment, hydrophobic, hydrogen bonding, Van der Waals 5 interactions, electrostatic interactions or a combination of these interactive forces may also contribute to the retention of the biologically active agent/secondary carrier in the final composition. Compounds containing one or more of the following functional groups:-NH 2 , -SH, -OH, -PH 2 , -CO-NH-NH 2 , -CO 2
N(COCH
2 ), -CO 2 H, -CHO, 10 -CHOCH 2 , -N=C=-O, -SO 2
CH=CH
2 , -N(COCH 2
)
2 , -S-S-(C 5
H
4 N), CH 2 =CH-,
CH
2 =CH-COO-, CH 2 =CH-CO-NH- etc. are compounds that can be incorporated into the secondary carriers thereby providing the secondary carriers with functional groups that are capable of reacting with the starting components of the crosslinked composition. 15 Examples of useful amino compounds that can be incorporated into the secondary carriers to provide functional groups on the secondary carrier include phosphatidyl ethanolamine lipids (for example, Avanti Polar Lipids, Inc. Catalogue # 850757, 850756, 850759, 850801, 850758, 850802, 850804, 850806, 850697, 850699, 850700, 850702, 850745, 850705, 850402, 20 850706, 830756C, 830756P, 850715, 850725, 85T725, 850755, 850795, 850800, 850797, 870125, 870122, 870140, 870142, 856705, 856715, 846725), alkyl amines, aryl amines, and cycloalkyl amines. Examples of useful thiol compounds that can be incorporated into the secondary carriers to provide functional groups on the secondary carrier 25 includes 1,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol (Sodium Salt) (Avanti Polar Lipids, Catalogue # 870160), alkyl thiols, and aryl thiols. Other methods of incorporated a drug with Compound, and Compound 2 are illustrated in PCT International Publication No. WO 00/09087. The cells or genes may be either allogeneic or xenogeneic in 30 origin. For example, the compositions can be used to deliver cells or genes from other species which have been genetically modified. Because the 114 WO 2004/060346 PCT/US2003/041580 compositions of the invention are not easily degraded in vivo, cells and genes entrapped within the crosslinked polymer compositions will be isolated from the patient's own cells and, as such, will not provoke an immune response in the patient. In order to entrap the cells or genes within a crosslinked polymer 5 matrix, the first polymer and the cells or genes may be pre-mixed, then the second polymer is mixed into the first polymer/cell or gene mixture to form a crosslinked matrix, thereby entrapping the cells or genes within the matrix. As discussed above for biologically active agents, when used to deliver cells or genes, the synthetic polymers preferably also contain 10 biodegradable groups to aid in controlled release of the cells or genes at the intended site of delivery. Composition Formulatidn The compositions of the present invention comprise two separate parts, or "components", which may be in liquid or solid form. In a preferred 15 embodiment, both components are liquids, such that each can be easily applied separately to the site of administration. Accordingly, one of the components may be in the form of a dry powder that becomes mixed with the second component, which is in liquid form, when each are sprayed separately onto the tissue, or by mixing at the tissue site. It is also possible to have both 20 components delivered to the site as powders, to be mixed with buffer at the site of administration. In an alternative embodiment, both components can be mixed together in a single aqueous medium in which they are both unreactive, i.e., such as in a low pH buffer. Thereafter, they can be sprayed onto the tissue site 25 along with a high pH buffer, after which they will rapidly react and form a gel. The concentration of the reactive compounds in each of the composition components necessarily depends on a number of factors. For example, if the composition components are each 4-arm PEGs (i.e., PEG-PEG compositions), a concentration of 20-25% by weight in each of the two 30 components before mixing results in a gel after mixing with an elastic modulus, 115 WO 2004/060346 PCT/US2003/041580 G', of approximately 10 5 -106 dynes/cm 2 , which is adequate for use as a surgical sealant. Using methylated collagen and 4-arm succinimidyl PEG, concentrations of 2-4% and 0.2-0.4%, respectively, result in gels with cohesive strengths that are comparable to PEG-PEG gels by about 10-15%. Using 5 albumin as one of the components, concentrations of 30% or more achieve a similar cohesive strength. The appropriate concentration of the compound, and other optional ingredients, in each component, and thus the relative concentration of the matrix components in the final gel matrix, can easily be optimized to achieve the desired gelation time and gel strength using routine 10 experimentation. Using the preferred four-arm PEGs described above, the synthetic polymer is generally present at a concentration of 2 to 50% (w/v), and more preferably 10-25%. The liquid components of the compositions of the present invention are each separately prepared by adding the activated synthetic 15 polymer (in dry form or as a concentrated solution) to a liquid medium. Suitable liquid media include aqueous buffer solutions, such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM. In general, the sulfhydryl-reactive PEG is prepared in water or a dilute buffer, with a pH of 20 between around 2 to 6. Buffers with pHs between about 8 to 10.5 for preparing the sulfhydryl-PEG component are useful to achieve fast gelation time of compositions containing mixtures of sulfhydryl-PEG/SG-PEG. These include carbonate, borate and AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]2 hydroxy-propane-sulfonic acid). In contrast, using a combination of maleimidyl 25 PEG and sulfhydryl-PEG, a pH of around 5 to 9 is preferred for the liquid medium used to prepare the sulfhydryl PEG. A particularly preferred composition for hemostatic applications to actively bleeding tissue sites comprises a mixture of maleimidyl and succinimidyl PEG as the first component, and sulfhydryl PEG as the second component. Such compositions 30 produce gels with enhanced biodegradability and superior gel times when 116 WO 2004/060346 PCT/US2003/041580 compared to compositions having only maleimidyl PEG or succinimicyl PEG alone. The pH of the aqueous buffer solution that is used for each of the two (or more) composition components should be adjusted using routine 5 optimization to achieve a final pH that is conducive to rapid gelation, without causing instantaneous gelation which interferes with the delivery process. For example, both amino PEG and sulfhydryl PEG need a basic pH to enhance nucleophilicity. The effects of pH on gel time are discussed below in the Examples. 10 Use and Administration The compositions of the present invention are generally delivered to the site of administration in such a way that the two (or more) individual reactive components of the composition come into contact with one another for the first time at the site of administration, or immediately preceding 15 administration to the tissue. Thus, the compositions of the present invention are preferably delivered to the site of administration using an apparatus that allows the two components to be delivered separately. Such delivery systems usually involve two-compartment single exit or dual exit spray devices. Alternatively, the two reactive components can be delivered separately using 20 any type of controllable extrusion system, or they can be delivered manually in the form of separate pastes, liquids or dry powders, and mixed together manually at the site of administration. Many devices that are adapted for delivery of two-component tissue sealants/hemostatic agents are well known in the art and can also be used in the practice of the present invention. In this 25 regard, see, for example, U.S. Patent No. 6,328,229. Yet another way of delivering the compositions of the present invention is to prepare the two reactive components (or the single reactive component in the case of sulfhydryl-containing components that are designed to form disulfide bonds) in inactive form as either a liquid or powder. Such 30 compositions can then be activated after application to the tissue site, or 117 WO 2004/060346 PCT/US2003/041580 immediately beforehand, by applying an activator. In one embodiment, the activator is a buffer solution having a pH that will activate the composition once mixed therewith. See Example 12 for a description of a sulfhydryl-containing PEG composition that is maintained at a low pH until administration, then mixed 5 with a high pH buffer at the application site to initiate gelation. The compositions of the present invention can be used in a variety of different pharmaceutical applications. In general, the compositions described herein can be adapted for use in any tissue engineering application where synthetic gel matrices are currently being utilized. For example, the 10 compositions of the present invention are useful as tissue sealants, in tissue augmentation, in tissue repair, as hemostatic agents, in preventing tissue adhesions, in providing surface modifications, and in drug/cell/gene delivery applications. One of skill in the art could easily determine the appropriate administration protocol to use with any composition having a known gel 15 strength and gelation time based on the principles described herein and well known scientific principles. A more detailed description of several specific applications is given below: Tissue Sealants & Adhesives In a preferred application, the compositions described herein can 20 be used for medical conditions that require a coating or sealing layer to prevent the leakage of gases, liquid or solids. The method entails applying both components to the damaged tissue or organ to seal 1) vascular and or other tissues or organs to stop or minimize the flow of blood; 2) thoracic tissue to stop or minimize the leakage of air; 3) gastrointestinal tract or pancreatic tissue to 25 stop or minimize the leakage of fecal or tissue contents; 4) bladder or ureters to stop or minimize the leakage of urine; 5) dura to stop or minimize the leakage of CSF; and 6) skin or serosal tissue to stop the leakage of serosal fluid. These compositions may also be used to adhere tissues together such as small vessels, nerves or dermal tissue. The material can be used 1) by 30 applying it to the surface of one tissue and then a second tissue may be rapidly 118 WO 2004/060346 PCT/US2003/041580 pressed against the first tissue or 2) by bringing the tissues in close juxtaposition and then applying the material. Surgical Adhesions Another application is a method of reducing the formation of 5 adhesions after a surgical procedure in a patient. The method entails applying the material onto the damaged tissue or organ either by spraying both components together or by applying previously admixed components. The components will react together to form a hydrogel on the tissue surface. The medical procedures include gynecological, abdominal, neurosurgical, cardiac, 10 tendon and orthopedic indications. General Procedure A Sprague Dawley rats are prepared for surgery by anaesthetic induction with 5% halothane in an enclosed chamber. Animals are transferred to the surgical table, and anaesthesia maintained by nose cone on halothane 15 throughout the procedure and Buprenorphen 0.035 mg/kg is injected intramuscularly. The abdomen is shaved, sterilized, draped and entered via a midline incision. The caecum is lifted from the abdomen and placed on sterile gauze dampened with saline. Dorsal and ventral aspects of the caecum are scraped a total of 45 times over the terminal 1.5 cm using a #10 scalpel blade, 20 held at a 450 angle. Blade angle and pressure are controlled to produce punctuated bleeding, while avoiding severe tissue damage or tearing. The left side of the abdominal cavity is retracted and everted to expose a section of the peritoneal wall nearest the natural resting caecal location. The exposed superficial layer of muscle (transverses abdominis) is 25 excised over an area of 1.0 X 1.5 cm 2 . Excision includes portions of the underlying internal oblique muscle, leaving behind some intact and some torn fibres from the second layer. Minor local bleeding is tamponaded until controlled. 119 WO 2004/060346 PCT/US2003/041580 A test formulation is deployed at the wounded areas, on the abraded sidewall, between the caecum and sidewall. The formulation is deployed using either a syringe spray system or an air-assisted syringe system. The abraded caecum is then positioned over the sidewall wound and sutured at 5 four points immediately beyond the dorsal corners of the wound edge. The large intestine is replaced in a natural orientation continuous with the caecum. The abdominal incision is closed in two layers with 4-0 silk sutures. Healthy subjects are followed for one week, and then euthanized by lethal injection for post mortem examination to score. Severity of post 10 surgical adhesions is scored by independently assessing the tenacity and extent of adhesions at the site of caecal-sidewall abrasion, at the edges of the abraded site, and by evaluating the extent of intestinal attachments to the exposed caecum. Adhesions are scored on a scale of 0-4 with increasing severity and tenacity. The extent of adhesion is scored as a percent of the 15 injured area that contained adhesions. General Procedure B Female New Zealand white rabbits weighing between 3-4 kg are used for surgeries. The animals are acclimated in the vivarium for a minimum of 5 days prior to study initiation and housed individually. Animals are 20 anesthetized by a single injection of ketamine hydrochloride (35 mg/kg) and xylanzine hydrochloride (5 mg/kg). Once sedated, anesthesia is induced with halothane or isofluorane delivered through a mask until the animal is unconscious, when an endotracheal tube is inserted for delivery of halothane or isofluorane to sustain surgical anesthesia. The abdomen is shaved, swabbed 25 with antiseptic, and sterile-draped for surgery. A midline vertical incision 6-7 cm in length is made with a #10 scalpel blade. The uterine horns are brought through the incision and each horn is abraded 20 times in each direction with a #10 scalpel blade held at a 450 angle. A region of the uterine horn, approximately 2 cm in length is abraded along the circumference of the horn, 30 beginning 1 cm from the ovaric end. This injury results in generalized erythema 120 WO 2004/060346 PCT/US2003/041580 without areas of active bleeding. Each side of the abdominal cavity is retracted and everted to expose a section of the peritoneal wall nearest the natural resting location of the horn. The sidewall apposed to the abraded uterine horn is injured by removing a 2.0 X 0.5 cm 2 area of the peritoneum. The abraded 5 uterine horn is then positioned over the sidewall wound and sutured at four points of the wound edge. Following completion of the abrasion, before closure, animals are randomized into treatment and non-treatment groups. Treated animals have approximately 1 ml of the desired formulation applied to each horn at the site of attachment to the sidewall. Healthy subjects are 10 followed for one week, and then euthanized by lethal injection for post mortem examination to score the severity of inflammation and adhesions using established scoring systems. Post-surgical adhesions are scored by independently assessing the extent, severity and tenacity of adhesions of each horn to the peritoneal sidewall. Adhesions are scored on a scale of 0-4 15 depending involvement of the horn in adhesions and a scale of 0-3 with increasing severity and tenacity. EXAMPLES EXAMPLE 1 PREPARATION OF A Two-COMPONENT TISSUE SEALANT COMPOSITION 20 a. First Component Pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate ("SG-PEG") (mol. wt. 10,000) is dissolved in 0.5 mM sodium phosphate pH 6.0 at a concentration of 20% w/v. (This solution is not stable in aqueous media due to the susceptibility of the active ester to hydrolysis and 25 should be used within one hour of preparation). b. Second Component Pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl (mol. wt. 10,000) is dissolved in 300 mM sodium phosphate/sodium carbonate buffer ("P/C buffer"), pH 9.6, at a concentration of 20% w/v. P/C buffer is prepared as 121 WO 2004/060346 PCT/US2003/041580 follows: 300 mM sodium monobasic phosphate is mixed with 300 mM sodium carbonate to achieve pH 9.6. The final molarity is approximately 117 mm phosphate and 183 mM carbonate. This solution is stable in aqueous media, but care should be taken to prevent the exposure of the solution to oxygen to 5 prevent oxidation to disulfide. Although pH is preferred for certain compositions, a pH of 8 to 10.5 is generally believed to be suitable for use in the practice of the present invention. EXAMPLE 2 SURGICAL SEALING OF ARTERIES 10 The right carotid artery of New Zealand white rabbits is exposed. The rabbits are treated with 200 U/kg of heparin and the vessel is clamped proximally and distally using atraumatic vascular clamps. A puncture hole is made in the carotid artery using a 27G needle. The control rabbits are treated with tamponade until hemostasis is achieved. For the treated rabbits, 15 approximately 0.5 mL of each of the two components of the compositions prepared as described in Example I are delivered to the defect site using a two component sprayer (Duo Flow, Hemaedics, Malibu, Calif.). After the material is allowed to set for 30 sec, the clamps are removed and the time to hemostasis and the blood loss are measured. The arteries of the control rabbits also 20 remain clamped for 30 sec for consistency. The results are shown in Table 1. TABLE 1 Blood Loss and Time to Hemostasis as a Function of Treatment Treatment Blood Loss (g) Time to Hemostasis (sec) Tamponade (n = 18) 5.7 ± 3.4 144 ± 34 Hydrogel (n = 17) 1.0 ± 2.5 31 ± 65 The above results illustrate that the composition significantly reduces the amount of blood loss and time to hemostasis from a punctured 25 artery. 122 WO 2004/060346 PCT/US2003/041580 EXAMPLE 3 SURGICAL SEALING OF AN EPTFE GRAFT The dogs are treated with heparin to achieve an activated clotting time of greater than 480 sec. The left iliac of the dogs is exposed and isolated 5 using atraumatic vascular clamps placed distally and proximally. A 5 cm segment of the artery is excised and replaced with an ePTFE (polythetrafluoroethylene) graft of the same diameter. Prior to the completion of the anastamosis, the graft was de-aired using a 27G needle. Approximately 3.0 mL of each of the two components of the composition prepared according to 10 Example 1 is delivered to the defect site using a two component sprayer (Cohesion Technologies, Inc., Palo Alto, Calif.). After the material is allowed to set for 30 sec, the clamps are removed and the time to hemostasis and the blood loss are measured. The procedure was repeated on the left iliac, with the exception of material application. The right iliac received only tamponade 15 treatment. The results are shown in Table 2. TABLE 2 Blood Loss and Time to Hemostasis as a Function of Treatment Treatment Blood Loss (g) Time to Hemostasis (sec) Tamponade (n = 2) 244,180 >15, >15 Hydrogel (n = 2) 18, 7 3.3, 2.3 The above results illustrate that this composition significantly reduces the amount of blood loss and time to hemostasis from an ePTFE 20 anastamosis. EXAMPLE 4 ENHANCED BIOCOMPATIBILITY OF THIOESTER-LINKED FORMULATIONS Up to six subcutaneous pockets are made on the backs of New Zealand white rabbits. Approximately 1.0 mL of each of the components of the 123 WO 2004/060346 PCT/US2003/041580 composition described in Example 1 is delivered to the defect site using a two component sprayer (Cohesion Technologies, Inc., Palo Alto, Calif.) for liquid formulations or a spatula for formulations that are gelled ex-vivo. The grading key is shown in Table 3 and the results are shown in Table 4. 5 TABLE 3 Grading Key for Biocompatibiltiy Experiments Score Gross Observations Histological Observations - All tissues appeared normal all tissues appeared normal, no inflammation + mild foreign body response mild inflammation ++ moderate foreign body response moderate inflammation +++ marked foreign body response marked inflammation ++++ Severe foreign body response severe inflammation TABLE 4 Results for Biocompatibility Experiments Results Gross Histological Obser- Obser Test Description vations vations A Surgical control - + B Fibrillar collagen - + C 20% w/v tetra-SG PEG 10,000 ++++ ++++ 20% w/v tetra-amino PEG 10,000 D 20% w/v tetra-SG PEG 10,000 ++ ++ 20% w/v tetra-sulfhydryl PEG 10,000 E 20% w/v tetra-SG PEG 10,000 + ++ 20% w/v tetra-amino PEG 10,000; gelled ex-vivo; treated with mono-SG PEG 5000 F 20% w/v tetra-SG PEG 10,000 ++++ ++++ 20% wiv di-sulfhydryl PEG 3,400; gelled ex-vivo; treated with di-amino PEG 3400 Experiments A and B show a mild gross and histological response of fibrillar collagen (Cohesion Technologies, Palo Alto, CA) and the surgical 10 control. Experiment C shows a severe response to hydrogels made with amino-PEG. The response consists of thick encapsulation of the hydrogel and abscess formation. By substitution of sulfhydryl-PEG for amino-PEG, as in Experiment D, the biocompatibility of the hydrogel is significantly improved. 124 WO 2004/060346 PCT/US2003/041580 Experiment E involves forming an amino hydrogel ex-vivo and incubating the hydrogel in a solution of mono-SG PEG, 5000 mol. wt. During the incubation period, the mono-SG PEG reacts with the free amines present on the hydrogel network, thus reducing the amount of free amines on the polymeric network. 5 This treatment enhances the biocompatibility of the hydrogel. Experiment F involves forming a sulfhydryl hydrogel ex-vivo and incubating the hydrogel in a solution of mono-SG PEG, 5000 mol. wt. During the incubation period, the di amino PEG reacts with the free SG groups present on the hydrogel network, thus increasing the amount of free amines on the polymeric network. This 10 treatment decreases the biocompatibility of the hydrogel. Thus, these results show the enhanced biocompatibility of sulfhydryl formulations over amino formulations. EXAMPLE 5 EFFECT OF BUFFER AND REACTIVE GROUP ON GEL TIMES 15 A desirable characteristic of the compositions described herein is their ability to rapidly achieve gelation. In this experiment, the effects of buffer strength and composition on gelation kinetics are studied. For all experiments, the tetra-functional SG PEG described in Example 1 is dissolved in 0.5 mM sodium phosphate, pH 6.0, and the tetra-sulfhydryl PEG described in Example 20 1, or the equivalent tetra-amino PEG is dissolved in the buffer listed in Table 5. 125 WO 2004/060346 PCT/US2003/041580 TABLE 5 Effect of Phosphate vs. Carbonate Buffer on Amino and Sulfhydryl Fomulations Gel Time Test Formulation Buffer (sec) A 10% w/v tetra-SG PEG 10,000 + 300 mM 16 10% w/v tetra-amino PEG 10,000 dibasic sodium phosphate pH 9 B 10% w/v tetra-SG PEG 10,000 + 300 mM 55 10% w/v tetra-sulfhydryl PEG 10,000 dibasic sodium phosphate pH 9 C 10% w/v tetra-SG PEG 10,000 + 300 mM 14 10% w/v tetra-amino PEG 10,000 sodium carbonate pH 9 D 10% wlv tetra-SG PEG 10,000 + 300 mM 9 10% wiv tetra-sulfhydryl PEG 10,000 sodium carbonate pH 9 E 10% wlv tetra-SG PEG 10,000 + P/C Buffer 3 10% w/v tetra-sulfhydryl PEG 10,000 pH 9.6 Experiments A and B show the difference in gel times in amino formulations and sulfhydryl formulations in phosphate buffer. In this buffer, an 5 increase in gelation rate is observed for sulfhydryl formulations compared to amino formulations. Experiments C and D show the difference in gelation times in amino formulations and sulfhydryl formulations in carbonate buffer. As shown, a decrease in gel time is observed for sulfhydryl formulations in carbonate buffer. In the preferred P/C Buffer, a gel time of 3 seconds is 10 observed. EXAMPLE 6 RHEOMETRIC MEASUREMENTS The first component (tetra-functional Sulfhydryl-PEG, 10,000 mol. wt.) was prepared according to Example 1 and suspended in P/C Buffer. The 15 second component (tetra-functional SG-PEG, 10,000 mol. wt.) was prepared according to Example 1 in 0.5 mM phosphate, pH 6.0. The two components (0.6 ml each) were loaded in a dual-syringe device with joiner and cannula. The cannula contained a mixing element. The solutions were mixed, and the resultant mixture was immediately delivered into a parallel plate cell of a 20 Rheometrics Fluids Spectrometer 8500 (Rheometrics, Inc., Piscataway, NJ). 126 WO 2004/060346 PCT/US2003/041580 The upper platen had a diameter of 25 mm, and the gap between upper and lower parallel plates was 1.5 mm. Gelation began immediately upon mixing of the formulation. The instrument was started, and G' and G" (elastic and viscous moduli, respectively) 5 were measured at 1% strain and 1 radian/sec. In less than a minute, G' was near 104 dynes/cm 2 , which is characteristic of a soft rubbery material. G' began to plateau within 15 min, and continued to rise very gradually for more than an hour afterwards. G" was in the order of 102 dynes/cm 2 , and declined gradually. These results are consistent with a rapidly gelling material. G' and G" for the 10 unreacted starting materials was about 1-10 dynes/cm 2 . These results are depicted in FIG. 4. In this experiment, the rheometer cannot precisely quantitate G' and G" below about 50 dynes/cm 2 . In addition, the gelation occurred so rapidly that the mixture only filled 30 to 95% of the desired space-there was gelled fluid 15 surrounding the plate, but not between the plates. Even with these limitations, a measurement of the elastic (G') and viscous modulus (G") as a function of time can still be made, and the kinetics of gelation can be followed. As indicated in this experiment, a G' of greater than 102 dynes/cm 2 in less than one minute indicates rapid gelation. 20 EXAMPLE 7 EFFECTS OF BUFFERS ON GEL TIME USING SULFHYDRYL-PEG AND N-HYDROXY SUCCINIMIDYL-PEG (NHS-PEG) All tests were done with 50 ml of 20% (w/v) 4 arm, 10,000 mol. wt., tetrafunctional SG-PEG mixed with 50 ml of 20% (w/v) 4 arm, 10,000 mol. 25 wt., tetra-functional sulfhydryl-PEG). Different buffers were used, and the times to gel were noted. The SG-PEG was dissolved in 0.5 mM phosphate, pH 6.0 for all tests. The sulfhydryl-PEG was dissolved in the buffers given below at a pH of 9.6 and times to gel are noted. 127 WO 2004/060346 PCT/US2003/041580 TABLE 6 Effect Buffers on Gelation Time Gel Time Test Buffer (Sec) A P/C Buffer 8 B 150 mM phosphate 35 C 58 mM phosphate 138 91 mM sodium chloride D 58 mM phosphate <19 91 mM borate E 58 mM phosphate 8 91 mM AMPSO* *(3[1,1-dimethyl-2-hydroxy-ethyl)amino]-2-hydroxypropane-sulfonic acid 5 As shown, buffers with pKs between 8 and 10.5 (borate, 8.1; carbonate, 10.3; AMPSO, 9.0), and mixtures thereof, are suitable EXAMPLE 8 SULFHYDRYL-REACTIVE PEGS The gelation characteristics of several different formulations are 10 described below: 8a: Gelation of Di Functional Maleimidyl-PEG, 3400 mol. wt. (MAL-PEG) with Tetra-Sulfhydryl PEG, 10,000 mol. wt. A 20% (w/v) solution of MAL-PEG in 0.5 mM sodium phosphate, pH 6.0, was mixed rapidly with an equal volume of 20% (w/v) tetra-sulfhydryl 15 PEG in 150 mM sodium phosphate, pH 5.0. Gelation occurred in 15 sec. The gel became a firm, rubbery solid in a minute or less. 8b: Gelation of Difunctional lodoacetamide PEG, 3,400 mol. wt. ("lAM-PEG") with Tetra-Sulfhydryl PEG, 10,000 mol. wt. IAM-PEG was dissolved at 20% (w/v) in 0.5 mM sodium 20 phosphate, pH 6.0, and mixed rapidly with a 20% (w/v) solution of tetra sulfhydryl PEG in P/C Buffer sodium phosphate-carbonate, pH 9.6. Gelation occurred in less than 40 sec. A firm gel formed within 2 min. 128 WO 2004/060346 PCT/US2003/041580 8c: Gelation of Tetra-Sulfhydryl PEG, 10.000 mol. wt., with Dilute Hydrogen Peroxide A 20% (w/v) solution of tetra-sulfhydryl PEG in PIC Buffer, was mixed with an equal volume of 0.1% (w/v) hydrogen peroxide. Gelation 5 occurred in 15 sec. A firm gel formed in less than 2 min. EXAMPLE 9 BLOOD COAGULATION ACTIVITY OF THROMBIN INCORPORATED INTO PEG COMPOSITIONS This experiment demonstrates that hemostatic PEG gels 10 containing active thrombin protein can be formed on tissue. 9a: Thrombin Incorporated into Tetra-Sulfhydryl PEG Gelled with Hydrogen Peroxide 20 mg of tetra-sulfhydryl PEG, 10,000 mol. wt., were dissolved in 80 pl of PC Buffer, and 11 pl of bovine thrombin at 8850 NH units/ml in 0.72 M 15 sodium chloride (Thrombin topical, USP, Gentrac, Inc., Middleton, Wis.) were added. This solution of tetra-sulfhydryl PEG and thrombin was then mixed with 100 pl of 0.1% (w/v) hydrogen peroxide in water, by stirring rapidly in a 1.5 ml plastic tube. The mixture gelled in less than 40 sec, due to oxidation of the sulfhydryl groups to disulfide bonds. After 1.5 min, the gel was a firm, rubbery 20 solid. On top of this gel was layered 200 pl of rabbit blood plasma. The plasma had been separated from citrated blood and contained approximately 11 mM citrate. Just prior to addition, this citrated blood plasma was re-calcified by addition of 8 pl of 0.5 M calcium chloride, to achieve a concentration of about 20 mM calcium. This re-calcified blood plasma was observed to form a fibrin 25 clot 1.5 minutes after layering onto the PEG gel. The clotting reaction was taken as evidence for the presence of active thrombin in the PEG gel. When control studies are performed, a second oxidized sulfhydryl PEG gel without thrombin does not clot rabbit plasma until 20 minutes have elapsed. As a further control, re-calcified rabbit plasma is held in an identical 30 plastic tube; and it clots spontaneously after 13 minutes. Therefore, the 129 WO 2004/060346 PCT/US2003/041580 sulfhydryl-PEG gel without thrombin clots blood no faster than control re calcified plasma. When the analogous experiment was attempted with tetra sulfhydryl PEG and tetra-SG-PEG, plus thrombin, no enhanced clotting time of 5 plasma was observed. Clotting of plasma was delayed beyond 25 minutes. This result is interpreted to indicate that SG-PEG inactivated thrombin, presumably by binding PEG to lysine side chains of thrombin and interfering with its enzymatic activity. 9b: Thrombin Incorporated into LAM-PEG/Sulfhydryl-PEG gel 10 20 mg of tetra-sulfhydryl PEG, 10,000 mol. wt. are dissolved in 80 pl of PC Buffer along with 11 pl of thrombin, as in 9a. above. 20 mg of LAM PEG are dissolved in 80 pl of 0.5 mM sodium phosphate, pH 6.0. The two solutions are rapidly mixed in a 1.5 ml plastic tube. The mixture has a gel time less than 30 sec and is a rubbery gel by 1.5 minutes. Re-calcified rabbit 15 plasma (200 pl) is layered on top of the gel, and a fibrin clot forms in this plasma in less than two minutes after layering onto the gel. A control reaction without thrombin forms a fibrin clot more than 18 minutes after layering onto the PEG gel. The rapid formation of a fibrin clot in the sample containing thrombin is taken as evidence for the presence of active thrombin in the PEG gel. 20 9c: Thrombin Incorporated into NEM-PEG/Sulfhydryl PEG gel 20 mg of tetra-sulfhydryl PEG, 10,000 mol wt., is dissolved in 80 pl of 150 mM sodium phosphate, pH 5.0, along with 11 pl of thrombin, as in 9a above. 20 mg of NEM-PEG are dissolved in 0.5 mM sodium phosphate, pH 6.0. The two solutions are rapidly mixed in a plastic tube. Gelation occurs in 25 15 sec. 15 ml of P/C Buffer, are layered onto the top of the PEG gel to adjust the pH to 7-9. Then, 200 pl of re-calcified rabbit plasma are added. A fibrin clot formed in 1.5 min. after addition of the plasma. Control gels with no thrombin form a fibrin clot after 30 min. Again, the rapid formation of a fibrin clot in the PEG gel with thrombin is taken as evidence for the presence of active thrombin. 30 9d: Gelation of Layered Gels with Thrombin 130 WO 2004/060346 PCT/US2003/041580 In order to provide a gel formulation from SG-PEG and sulfhydryl PEG to which thrombin can be added and remain active, a "gel layering" technique can be used. First, the tetra-sulfhydryl-PEG and tetra-Se-PEG gel at 20% solids, prepared according to Example 1 are sprayed onto sheets as 5 described in Example 2. The sheets are coarse fibered collagen hydrated by saline, which simulates a tissue surface. The total volume is approximately 0.5 ml. This formula gels in 18-15 sec. At 16 seconds, a second gel mixture of tetra-sulfhydryl PEG, di-maleimidyl PEG, both at 20% solids, and thrombin (700 NIH units/mi) of total gel mixture, total volume approx. 0.5 ml, are sprayed on 10 top of the first gel. This second gel layer gels at about 2 minutes. At 3 min after the first gel is sprayed, 0.4 ml of re-calcified rabbit blood plasma, prepared as described above are layered on top of the PEG gel. This plasma clots 1.5 minutes after it is layered onto the PEG gel. The formation of a fibrin clot at this early time, compared to a non-thrombin control, is taken as evidence for active 15 thrombin in the PEG gel. EXAMPLE 10 GELATION USING POWDERED FORMULATIONS 10 mg of powdered tetra-SG PEG, 10,000 mol. wt., is spread on the surface of a piece of weighing paper. 10 mg of tetra-sulfhydryl PEG, 10,000 20 mol. wt., is dissolved in 80 pl of P/C buffer. The sulfhydryl-PEG solution is loaded into a 1 cc syringe with a Haemedics (Malibu, Calif.) spray head and sprayed onto the SG-PEG on the weighing paper. The sprayed fluid is not stirred or mixed. It begains to gel in 27 seconds and forms a firm, rubbery layer by 2 min. This test shows that components in powdered form are also suitable 25 for use in the present invention. 131 WO 2004/060346 PCT/US2003/041580 EXAMPLE 11 COLLAGEN-CONTAINING COMPOSITIONS Methylated collagen is prepared by the following process: bovine corium collagen is solubilized using pepsin and purified as described in U.S. 5 Pat. No. 4,233,360. This purfied, solubilized collagen is precipitated by neutralization into 0.2M sodium phosphate, pH 7.2. The precipitate is isolated by centrifugation to a final concentration of 70 mg/ml. The material is dried for two days, and then pulverized. Dry methanol containing HCI (to 0.1 N) is added (40 ml) and stirred for four days. Collagen is separated from the acidic 10 methanol, vacuum dried and sterilized by irradiation. The final product is disolved in water at a pH of 3-4. For delivery as a sealant, 10 mg of the methylated collagen, 100 mg of tetra-functional sulfhydryl-PEG, 10,000 mol. wt., and 100 mg of tetra functional SG PEG, 10,000 mol. wt., are dissolved in water at pH 3-4 to a final 15 volume of I ml (first component). The second component is 1 ml of P/C Buffer. Each component is placed in a syringe and mixed and sprayed on the desired test site using a dual-syringe delivery system as described in Example 1. The applied mixture gels in less than 3 seconds. The adhesive and cohesive properties of the gel are examined in 20 a burst test. This test is conducted on a pressure gauge apparatus (PSI-Tronix, Model PG5000, Tulare, Calif.) connected by a pressure line to a circular sample plate with a 2 mm diameter central orifice. Sealant formulations are sprayed onto the plate to seal the orifice. To simulate bonding of the formulations to tissue, the sample plate has a circular sheet of coarse-fibered collagen 25 fastened to it, with a 2 mm hole pierced into it and displaced 2-3 mm from the sample plate orifice. Burst strength is measured as a function of the pressure it takes to force saline at a flow rate of 5 ml/min through the sealant gel. The results are given below in Table 7. 132 WO 2004/060346 PCT/US2003/041580 TABLE 7 Burst Strength Measurements of Collacen-Containing Compositions Material Burst Strength, mm Hg Sulfhydryl-PEG/SG-PEG 100-180 Sulfhydryl-PEG/SG-PEG/ 122-205 Methylated Collagen Both formulations have gel times less than 3 seconds. As shown above, the addition of collagen to the formulation enhances burst strength. 5 EXAMPLE 12 SYNTHESIS OF "12-ARM" PEG COMPOUNDS A 12-arm electrophilic PEG compound is formed from I mole of 4 arm sulfhydryl PEG, 10,000 mol. wt., and 4 moles of 4-arm SG-PEG, 10,000 mol. wt. The resulting compound is depicted in FIG. 5a. As shown, the 10 compound core is pentaerythritol PEG ether tetra-sulfhydryl and the end functional group is succinimide. As long as the functional groups are reactive with one another to form chemical bonds, the sulfhydryl group, X, can be replaced with other nucleophilic groups, such as NH 2 , etc., and the succinimidyl group, Y, can be replaced with other electrophilic groups, such as maleimide, 15 carbonyl imidazole, or isocyanate. This method is also used to prepare the 12 arm nucleophilic PEG compound depicted in FIG. 5b by reacting 4 moles of 4 arm sulfhydryl PEG with 1 mole of 4-arm SG-PEG. It should be understood that such reactions produce a heterogeneous population of activated PEG product, some having less than 12 arms, and some having more than 12 arms. 20 As used herein, a "12-arm" PEG also refers to such heterogeneous reaction products that have an average of about 12 arms on each molecule. 12a: 12 arm Sulfhydryl PEG Eight grams of pentaerythritol (polyethylene glycol)ether tetra sulfhydryl was dissolved in a mixture of 100 mL of methylene chloride and 100 25 mL oftriethylamine. Two grams of pentaerythritol (polyethylene glycol)ether tetra succinimidyl glutarate in 40 mL of methylene chloride was slowly added 133 WO 2004/060346 PCT/US2003/041580 with stirring at room temperature under argon overnight. The solvent was removed and the product was isolated by recrystallilzation in ethanol and dried. 12b: 12 arm Succinimidyl PEG Two grams of pentaerythritol (polyethylene glycol)ether tetra 5 succinimidyl glutarate was dissolved in 50 mL of methylene chloride. 0.5 grams of pentaerythritol (polyethylene glycol)ether tetra amine in 10 mL of methylene chloride was slowly added with stirring at room temperature under argon overnight. The solvent was removed and the product was isolated by recrystallization in ethanol and dried. 10 When the two compounds were tested for burst strength as described in Example 12, they demonstrated a burst strength of greater than 150 mm Hg and a gel time of less than 2 seconds. EXAMPLE 13 PREPARATION OF MICROSPHERES WITH AND WITHOUT PACLITAXEL 15 A) PVA solution preparation 1. In a 1000ml beaker, 1000ml of distilled water and 100g of PVA (Aldrich 13-23K, 98% hydrolyzed) are weighed. A two-inch stirrer bar is placed into the beaker. The suspension is heated up to 75-80 0 C during stirring. The PVA is dissolved completely (should form a clear solution). 20 2. The 10% PVA solution (w/v) is cooled down to room temperature and filtered through a syringe in-line filter. Stored at 2-80C for use. B) PLGA solution preparation with or without paclitaxel 1. Appropriate amount of paclitaxel and PLGA (for a total of 1.0g) are weighed and transferred into the 20ml scintillation vial. 25 2. 10OmL of HPLC grade dichloromethane (DCM) is added into the vial to dissolve the PLGA with or without paclitaxel. 3. The polymer with or without paclitaxel is dissolved in DCM by placing the vial on an orbital shaker. The orbital shaker is set at 4. Preparation of the microspheres with diameter less than 25mm 134 WO 2004/060346 PCT/US2003/041580 1. 100ml of 10% PVA solution is transferred into a 400ml beaker. The beaker is secured by a double side adhesive tape onto the fume hood. A peddler with 3 blades is placed into the beaker with 0.5 cm above the bottom. The motor is turned on to 2.5 (Dyna-Mix from Fisher Scientific) at first. 5 The 1Oml PLGA/paclitaxel solution is poured into the PVA solution during agitation. Gradually turn up the agitation rate to 5.0. The stirring is maintained for 2.5 to 3.0 hours. 2. The obtained microspheres are filtered through a set of sieves with 53mm (top) and 25mm (bottom) into a 1 00ml beaker. The 10 microspheres are washed using distilled water while filtering. The filtered microspheres are centrifuged (1000rpm, 1Omin.) and re-suspended/washed with 1 00ml distilled water three times to clean the PVA. 3. The washed microspheres are transferred into the freeze dried beaker using a small amount of distilled water (20-30ml). The beaker is 15 then sealed and placed into a -20oC freezer over night. 4. The frozen microspheres are then freeze-dried using a freeze-drier for about 3 days. The dried microspheres are transferred into 20ml scintillation vial and stored at -20 0 C. In a similar manner described above, other biologically active 20 agents, as described above, can be incorporated into a microsphere formulation. EXAMPLE 14 MYCOPHENOLIC ACID INCORPORATION INTO MICROSPHERES Mycophenolic acid was incorporated into microspheres in a 25 similar manner as described in Example 13. 135 WO 2004/060346 PCT/US2003/041580 EXAMPLE 15 INCORPORATION OF PACLITAXEL-LOADED MICROSPHERES - METHOD 1 Various amounts of the microspheres prepared in Example 13 are weighed out and mixed with the pentaerythritol poly(ethylene glycol)ether tetra 5 succinimidyl glutarate. The formulation is then prepared in the same manner as that described in Example 1. Microspheres loaded with other agents, for example mycophenolic acid, are incorporated into the compostion in a similar manner. EXAMPLE 16 10 INCORPORATION OF PACLITAXEL-LOADED MICROSPHERES - METHOD 2 Various amounts of the microspheres prepared in Example 13 are weighed out and mixed with 0.5 mM sodium phosphate pH 6.0 buffer. The microsphere containing buffer is then used to prepare the formulation in the same manner as that described in example 1. Microspheres loaded with other 15 agents, for example mycophenolic acid, are incorporated into the compostion in a similar manner. EXAMPLE 17 PREPARATION OF CHLORPROMAZINE MICROSPHERES Various amounts of chlorpromazine are dissolved in 1 mL 5% 20 PVA solution. This solution is then added to 10 mL dichloromethane (DCM) that is in a 25 mL beaker. The solution is homogenized (setting 5) for 2 minutes using a tissue homogenizer. The resultant solution is then poured into 50 mL 5% PVA solution. The solution is then homogenized (setting 5) for 2 minutes. The sample is then placed on the rotavap and the solvent is gradually removed 25 using a shallow increasing vacuum gradient. Once the majority of the DCM is removed, the sample is frozen and freeze dried. 136 WO 2004/060346 PCT/US2003/041580 EXAMPLE 18 EFFICACY OF DRUG LOADED FORMULATIONS - ADHESION PREVENTION The compositions prepared in Examples 1,15, 16 and 17 are tested in the rat cecal side wall mbdel (see General Method A) and the rabbit 5 uterine horn model (see General Method B). The compositions as prepared in Examples 1, 15 and 16 were applied to the site of injury as a spray using an air assisted spray device (available from Cohesion Technologies or Micromedics) that mixed the 2 component solutions. EXAMPLE 19 10 DIRECT INCORPORATION OF DRUGS INTO RAPID GELLING FORMULATION: MYCOPHENOLIC ACID (MPA)-PREMIX Reagents: Syringe 1: A 1 mL syringe equipped with a BBraun luer-lock mixing connector (FDC1000/415080) containing PEG-SG4 (tetra functional poly(ethylene glycol) 15 succinimidyl glutarate) 50mg, PEG-SH4 (tetra functional poly(ethylene glycol) thiol 50mg and MPA (mycophenolic acid) 5 to 45 mg. The mycophenolic acid was less than 100 um in particles size. This was obtained by using a 100 um sieve. Syringe 2: A 1 mL capped syringe with 0.25 mL 6.3mM HCl solution. 20 Syringe 3: A 1 mL capped syringe with 0.25 mL 0.12 M monobasic sodium phosphate and 0.2 M sodium carbonate (pH 9.7). Applicator: Micromedics Y-shaped blending connector with a spray-tip (SA 3674), or similar. 25 Procedure: Syringe 1 containing the solids and syringe 2 containing the acidic solution was mixed through the green mixing connector by repeatedly transferring from one syringe to the other by pushing the plungers back and forth. After complete mixing, all of the formulation was pushed into one of the 30 syringes which was attached to one inlet of the Y-shaped applicator equipped 137 WO 2004/060346 PCT/US2003/041580 with the spray tip. Syringe 3 containing the pH 9.7 solution was attached onto the other inlet of the Y-shaped applicator. A connector clip was attached to the plungers of the two syringes. The formulation was applied by quickly and evenly depressing the connected syringe plungers. 5 For mycophenolic acid amounts in the 50 to 100 mg range, a 1 mL capped syringe with 0.25 mL 0.24 M monobasic sodium phosphate adjusted to pH 10 with sodium carbonate was used as syringe 3. EXAMPLE 20 DIRECT INCORPORATION OF DRUGS INTO RAPID GELLING FORMULATION: CELLCEPT 10 PREMIX CELLCEPT (Syntex Laboratories, Inc., Palo Alto, CA) was incorporated into the composition in a similar manner to that described in Example 19. 5 mg CELLCEPT was added to the 2 PEG components in syringe 1. The composition was prepared and applied as described in Example 19. 15 mycophenolic acid was included in these compositions. EXAMPLE 21 DIRECT INCORPORATION OF DRUGS INTO RAPID GELLING FORMULATION: CHLORPROMAZINE (CPZ)-PREMIX In a similar manner to that described in Example 19, 20 Chlorpromazine was incorporated into the composition. Compositions containing between 5 and 20 mg Chlorpromazine were prepared in a similar manner as to that described in Example 19. No mycophenolic acid was included in these compositions. EXAMPLE 22 25 DIRECT INCORPORATION OF DRUGS INTO RAPID GELLING FORMULATION: MYCOPHENOLIC ACID - SEPARATE DRUG COMPONENT Components: 138 WO 2004/060346 PCT/US2003/041580 Syringe 1: A 1 mL syringe equipped with a BBraun luer-lock mixing connector (FDC1000/415080) containing 50 mg PEG-SG4 (tetra functional poly(ethylene glycol) succinimidyl glutarate) and 50 mg PEG-SH4 (tetra functional poly(ethylene glycol) thiol). 5 Syringe 2: 1 mL syringe equipped with a BBraun luer-lock mixing connector (FDC1000/415080) containing between 5 and 45 mg MPA (mycophenolic acid) [sieved to a particle size less than 00 micron]. Syringe 3: A 1 mL capped syringe with 0.25 mL 6.3mM HCI solution. Syringe 4: A 1 mL capped syringe with 0.25 mL 0.12 M monobasic sodium 10 phosphate and 0.2 M sodium carbonate (pH 9.7). Applicator: Micromedics Y-shaped blending connector with a spray-tip(SA 3674), or similar. Procedure: Syringe 1 containing the solids was connected to syringe 3 15 containing the acidic solution through the green mixing connector. The contents were mixed by using the plungers to transfer the onetnes of one syringe into the other. This process was repeated at least 20 times. After complete mixing, all of the formulation was pushed into one of the syringes which was attached to one inlet of the Y-shaped applicator equipped with the spray tip. Syringe 4 and 20 2 (containing the drug) were similarly mixed and attached onto the other inlet of the Y-shaped applicator. A connector clip was attached to the plungers of the two syringes The formulation was applied by quickly and evenly depressing the connected syringe plungers. For mycophenolic acid amounts in the 50 to 100 mg range, a 1 25 mL capped syringe with 0.25 mL 0.24 M monobasic sodium phosphate adjusted to pH 10 with sodium carbonate was used as syringe 4. 139 WO 2004/060346 PCT/US2003/041580 EXAMPLE 23 DIRECT INCORPORATION OF DRUGS INTO RAPID GELLING FORMULATION: CELLCEPT PREMIX CELLCEPT was incorporated into the composition in a similar 5 manner to that described in Example 22. 5 mg CELLCEPT was contained in syringe 2. The composition was prepared and applied as described in Example 22. Mycophenolic acid was included in these compositions. EXAMPLE 23 MYCOPHENOLIC ACID-CONTAINING MICROSPHERES PREPARED BY SPRAY DRYING 10 Poly(L-Jactic acid) (Mw 2000), was dissolved in methylene chloride to result in a 0.2% solution. MPA was added in at different weight ratios relative to the carrier polymer. These ranged from 10 to 50%. The resulting solution was spray dried using a Buchi Research Spray Drier and the following conditions: Inlet temperature 50 'C, outlet temperature < 39 OC, aspirator 100%, 15 flow rate 700 L/hr. The collected microspheres were further dried under vacuum. MPA-containing microspheres were made in a similar manner to that described above except that poly(caprolactone) (Mw 9,000), PLGA (Mw 54K), PLURONIC-F127 or methoxy poly(ethylene glycol 5000)-block-poly (DL-lactide) (65:35 or 60:40 PEG:PDLLA weight ratio) were used instead of the poly(L 20 lactic acid). EXAMPLE 23 CHLORPROMAZINE-CONTAINING MICROSPHERES PREPARED BY SPRAY DRYING Methoxy poly(ethylene glycol 5000)-block-poly (DL-lactide) (65:35 PEG:PDLLA weight ratio) or PLURONIC-F127 was dissolved in methylene 25 chloride to result in a 0.2% solution. Chlorpromazine was added in 10% weight ratio relative to the carrier polymer. The resulting solution was spray dried using a Buchi Research Spray Drier and the following conditions: Inlet temperature 50 140 WO 2004/060346 PCT/US2003/041580 oC, outlet temperature < 39 OC, aspirator 100%, flow rate 700 L/hr. The collected microspheres were further dried under vacuum. EXAMPLE 24 PACLITAXEL-CONTAINING MICROSPHERES PREPARED BY SPRAY DRYING 5 Methoxy poly(ethylene glycol 5000)-block-poly (DL-lactide) (65:35 or 60:40 PEG:PDLLA weight ratio) was dissolved in methylene chloride to result in a 0.2% solution. Paclitaxel was added in 10% weight ratio relative to the carrier polymer and the resulting solution was spray dried using a Buchi Research Spray Drier and the following conditions: Inlet temperature 50 C, 10 outlet temperature < 39 OC, aspirator 100%, flow rate 700 L/hr. The collected microspheres were further dried under vacuum. EXAMPLE 25 MYCOPHENOLIC ACID-CONTAINING MICROSPHERES (< 10 MICRONS) PREPARED BY EMULSION METHOD 15 Into a 600mL beaker was added 100mL of freshly prepared 10% polyvinyl alcohol (PVA) solution and 10 OmL of pH 3 acetic acid solution saturated with MPA. This acidified PVA solution was stirred at 2000 rpm for 30 minutes. Meanwhile, solution containing between 80-400 mg MPA and 800 mg PLGA in 20mL dichloromethane were prepared. Each of these 20 dichloromethane solutions were individually added drop wise to a PVA solution while stirring at 2000 rpm with a Fisher Dyna-Mix. After addition was complete, the solution was allowed to stir for 45 minutes. The microsphere solution was transferred to falcon tubes, washed with a pH 3 acetic acid solution saturated with MPA, and centrifuged at 2600 rpm for 10 minutes. The aqueous layer was 25 decanted and the washing, centrifuging and decanting was repeated 3 times. The washed microspheres from each batch were freeze-dried. 141 WO 2004/060346 PCT/US2003/041580 EXAMPLE 26 MYCOPHENOLIC ACID-CONTAINING MICROSPHERES (50-130 MICRONS) PREPARED BY EMULSION METHOD Into a 600mL beaker was added 100mL of freshly prepared 1% 5 polyvinyl alcohol solution and 10mL of pH 3 acetic acid solution saturated with MPA. This acidified PVA solution was stirred at 500 rpm for 30 minutes. Meanwhile, a solution of 80-400 mg MPA and 800 mg PLGA in 20mL dichloromethane was prepared. This dichloromethane solution was added drop wise to the PVA solution while stirring at 500 rpm with a Fisher Dyna-Mix. After 10 addition was complete, the solution was allowed to stir for 45 minutes. The microsphere solution was transferred to falcon tubes, washed with a pH 3 acetic acid solution saturated with MPA, and centrifuged at 2600 rpm for 10 minutes. The aqueous layer was decanted and the washing, centrifuging and decanting was repeated 3 times. The combined, washed microspheres were 15 freeze-dried to remove any excess water. The product was sieved to isolate microspheres of 53-125pm size. EXAMPLE 27 INCORPORATION OF DRUG-LOADED CARRIERS INTO THE PEG COMPOSITIONS Drug-loaded microspheres, 5 to 100 mg, were incorporated into 20 compositions as a mixture in a similar manner as to that described in Example 19 or as a separate component in a manner similar to that described in Example 22. EXAMPLE 28 INCORPORATION OF ADDITIVES INTO MPA-LOADED MICROSPHERES 25 Methoxy poly(ethylene glycol 5000)-block-poly (DL-lactide) (65:35 or 60:40 PEG:PDLLA weight ratio) was dissolved in the appropriate solvent (see below) to result in a 0.2% solution. MPA was added in 10% weight ratio relative to the carrier polymer. Different additives were then individually added 142 WO 2004/060346 PCT/US2003/041580 to the drug/polymer solution. The nature of the additive and the amounts used are described below: Additives: Concentration: Solvent: 5 Histidine 1-3 molar ratio to MPA Methylene Chloride Spermidine 1-1/3 molar ratio to MPA Methylene Chloride 1,2 dipalmitoyl-sn-glycero 3-phosphoethanolamine 1-15% (wlw) to carrier Chloroform 10 1,2, dimyristoyl-sn-glycero 3-ethylphosphocholine chloride 1-15% (wlw) to carrier) Chloroform Palmitic Acid 1-15% (wlw) to carrier) Methylene Chloride Cholic Acid 1-15% (w/w) to carrier) Methylene Chloride 15 The resulting solution was spray dried using a Buchi Research Spray Drier and the following conditions:. Inlet temperature 50 0 C, outlet temperature < 39'C, aspirator 100%, flow rate 700 L/hr. The collected microspheres were further dried under vacuum. The drug-loaded microspheres were used in direct combination with the PEG reagents, as described in 20 Example 19 or as a separate component as described in Example 22. EXAMPLE 29 RAT SURGICAL ADHESIONS MODEL TO ASSESS FIBROSIS INHIBITING AGENTS Sprague Dawley rats are prepared for surgery by anaesthetic induction with 5% halothane in an enclosed chamber. Anaesthesia is 25 maintained by nose cone on halothane throughout the procedure and Buprenorphen 0.035 mg/kg is injected intramuscularly. The abdomen is shaved, sterilized, draped and entered via a midline incision. The caecum is lifted from the abdomen and placed on sterile gauze dampened with saline. Dorsal and ventral aspects of the caecum are scraped a total of 45 times over 30 the terminal 1.5 cm using a #10 scalpel blade, held at a 450 angle. Blade angle and pressure are controlled to produce punctuated bleeding, while avoiding severe tissue damage or tearing. 143 WO 2004/060346 PCT/US2003/041580 The left side of the abdominal cavity is retracted and everted to expose a section of the peritoneal wall nearest the natural resting caecal location. The exposed superficial layer of muscle (transverses abdominis) is excised over an area of 1.0 X 1.5 cm 2 . Excision includes portions of the 5 underlying internal oblique muscle, leaving behind some intact and some torn fibres from the second layer. Minor local bleeding is tamponaded until controlled. A test formulation is deployed at the wounded areas, on the abraded sidewall, between the caecum and sidewall. The formulation is 10 deployed using either a syringe spray system or an air-assisted syringe system. The abraded caecum is then positioned over the sidewall wound and sutured at four points immediately beyond the dorsal corners of the wound edge. The large intestine is replaced in a natural orientation continuous with the caecum. The abdominal incision is closed in two layers with 4-0 silk sutures. 15 Rats are followed for one week, and then euthanized by lethal injection for post mortem examination to score. Severity of post-surgical adhesions is scored by independently assessing the tenacity and extent of adhesions at the site of caecal-sidewall abrasion, at the edges of the abraded site, and by evaluating the extent of intestinal attachments to the exposed 20 caecum. Adhesions are scored on a scale of 0-4 with increasing severity and tenacity. The extent of adhesion is scored as a percent of the injured area that contained adhesions. EXAMPLE 30 SCREENING ASSAY FOR ASSESSING THE EFFECT OF MITOXANTRONE 25 ON CELL PROLIFERATION Fibroblasts at 70-90% confluency are trypsinized, replated at 600 cells/well in media in 96-well plates and allowed to attachment overnight. Mitoxantrone is prepared in DMSO at a concentration of 10-2 M and diluted 10 fold to give a range of stock concentrations (10-8 M to 10-2 M). Drug dilutions 30 are diluted 1/1000 in media and added to cells to give a total volume of 200 144 WO 2004/060346 PCT/US2003/041580 pL/well. Each drug concentration is tested in triplicate wells. Plates containing fibroblasts and mitoxantrone are incubated at 37 0 C for 72 hours (In vitro toxicol. (1990) 3: 219; Biotech. Histochem. (1993) 68: 29; Anal. Biochem. (1993) 213: 426). 5 To terminate the assay, the media is removed by gentle aspiration. A 1/400 dilution of CYQUANT 400X GR dye indicator (Molecular Probes; Eugene, OR) is added to 1X Cell Lysis buffer, and 200 pL of the mixture is added to the wells of the plate. Plates are incubated at room temperature, protected from light for 3-5 minutes. Fluorescence is read in a 10 fluorescence microplate reader at -480 nm excitation wavelength and ~520 nm emission maxima. Inhibitory concentration of 50% (ICo50) is determined by taking the average of triplicate wells and comparing average relative fluorescence units to the DMSO control. An average of n=4 replicate experiments is used to determine IC5o values. The results of the assay are 15 shown in FIG. 6 (IC50o=20 nM for proliferation of human fibroblasts). EXAMPLE 31 SCREENING ASSAY FOR ASSESSING THE EFFECT OF MITOXANTRONE ON NITRIC OXIDE PRODUCTION BY MACROPHAGES 20 The murine macrophage cell line RAW 264.7 is trypsinized to remove cells from flasks and plated in individual wells of a 6-well plate. Approximately 2 X 106 cells are plated in 2 mL of media containing 5% heat inactivated fetal bovine serum (FBS). RAW 264.7 cells are incubated at 37 0 C for 1.5 hours to allow adherence to plastic. Mitoxantrone is prepared in DMSO 25 at a concentration of 10-2 M and serially diluted 10-fold to give a range of stock concentrations (10-8 M to 10
-
2 M). Media is then removed and cells are incubated in 1 ng/mL of recombinant murine IFNy and 5 ng/mL of LPS with or without mitoxantrone in fresh media containing 5% FBS. Mitoxantrone is added to cells by directly adding mitoxantrone DMSO stock solutions, prepared earlier, 30 at a 1/1000 dilution, to each well. Plates containing IFNy, LPS plus or minus 145 WO 2004/060346 PCT/US2003/041580 mitoxantrone are incubated at 37°C for 24 hours (Chem. Ber. (1879) 12: 426; J. AOAC (1977) 60-594; Ann. Rev. Biochem. (1994) 63:175). At the end of the 24 hour period, supernatants are collected from the cells and assayed for the production of nitrites. Each sample is tested in 5 triplicate by aliquoting 50 pL of supernatant in a 96-well plate and adding 50 pL of Greiss Reagent A (0.5 g sulfanilamide, 1.5 mL H 3
PO
4 , 48.5 mL ddH 2 0) and 50 pL of Greiss Reagent B (0.05 g N-(1-Naphthyl)-ethylenediamine, 1.5 mL
H
3
PO
4 , 48.5 mL ddH 2 0). Optical density is read immediately on microplate spectrophotometer at 562 nm absorbance. Absorbance over triplicate wells is 10 averaged after subtracting background and concentration values are obtained from the nitrite standard curve (1 pM to 2 mM). Inhibitory concentration of 50% (IC50) is determined by comparing average nitrite concentration to the positive control (cell stimulated with IFNy and LPS). An average of n=4 replicate experiments is used to determine IC50 values for mitoxantrone. The results of 15 the assay are shown in FIG. 7 (Mitoxantrone IC50=927 nM for Greiss assay in RAW 264.7 cells). EXAMPLE 32 SCREENING ASSAY FOR ASSESSING THE EFFECT OF BAY 11-7082 ON TNF-ALPHA PRODUCTION BY MACROPHAGES 20 The human macrophage cell line, THP-1 is plated in a 12 well plate such that each well contains 1 X 106 cells in 2 mL of media containing 10% FCS. Opsonized zymosan is prepared by resuspending 20 mg of zymosan A in 2 mL of ddH 2 0 and homogenizing until a uniform suspension is obtained. Homogenized zymosan is pelleted at 250 g and resuspended in 4 25 mL of human serum for a final concentration of 5 mg/mL. and incubated in a 37'C water bath for 20 minutes to enable opsonization. Bay 11-7082 is prepared in DMSO at a concentration of 102 M and serially diluted 10-fold to give a range of stock concentrations (10-" M to 10
-
2 M) (J. Immunol. (2000) 165: 411-418; J. Immunol. (2000) 164: 4804-4811; J. Immunol Meth. (2000) 235 (1 30 2): 33-40). 146 WO 2004/060346 PCT/US2003/041580 THP-1 cells are stimulated to produce TNFa by the addition of 1 mg/mL opsonized zymosan. Bay 11-7082 is added to THP-1 cells by directly adding DMSO stock solutions, prepared earlier, at a 1/1000 dilution, to each well. Each drug concentration is tested in triplicate wells. Plates are incubated 5 at 370C for 24 hours. After a 24 hour stimulation, supernatants are collected to quantify TNFa production. TNFa concentrations in the supernatants are determined by ELISA using recombinant human TNFa to obtain a standard curve. A 96-well MaxiSorb plate is coated with 100 pL of anti-human TNFa Capture Antibody 10 diluted in Coating Buffer (0.1M Sodium carbonate pH 9.5) overnight at 40C. The dilution of Capture Antibody used is lot-specific and is determined empirically. Capture antibody is then aspirated and the plate washed 3 times with Wash Buffer (PBS, 0.05% Tween-20). Plates are blocked for 1 hour at room temperature with 200 pL/well of Assay Diluent (PBS, 10% FCS pH 7.0). 15 After blocking, plates are washed 3 times with Wash Buffer. Standards and sample dilutions are prepared as follows: (a) sample supernatants are diluted 1/8 and 1/16; (b) recombinant human TNFa is prepared at 500 pg/mL and serially diluted to yield as standard curve of 7.8 pg/mL to 500 pg/mL. Sample supernatants and standards are assayed in triplicate and are incubated at room 20 temperature for 2 hours after addition to the plate coated with Capture Antibody. The plates are washed 5 times and incubated with 100 pL of Working Detector (biotinylated anti-human TNFa detection antibody + avidin HRP) for 1 hour at room temperature. Following this incubation, the plates are washed 7 times and 100 pL of Substrate Solution (Tetramethylbenzidine, H 2 0 2 ) 25 is added to plates and incubated for 30 minutes at room temperature. Stop Solution (2 N H 2
SO
4 ) is then added to the wells and a yellow colour reaction is read at 450 nm with A correction at 570 nm. Mean absorbance is determined from triplicate data readings and the mean background is subtracted. TNFa concentration values are obtained from the standard curve. Inhibitory 30 concentration of 50% (IC50) is determined by comparing average TNFa concentration to the positive control (THP-1 cells stimulated with opsonized 147 WO 2004/060346 PCT/US2003/041580 zymosan). An average of n=4 replicate experiments is used to determine IC 50 values for Bay 11-7082. The results of the assay are shown in FIG. 8 (Bay 11 7082 IC 50 =810 nM TNFa production by THP-1 cells). EXAMPLE 33 5 RABBIT SURGICAL ADHESIONS MODEL TO ASSESS FIBROSIS INHIBITING AGENTS The rabbit uterine horn model is used to assess the anti-fibrotic capacity of formulations in vivo. Mature New Zealand White (NZW) female rabbits are placed under general anesthetic. Using aseptic precautions, the abdomen is opened in two layers at the midline to expose the uterus. Both 10 uterine horns are lifted out of the abdominal cavity and assessed for size on the French Scale of catheters. Horns between #8 and #14 on the French Scale (2.5-4.5 mm diameter) are deemed suitable for this model. Both uterine horns and the opposing peritoneal wall are abraded with a #10 scalpel blade at a 450 angle over an area 2.5 cm in length and 0.4 cm in width until punctuate 15 bleeding is observed. Abraded surfaces are tamponaded until bleeding stops. The individual horns are then opposed to the peritoneal wall and secured by two sutures placed 2 mm beyond the edges of the abraded area. The formulation is applied and the abdomen is closed in three layers. After 14 days, animals are evaluated post mortem with the extent and severity of adhesions 20 being scored both quantitatively and qualitatively. EXAMPLE 34 SCREENING PROCEDURE FOR ASSESSMENT OF PERIGRAFT REACTION Large domestic rabbits are placed under general anesthetic. Using aseptic precautions, the infrarenal abdominal aorta is exposed and 25 clamped at its superior and inferior aspects. A longitudinal arterial wall arteriotomy is performed and a 2 millimeter diameter, 1 centimeter long segment of PTFE graft is inserted within the aorta and the proximal and distal aspect of the graft is sewn so that the entire aortic blood flow is through the 148 WO 2004/060346 PCT/US2003/041580 graft which is contained in the abdominal aorta in the manner of open surgical abdominal aortic repair in humans (except that no aneurysm is present in this model). The aortotomy is then surgically closed and the abdominal wound closed and the animal recovered. 5 The animals are randomized to receive standard PTFE grafts or grafts of which the middle 1 cm is coated alone circumferentially with nothing, or with an agent that induces a vessel wall reaction or adhesion between a stent graft and vessel wall alone or contained in a slow release, polymer. The animals are sacrificed between 1 and 6 weeks post surgery, 10 the aorta is removed en bloc and the area in relation to the graft is grossly examined for adhesive reaction. Any difference in morphology or histology of the vessel wall from portions of the artery which contain no graft, portion which contain graft without coating, and portion which contained graft with coating is noted. 15 EXAMPLE 35 ANIMAL ABDOMINAL AORTic ANEURYSM MODEL Pigs or sheep are placed under general anesthetic. Using aseptic precautions the abdominal aorta is exposed. The animal is heparinized and the aorta is cross clamped below the renal arteries and above the bifurcation. 20 Collaterals are temporarily controlled with vessel loops or clips that are removed upon completion of the procedure. A longitudinal aortotomy is created in the arterial aspect of the aorta, and an elliptical shaped patch of rectus sheath from the same animal is sutured into the aortotomy to create an aneurysm. The aortic clamps from the lumbar arteries and collaterals are 25 removed and the abdomen closed. After 30 days, the animal is reanesthesized and the abdominal wall again opened. A cutdown is performed on the iliac artery and through this, a stent graft is positioned across the infrarenal abdominal aorta aneurysm extending from normal infrarenal abdominal aorta above to normal infrarenal abdominal aorta below the surgically created 30 aneurysm and the device is released in a conventional way. 149 WO 2004/060346 PCT/US2003/041580 Animals are randomized into groups of 5 receiving uncoated stent grafts, stent graft containing slow release polymer alone, and stent graft containing a biologically active or irritative substance as determined by the previously mentioned screening exam. After closure of the arteriotomy and of 5 the abdominal wound, the animal is allowed to recover. At 6 weeks and 3 months post stent graft insertion, the animal is sacrificed and the aorta removed en bloc. The infrarenal abdominal aorta is examined for evidence of histologic reaction and perigraft leaking. EXAMPLE 36 10 SCREENING PROCEDURE FOR ASSESSMENT OF PERIGRAFT REACTION Large domestic rabbits are placed under general anesthetic. Using aseptic precautions, the infrarenal abdominal aorta is exposed and clamped at its superior and inferior aspects. A longitudinal arterial wall arteriotomy is performed and a 2 millimeter diameter, 1 centimeter long 15 segment of PTFE graft is inserted within the aorta and the proximal and distal aspect of the graft is sewn so that the entire aortic blood flow is through the graft which is contained in the abdominal aorta in the manner of open surgical abdominal aortic repair in humans (except that no aneurysm is present in this model). The aortotomy is then surgically closed and the abdominal wound 20 closed and the animal recovered. The animals are randomized to receive standard PTFE grafts, silk stent grafts, or silk stent grafts coated with other agents as described above. The animals are sacrificed between 1 and 6 weeks post surgery, the aorta is removed en bloc and the area in relation to the graft is grossly 25 examined for adhesive reaction. Any difference in morphology or histology of the vessel wall from portions of the artery that contain no graft, portion which contain graft without coating, and portion which contained graft with coating is noted. 150 WO 2004/060346 PCT/US2003/041580 All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. 5 From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. 151

权利要求:
Claims (126)
[1] 1. A biocompatible gel-forming drug-delivering composition for in vivo administration, comprising: a drug; a first component comprising at least one sulfhydryl group containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 (SH)m,, wherein m 2; and a second component comprising at least one sulfhydryl reactive group-containing compound in either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; wherein at least one of the first or second components is a polyalkylene oxide and wherein the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute.
[2] 2. The composition of claim 1, wherein m and n are each 4.
[3] 3. The composition of claim 1, wherein m and n are each 12.
[4] 4. The composition of claim 1, wherein the first component is a polyalkylene oxide.
[5] 5. The composition of claim 1, wherein the second component is a polyalkylene oxide. 152 WO 2004/060346 PCT/US2003/041580
[6] 6. The composition of claim 1, wherein the first and second components are polyalkylene oxides.
[7] 7. The composition of claim 6, wherein the polyalkylene oxides are polyethylene glycol.
[8] 8. The composition of claim 1, wherein only one of the first or second components is a polyalkylene oxide.
[9] 9. The composition of claim 8, wherein one of the components is a polyalkylene oxide and the other component is a functionally activated succinimidyl or maleimidyl compound which is not a polymer.
[10] 10. The composition of claim 1, wherein the covalent bonds are thioester linkages.
[11] 11. The composition of claim 1, wherein the covalent bonds are thioether linkages.
[12] 12. The composition of claim 1, wherein the covalent bonds are sulfhydryl linkages.
[13] 13. The composition of claim 1, wherein the drug is hydrophobic.
[14] 14. The composition of claim 1, wherein the drug is an angiogenesis inhibitor.
[15] 15. The composition of claim 1, wherein the drug is a 5 Lipoxygenase inhibitor or antagonist. 153 WO 2004/060346 PCT/US2003/041580
[16] 16. The composition of claim 1, wherein the drug is a chemokine receptor antagonist.
[17] 17. The composition of claim 1, wherein the drug is a cell cycle inhibitor or an analogue or derivative thereof.
[18] 18. The composition of claim 17, wherein the cell cycle inhibitor is a microtubule stabilizing agent.
[19] 19. The composition of claim 18, wherein the microtubule stabilizing agent is paclitaxel, docetaxel, or Peloruside A.
[20] 20. The composition of claim 17, wherein the cell cycle inhibitor is a taxane.
[21] 21. The composition of claim 18, wherein the taxane is paclitaxel or an analogue or derivative thereof.
[22] 22. The composition of claim 17, wherein the cell cycle inhibitor is an antimetabolite, an alkylating agent, or a vinca alkaloid.
[23] 23. The composition of claim 22, wherein the vinca alkaloid is vinblastine, vincristine, vincristine sulfate, vindesine, vinorelbine, or an analogue or derivative thereof.
[24] 24. The composition of claim 17, wherein the cell cycle inhibitor is camptothecin or an analogue or derivative thereof.
[25] 25. The composition of claim 17, wherein the cell cycle inhibitor is selected from the group consisting of mitoxantrone, etoposide, 5-fluorouracil, 154 WO 2004/060346 PCT/US2003/041580 doxorubicin, methotrexate, Mitomycin-C, CDK-2 inhibitors, and analogues and derivatives thereof.
[26] 26. The composition of claim 1, wherein the drug is a cyclin dependent protein kinase inhibitor or an analogue or derivative thereof.
[27] 27. The composition of claim 1, wherein the drug is an EGF (epidermal growth factor) kinase inhibitor or an analogue or derivative thereof.
[28] 28. The composition of claim 1, wherein the drug is an elastase inhibitor or an analogue or derivative thereof.
[29] 29. The composition of claim 1, wherein the drug is a factor Xa inhibitor or an analogue or derivative thereof.
[30] 30. The composition of claim 1, wherein the drug is a farnesyltransferase inhibitor or an analogue or derivative thereof.
[31] 31. The composition of claim 1, wherein the drug is a fibrinogen antagonist or an analogue or derivative thereof.
[32] 32. The composition of claim 1, wherein the drug is a guanylate cyclase stimulant or an analogue or derivative thereof.
[33] 33. The composition of claim 1, wherein the drug is a heat shock protein 90 antagonist or an analogue or derivative thereof.
[34] 34. The composition of claim 1, wherein the drug is an HMGCoA reductase inhibitor or an analogue or derivative thereof. 155 WO 2004/060346 PCT/US2003/041580
[35] 35. The composition of claim 1, wherein the drug is a hydroorotate dehydrogenase inhibitor or an analogue or derivative thereof.
[36] 36. The composition of claim 1, wherein the drug is an IKK2 inhibitor or an analogue or derivative thereof.
[37] 37. The composition of claim 1, wherein the drug is an IL-1, ICE, or IRAK antagonist or an analogue or derivative thereof.
[38] 38. The composition of claim 1, wherein the drug is an IL-4 agonist or an analogue or derivative thereof.
[39] 39. The composition of claim 1, wherein the drug is an immunomodulatory is rapamycin, tacrolimus, everolimus, biolimus, or an analogue or derivative thereof.
[40] 40. The composition of claim 1, wherein the drug is an inosine monophosphate dehydrogenase inhibitor or an analogue or derivative thereof.
[41] 41. The composition of claim 1, wherein the drug is a leukotreine inhibitor or an analogue or derivative thereof.
[42] 42. The composition of claim 1, wherein the drug is a MCP-1 antagonist or an analogue or derivative thereof.
[43] 43. The composition of claim 1, wherein the drug is a MMP inhibitor or an analogue or derivative thereof.
[44] 44. The composition of claim 1, wherein the drug is a NF kappa B inhibitor or an analogue or derivative thereof. 156 WO 2004/060346 PCT/US2003/041580
[45] 45. The composition of claim 1, wherein the drug is a NO antagonist or an analogue or derivative thereof.
[46] 46. The composition of claim 1, wherein the drug is a P38 MAP kinase inhibitor or an analogue or derivative thereof.
[47] 47. The composition of claim 1, wherein the drug is a phosphodiesterase inhibitor or an analogue or derivative thereof.
[48] 48. The composition of claim 1, wherein the drug is a TGF beta Inhibitor or an analogue or derivative thereof.
[49] 49. The composition of claim 1, wherein the drug is a thromboxane A2 antagonist or an analogue or derivative thereof.
[50] 50. The composition of claim 1, wherein the drug is a TNFa Antagonist, a TACE, or an analogue or derivative thereof.
[51] 51. The composition of claim 1, wherein the drug is a tyrosine kinase inhibitor or an analogue or derivative thereof.
[52] 52. The composition of claim 1, wherein the drug is a vitronectin inhibitor or an analogue or derivative thereof.
[53] 53. The composition of claim 1, wherein the drug is a fibroblast growth factor inhibitor or an analogue or derivative thereof.
[54] 54. The composition of claim 1, wherein the drug is a protein kinase inhibitor or an analogue or derivative thereof. 157 WO 2004/060346 PCT/US2003/041580
[55] 55. The composition of claim 1, wherein the drug is a PDGF receptor kinase inhibitor or an analogue or derivative thereof.
[56] 56. The composition of claim 1, wherein the drug is an endothelial growth factor receptor kinase inhibitor or an analogue or derivative thereof.
[57] 57. The composition of claim 1, wherein the drug is a retinoic acid receptor antagonist or an analogue or derivative thereof.
[58] 58. The composition of claim 1, wherein the drug is a platelet derived growth factor receptor kinase inhibitor or an analogue or derivative thereof.
[59] 59. The composition of claim 1, wherein the drug is a fibrinogin antagonist or an analogue or derivative thereof.
[60] 60. The composition of claim 1, wherein the drug is an antimycotic agent or an analogue or derivative thereof.
[61] 61. The composition of claim 1, wherein the drug is a bisphosphonate or an analogue or derivative thereof.
[62] 62. The composition of claim 1, wherein the drug is a phospholipase Al inhibitor or an analogue or derivative thereof.
[63] 63. The composition of claim 1, wherein the drug is a histamine H1/H2/H3 receptor antagonist or an analogue or derivative thereof.
[64] 64. The composition of claim 1, wherein the drug is a macrolide antibiotic or an analogue or derivative thereof. 158 WO 2004/060346 PCT/US2003/041580
[65] 65. The composition of claim 1, wherein the drug is an GPIIb Ila receptor antagonist or an analogue or derivative thereof.
[66] 66. The composition of claim 1, wherein the drug is an endothelin receptor antagonist or an analogue or derivative thereof.
[67] 67. The composition of claim 1, wherein the drug is a peroxisome proliferators-activated receptor agonist or an analogue or derivative thereof.
[68] 68. The composition of claim 1, wherein the drug is an estrogen receptor agent or an analogue or derivative thereof.
[69] 69. The composition of claim 1, wherein the drug is somatostatin or an analogue or derivative thereof.
[70] 70. The composition of claim 1, wherein the drug is a JNK Kinase inhibitor or an analogue or derivative thereof.
[71] 71. The composition of claim 1, wherein the drug is a melanocortin or an analogue or derivative thereof.
[72] 72. The composition of claim 1, wherein the drug is a raf kinase inhibitor or analogue or derivative thereof.
[73] 73. The composition of claim 1, wherein the drug is a lysylhydroxylase inhibitor or an analogue or derivative thereof.
[74] 74. The composition of claim 1, wherein the drug is an IKK 1/2 inhibitor or an analogue or derivative thereof. 159 WO 2004/060346 PCT/US2003/041580
[75] 75. The composition of claim 1, further comprising an anti inflammatory agent, an antithrombotic agent, an antibiotic, or a combination thereof.
[76] 76. The composition of claim 1, wherein the drug further comprises a polymer.
[77] 77. The polymer of claim 76, wherein the polymer is a polymer or copolymer comprising one or more of the residue units of the monomers, lactic acid, glycolic acid, D-lactide, L-lactide, D,L-lactide, glycolide, e caprolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one,
[78] 78. The polymer of claim 77, wherein the polymer is a block copolymers of the for A-B, A-B-A or B-A-B where A is a poly(alkylene oxide) and B is a degradable polyester.
[79] 79. The poly(alkylene oxide) in claim 78, wherein the poly(alkylene oxide) is poly(ethylene glycol), poly(propylene glycol), copolymers of ethylene oxide and propylene oxide or mono alkyl ethers thereof
[80] 80. The composition of claim 76, wherein the polymer is in the form of a microsphere.
[81] 81. The composition of claim 76, wherein the polymer is in the form of a nanosphere.
[82] 82. The composition of claim 76, wherein the polymer is in the form of a micelle. 160 WO 2004/060346 PCT/US2003/041580
[83] 83. The composition of claim 1, wherein the drug further comprises a non-polymeric carrier.
[84] 84. The composition of claim 1, wherein the drug is a hydrophobic drug in admixture with a secondary carrier to provide drug/carrier, the drug/carrier being in admixture with the first component to provide drug/carrier/first component, the drug/carrier/first component being suspended in an aqueous buffer solution.
[85] 85. The composition of claim 1, wherein the drug is hydrophilic.
[86] 86. The composition of claim 1, wherein the drug is a hydrophilic drug in admixture with a secondary carrier to provide drug/carrier, the drug/carrier being in admixture with the first component to provide drug/carrier/first component, the drug/carrier/first component being suspended in an aqueous buffer solution.
[87] 87. The composition of claim 1, wherein the first component is suspended in a buffer solution comprising a mixture of phosphate buffer and carbonate buffer.
[88] 88. The composition of claim 2, wherein the second component comprises a mixture of succinimidyl polyalkylene oxide and maleimidyl polyalkylene oxide.
[89] 89. A method for treating tissues, comprising the steps of: administering to a tissue site a first component comprising at least one sulfhydryl group-containing compound in liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; and 161 WO 2004/060346 PCT/US2003/041580 simultaneously or subsequently administering to the tissue site a second component comprising at least one sulfhydryl reactive group-containing compound either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2, and wherein at least one of the first or second components is a polyalkylene oxide; and simultaneously or subsequently administering to the tissue site a drug; and allowing the sulfhydryl groups and the sulfhydryl reactive groups to react with one another to form covalent bonds therebetween to form a gel in less than one minute.
[90] 90. A biocompatible gel-forming drug-delivering composition for in vivo administration with a gel time of less than one minute, comprising: polyalkylene oxide-(SH) 4 and drug in a liquid medium having a pH of between 8 and 10.5; and polyalkylene oxide-Y 4 , wherein Y is succinimidyl, in a liquid medium having an acidic pH.
[91] 91. A biocompatible gel-forming drug-delivering composition for in vivo administration with a gel time of less than one minute, comprising: polyalkylene oxide-(SH) 12 and drug in a liquid medium having an alkaline pH; and polyalkylene oxide-Y 1 2 in a liquid medium having an acidic pH, wherein Y is a succinimidyl or maleimidyl group.
[92] 92. A biocompatible gel-forming composition for in vivo administration, comprising: 162 WO 2004/060346 PCT/US2003/041580 a sulfhydryl group-containing polyalkylene oxide in a liquid medium having an acidic pH, wherein said sulfhydryl group-containing polyalkylene oxide is given by the formula Core-(SH)m, wherein m 2; a buffer solution with an alkaline pH; and drug in admixure with the polyalkylene oxide and/or the buffer solution; wherein the sulfhydryl groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute.
[93] 93. A biocompatible gel-forming drug-delivering composition for in vivo administration, comprising: at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; at least one sulfhydryl reactive group-containing compound either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; at least one drug in admixture with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl reactive group-containing compound; and collagen; wherein at least one of either the sulfhydryl group-containing compound or the sulfhydryl reactive group-containing compound is a polyalkylene oxide, and wherein the sulfhydryl groups and the sulfhydryl reactive groups are capable of reacting with one another to form covalent bonds therebetween.
[94] 94. The composition of claim 93, wherein m and n are each 4. 163 WO 2004/060346 PCT/US2003/041580
[95] 95. The composition of claim 93, wherein m and n are each 12.
[96] 96. The composition of claim 93 wherein the sulfhydryl group containing compound is a polyalkylene oxide.
[97] 97. The composition of claim 93, wherein the sulfhydryl reactive group-containing compound is a polyalkylene oxide.
[98] 98. The composition of claim 93, wherein both the sulfhydryl group-containing compound and the sulfhydryl reactive group-containing compound are polyalkylene oxides.
[99] 99. The composition of claim 98, wherein both the sulfhydryl group-containing compound and the sulfhydryl reactive group-containing compound are polyalkylene oxides.
[100] 100. The composition of claim 93, wherein only one of the first or second components is a polyalkylene oxide.
[101] 101. The composition of claim 100, wherein one of the components is a polyalkylene oxide and the other component is a functionally activated succinimidyl or maleimidyl compound which is not a polymer.
[102] 102. The composition of claim 93, wherein the covalent bonds are thioester linkages.
[103] 103. The composition of claim 93, wherein the covalent bonds are thioether linkages.
[104] 104. The composition of claim 93, wherein the covalent bonds are sulfhydryl linkages. 164 WO 2004/060346 PCT/US2003/041580
[105] 105. The composition of claim 93, wherein the drug is a hydrophobic drug.
[106] 106. The composition of claim 93, wherein the drug is a hydrophobic drug in admixture with a secondary carrier to provide drug/carrier, the drug/carrier being in admixture with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl reactive group-containing compound.
[107] 107. The composition of claim 93, wherein the sulfhydryl group containing compound is suspended in a buffer solution comprising a mixture of phosphate buffer and carbonate buffer.
[108] 108. The composition of claim 93, wherein the sulfhydryl reactive group-containing compound comprises a mixture of succinimidyl polyalkylene oxide and maleimidyl polyalkylene oxide.
[109] 109. The composition of claim 93, wherein the collagen is methylated collagen.
[110] 110. A biocompatible gel-forming drug-delivering composition for in vivo administration, comprising: (a) a first component in a liquid medium having an acidic pH comprising: (i) at least one sulfhydryl group-containing compound given by the formula Compound 1 -(SH)m, wherein m 2; (ii) at least one sulfhydryl reactive group-containing compound given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; and (iii) collagen; and 165 WO 2004/060346 PCT/US2003/041580 (b) a second component comprising a buffer having a pH of between 8 and 10.5; wherein a drug is present in admixture with either or both of the first component or the second component; and wherein at least one of either the sulfhydryl group containing compound or the sulfhydryl reactive group containing compound is a polyalkylene oxide.
[111] 111. The composition of claim 110 wherein the collagen is methylated collagen.
[112] 112. The composition of claim 110 wherein the second component is a buffer solution comprising a mixture of phosphate buffer and carbonate buffer.
[113] 113. A method for forming a drug delivery composition, comprising a) selecting a first component, a second component and a drug, wherein the first component comprises at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; and the second component comprises at least one sulfhydryl reactive group-containing compound in either a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n ; at least one of the first or second components is a polyalkylene oxide; 166 WO 2004/060346 PCT/US2003/041580 the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute; b) combining the first and second components in the presence of the drug, under conditions where the first component reacts with the second component.
[114] 114. A product produced by the method of claim 113.
[115] 115. A method for forming a drug delivery composition, comprising a) forming an admixture of polyalkylene oxide-(SH) 4 and drug in a liquid medium having a pH of between 8 and 10.5; and b) forming an admixture of polyalkylene oxide-Y 4 , wherein Y is succinimidyl and liquid medium, the admixture having an acidic pH.
[116] 116. The method of claim 115 further comprising combining the admixtures of steps a) and b).
[117] 117. A product produced by the method of claim 116.
[118] 118. A method for forming a biocompatible gel-forming drug delivering composition for in vivo administration with a gel time of less than one minute, comprising: a) preparing an admixture of polyalkylene oxide-(SH) 1 2 and drug in a liquid medium having an alkaline pH; and b) preparing polyalkylene oxide-Y 12 in a liquid medium having an acidic pH, wherein Y is a succinimidyl or maleimidyl group.
[119] 119. The method of claim 118 further comprising combining a) and b). 167 WO 2004/060346 PCT/US2003/041580
[120] 120. The product produced by the method of claim 119.
[121] 121. A method for forming a biocompatible gel-forming composition for in vivo administration, comprising: a) preparing a sulfhydryl group-containing polyalkylene oxide in a liquid medium having an acidic pH, wherein said sulfhydryl group containing polyalkylene oxide is given by the formula Core-(SH)m, wherein m 2; b) providing a buffer solution with an alkaline pH; and c) adding drug to either or both of a) and b); wherein the sulfhydryl groups react with one another to form covalent bonds therebetween when said components are mixed together to form a gel in less than one minute.
[122] 122. The method of claim 121 further comprising combining a) and b).
[123] 123. The product produced by the method of claim 122.
[124] 124. A method for forming a biocompatible gel-forming drug delivering composition for in vivo administration, comprising: a) providing an at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; b) providing an at least one sulfhydryl reactive group containing compound either in a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; 168 WO 2004/060346 PCT/US2003/041580 c) combining a drug with either or both of the at least one sulfhydryl group-containing compound and the at least one sulfhydryl reactive group-containing compound; and d) providing collagen; wherein at least one of either the sulfhydryl group-containing compound or the sulfhydryl reactive group-containing compound is a polyalkylene oxide; and wherein the sulfhydryl groups and the sulfhydryl reactive groups are capable of reacting with one another to form covalent bonds therebetween.
[125] 125. A method for forming a biocompatible gel-forming drug delivering composition for in vivo administration, comprising: a) providing an at least one sulfhydryl group-containing compound in a liquid medium having an alkaline pH, wherein said sulfhydryl group-containing compound is given by the formula Compound 1 -(SH)m, wherein m 2; b) providing an at least one sulfhydryl reactive group containing compound either in a liquid medium having a neutral or acidic pH or in powder form, wherein said sulfhydryl reactive group-containing compound is given by the formula Compound 2 -Yn, wherein Y is a sulfhydryl reactive group and wherein n 2; and c) providing collagen; wherein at least one of either the sulfhydryl group-containing compound or the sulfhydryl reactive group-containing compound is a polyalkylene oxide; and wherein the sulfhydryl groups and the sulfhydryl reactive groups are capable of reacting with one another to form covalent bonds therebetween.
[126] 126. The product produced by the method of claim 125. 169

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

CN110960507A|2018-09-30|2020-04-07|复旦大学|Calcium phosphate-lipid nano-drug co-delivery system composed of low-molecular-weight heparin and natural drug prodrug|

---

CN110960507B|2018-09-30|2022-03-18|复旦大学|Calcium phosphate-lipid nano-drug co-delivery system composed of low-molecular-weight heparin and natural drug prodrug|US3387001A|1964-10-19|1968-06-04|Lilly Co Eli|Novel aminoacyl esters of desacetyl vincaleukoblastine|

---

US3619371A|1967-07-03|1971-11-09|Nat Res Dev|Production of a polymeric matrix having a biologically active substance bound thereto|

---

SE343210B|1967-12-20|1972-03-06|Pharmacia Ab||

---

US3742955A|1970-09-29|1973-07-03|Fmc Corp|Fibrous collagen derived product having hemostatic and wound binding properties|

---

US3894000A|1971-01-27|1975-07-08|Upjohn Co|Ara-cytidine derivatives and process of preparation|

---

US4066650A|1971-02-11|1978-01-03|Egyud Laszlo G|Keto-aldehyde-amine addition products and method of making same|

---

CA955937A|1971-06-28|1974-10-08|Shionogi And Co. Ltd.|Cyclic phosphamide derivatives|

---

US3810473A|1972-12-04|1974-05-14|Avicon Inc|Liquid-laid, non-woven, fibrous collagen derived surgical web having hemostatic and wound sealing properties|

---

US3876501A|1973-05-17|1975-04-08|Baxter Laboratories Inc|Binding enzymes to activated water-soluble carbohydrates|

---

US3991045A|1973-05-30|1976-11-09|Asahi Kasei Kogyo Kabushiki Kaisha|N4 -acylarabinonucleosides|

---

GB1479268A|1973-07-05|1977-07-13|Beecham Group Ltd|Pharmaceutical compositions|

---

US4179337A|1973-07-20|1979-12-18|Davis Frank F|Non-immunogenic polypeptides|

---

DE2360794C2|1973-12-06|1984-12-06|Hoechst Ag, 6230 Frankfurt|Process for the production of peptides|

---

DE2546073A1|1974-10-15|1976-04-22|Asahi Chemical Ind|NUCLEOTIDE DERIVATIVES AND THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE IN MEDICINAL PRODUCTS|

---

US4012390A|1974-10-16|1977-03-15|Eli Lilly And Company|Vinblastinoic acid|

---

US3949073A|1974-11-18|1976-04-06|The Board Of Trustees Of Leland Stanford Junior University|Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution|

---

CH596313A5|1975-05-30|1978-03-15|Battelle Memorial Institute||

---

US4279817A|1975-05-30|1981-07-21|The United States Of America As Represented By The Department Of Health & Human Services|Method for producing dimer alkaloids|

---

IL47468A|1975-06-12|1979-05-31|Rehovot Res Prod|Process for the cross-linking of proteins using water soluble cross-linking agents|

---

US4258052A|1976-08-17|1981-03-24|Yu Ruey J|Treatment of psoriasis with nicotinamide analogues|

---

US4233360A|1975-10-22|1980-11-11|Collagen Corporation|Non-antigenic collagen and articles of manufacture|

---

US4488911A|1975-10-22|1984-12-18|Luck Edward E|Non-antigenic collagen and articles of manufacture|

---

US4057548A|1975-11-11|1977-11-08|Jacek Wiecko|Process for preparing methotrexate or an N-substituted derivative thereof and/or a di alkyl ester thereof and precursor therefor|

---

JPS549179B2|1976-01-22|1979-04-21|||

---

US4002531A|1976-01-22|1977-01-11|Pierce Chemical Company|Modifying enzymes with polyethylene glycol and product produced thereby|

---

NL7704659A|1976-05-12|1977-11-15|Battelle Institut E V|BONE REPLACEMENT, BONE JOINT, OR PROSTHESIS ANCHORING MATERIAL.|

---

DE2623420C2|1976-05-25|1978-07-06|Stiftung Deutsches Krebsforschungszentrum, 6900 Heidelberg|Process for the preparation of asymmetrically 13-disubstituted nitrosoureas|

---

GB1578348A|1976-08-17|1980-11-05|Pharmacia Ab|Products and a method for the therapeutic suppression of reaginic antibodies responsible for common allergic|

---

USRE30561E|1976-12-06|1981-03-31|Eli Lilly And Company|Vinca alkaloid intermediates|

---

JPS5512915B2|1977-02-03|1980-04-04|||

---

JPS53149985A|1977-05-31|1978-12-27|Asahi Chem Ind Co Ltd|Preparation of 5-fluorouracil derivatives|

---

US4164559A|1977-09-21|1979-08-14|Cornell Research Foundation, Inc.|Collagen drug delivery device|

---

SE7903361L|1978-04-20|1979-10-21|Johnson Matthey Co Ltd|COMPOSITIONS CONTAINING PLATINUM|

---

US4238480A|1978-05-19|1980-12-09|Sawyer Philip Nicholas|Method for preparing an improved hemostatic agent and method of employing the same|

---

US4390519A|1978-05-19|1983-06-28|Sawyer Philip Nicholas|Bandage with hemostatic agent and methods for preparing and employing the same|

---

US4404970A|1978-05-19|1983-09-20|Sawyer Philip Nicholas|Hemostatic article and methods for preparing and employing the same|

---

US4215062A|1978-05-22|1980-07-29|University Of Kansas Endowment Association|Anthracycline synthesis|

---

US4296105A|1978-08-03|1981-10-20|Institut International De Pathologie Cellulaire Et Moleculaire|Derivatives of doxorubicine, their preparation and use|

---

US4259242A|1978-10-10|1981-03-31|Eli Lilly And Company|Method of preparing vindesine sulfate|

---

JPS5559173A|1978-10-27|1980-05-02|Kaken Pharmaceut Co Ltd|Novel fluorouracil derivative|

---

US4210584A|1979-01-15|1980-07-01|Eli Lilly And Company|Vindesine synthesis|

---

JPS6023084B2|1979-07-11|1985-06-05|Ajinomoto Kk||

---

US4279812A|1979-09-12|1981-07-21|Seton Company|Process for preparing macromolecular biologically active collagen|

---

US4412947A|1979-09-12|1983-11-01|Seton Company|Collagen sponge|

---

US4371540A|1979-09-14|1983-02-01|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services|Nitroimidazoles of low toxicity and high activity as radiosensitizers of hypoxic tumor cells|

---

DE2943520C2|1979-10-27|1982-05-19|Fa. Carl Freudenberg, 6940 Weinheim|Process for the production of collagen sponge for medical or cosmetic purposes|

---

US4639456A|1980-06-10|1987-01-27|Omnichem S.A.|Vinblastin-23-oyl amino acid derivatives|

---

US4374414A|1980-06-26|1983-02-15|Gte Automatic Electric Labs Inc.|Arbitration controller providing for access of a common resource by a duplex plurality of central processing units|

---

CS216992B1|1980-07-21|1982-12-31|Miroslav Stol|Composite polymere material for the biological and medicinal utilitation and method of preparation thereof|

---

US4299778A|1980-07-21|1981-11-10|Shell Oil Company|N'Cyclopropyl-N--N-hydroxyureas|

---

JPS5929199B2|1980-08-25|1984-07-18|Ichimaru Fuarukosu Kk||

---

US4314380A|1980-09-26|1982-02-09|Koken Co., Ltd.|Artificial bone|

---

US4367239A|1980-09-29|1983-01-04|Kefalas A/S|Nitrosourea derivatives, pharmaceutical compositions thereof and method of preparation|

---

US4301277A|1980-10-20|1981-11-17|Sri International|3-Deamino-3- derivatives of daunorubicin and doxorubicin|

---

JPS5775993A|1980-10-30|1982-05-12|Tetsuo Suami|Novel nitrosourea derivative and its preparation|

---

JPS6041078B2|1980-11-05|1985-09-13|Nitsushin Seito Kk||

---

US4415665A|1980-12-12|1983-11-15|Pharmacia Fine Chemicals Ab|Method of covalently binding biologically active organic substances to polymeric substances|

---

US4314054A|1981-03-23|1982-02-02|Sri International|3'-Deamino-3'- derivatives of daunorubicin and doxorubicin|

---

US4494547A|1981-03-30|1985-01-22|North Carolina Central University|2H-isoindolediones, their synthesis and use as radiosensitizers|

---

US4414147A|1981-04-17|1983-11-08|Massachusetts Institute Of Technology|Methods of decreasing the hydrophobicity of fibroblast and other interferons|

---

US4375432A|1981-05-12|1983-03-01|Eli Lilly And Company|Method of preparing vincristine|

---

JPH026337B2|1981-06-10|1990-02-08|Ajinomoto Kk||

---

US4451568A|1981-07-13|1984-05-29|Battelle Memorial Institute|Composition for binding bioactive substances|

---

US4357274A|1981-08-06|1982-11-02|Intermedicat Gmbh|Process for the manufacture of sclero protein transplants with increased biological stability|

---

US4415628A|1981-10-26|1983-11-15|Seton Company|Moisture vapor permeable sheet materials|

---

JPH0525470B2|1981-10-30|1993-04-13|Nippon Chemiphar Co||

---

US4424208A|1982-01-11|1984-01-03|Collagen Corporation|Collagen implant material and method for augmenting soft tissue|

---

US4462992A|1982-02-08|1984-07-31|Research Corporation|Nitroimidazole radiosensitizers for hypoxic tumor cells and compositions thereof|

---

US4582640A|1982-03-08|1986-04-15|Collagen Corporation|Injectable cross-linked collagen implant material|

---

US4578067A|1982-04-12|1986-03-25|Alcon Inc.|Hemostatic-adhesive, collagen dressing for severed biological surfaces|

---

JPS6320143B2|1982-04-19|1988-04-26|Koken Kk||

---

US4563351A|1983-08-01|1986-01-07|Forsyth Dental Infirmary For Children|Self-gelling therapeutic compositions for topical application|

---

US4585859A|1983-05-24|1986-04-29|Sri International|Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin|

---

US4544516A|1982-07-28|1985-10-01|Battelle Development Corporation|Collagen orientation|

---

US4737544A|1982-08-12|1988-04-12|Biospecific Technologies, Inc.|Biospecific polymers|

---

US4973493A|1982-09-29|1990-11-27|Bio-Metric Systems, Inc.|Method of improving the biocompatibility of solid surfaces|

---

JPS59219300A|1983-05-27|1984-12-10|Nisshin Seito Kk|Sucrose nitrosourea derivative|

---

JPS6237020B2|1983-07-27|1987-08-10|Koken Kk||

---

US4902791A|1983-08-30|1990-02-20|Sanofi S.A.|Nitrosourea derivatives, process for their preparation and medicaments containing them|

---

US4490529A|1983-09-06|1984-12-25|Dana-Farber Cancer Institute, Inc.|Cysteic acid and homocysteic acid analogues of methotrexate and aminopterin|

---

US4894364A|1983-10-26|1990-01-16|Greer Sheldon B|Method and materials for sensitizing neoplastic tissue to radiation|

---

US4515637A|1983-11-16|1985-05-07|Seton Company|Collagen-thrombin compositions|

---

US4496689A|1983-12-27|1985-01-29|Miles Laboratories, Inc.|Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer|

---

CA1295796C|1984-03-27|1992-02-18|Conrad Whyne|Biodegradable matrix and methods for producing same|

---

JPS6110511A|1984-06-26|1986-01-18|Sumitomo Chem Co Ltd|Radiosensitizer for hypoxic cell|

---

US4789663A|1984-07-06|1988-12-06|Collagen Corporation|Methods of bone repair using collagen|

---

US4681091A|1984-08-03|1987-07-21|Picker Donald H|Combination modality cancer therapy|

---

JPH0575429B2|1984-08-07|1993-10-20|Ube Industries||

---

US4553974A|1984-08-14|1985-11-19|Mayo Foundation|Treatment of collagenous tissue with glutaraldehyde and aminodiphosphonate calcification inhibitor|

---

US4687820A|1984-08-22|1987-08-18|Cuno Incorporated|Modified polypeptide supports|

---

US4557764A|1984-09-05|1985-12-10|Collagen Corporation|Process for preparing malleable collagen and the product thereof|

---

US4563350A|1984-10-24|1986-01-07|Collagen Corporation|Inductive collagen based bone repair preparations|

---

US4588831A|1984-11-09|1986-05-13|Natec|Platinum complex compounds of substituted 5,8-dihydroxyl-1,4-naphthoquinone, and process for their production and use|

---

GB8430252D0|1984-11-30|1985-01-09|Beecham Group Plc|Compounds|

---

US4894366A|1984-12-03|1990-01-16|Fujisawa Pharmaceutical Company, Ltd.|Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same|

---

US4600533A|1984-12-24|1986-07-15|Collagen Corporation|Collagen membranes for medical use|

---

SU1261253A1|1984-12-27|1990-10-07|Отделение Института химической физики АН СССР|Oxoammonium derivatives of nitrosourea displaying antitumor activity, and method of producing same|

---

US4732863A|1984-12-31|1988-03-22|University Of New Mexico|PEG-modified antibody with reduced affinity for cell surface Fc receptors|

---

JPS61167616A|1985-01-22|1986-07-29|Adeka Argus Chem Co Ltd|Radiation-sensitizing agent|

---

US4841045A|1985-03-12|1989-06-20|University Of Vermont & State Agricultural College|Synthesis of vinblastine and vincristine type compounds|

---

US4642117A|1985-03-22|1987-02-10|Collagen Corporation|Mechanically sheared collagen implant material and method|

---

CA1260391A|1985-03-28|1989-09-26|Karl A. Piez|Xenogeneic collagen/mineral preparations in bonerepair|

---

US5032617A|1985-05-03|1991-07-16|Sri International|Substituted benzamide radiosensitizers|

---

US5215738A|1985-05-03|1993-06-01|Sri International|Benzamide and nicotinamide radiosensitizers|

---

FR2582651B1|1985-06-03|1987-08-28|Pf Medicament|PROCESS FOR THE PREPARATION OF VINCRISTINE|

---

DE3521684C2|1985-06-18|1989-04-06|Dr. Mueller-Lierheim Kg, Biologische Laboratorien, 8033 Planegg, De||

---

EP0206448B1|1985-06-19|1990-11-14|Ajinomoto Co., Inc.|Hemoglobin combined with a poly|

---

US4766106A|1985-06-26|1988-08-23|Cetus Corporation|Solubilization of proteins for pharmaceutical compositions using polymer conjugation|

---

JPS6230777A|1985-08-01|1987-02-09|Taisho Pharmaceut Co Ltd|Imidazole derivative|

---

JPS6230768A|1985-08-01|1987-02-09|Taisho Pharmaceut Co Ltd|Imidazole derivative|

---

JPH0720864B2|1985-08-15|1995-03-08|旭電化工業株式会社|Radiosensitizer|

---

US4851513A|1985-09-06|1989-07-25|Minnesota Mining And Manufacturing Company|Viscoelastic collagen solution for opthalmic use and method of preparation|

---

SU1336489A1|1985-10-24|1990-02-15|Отделение Института химической физики АН СССР|Method of producing nitroxyl derivatives of nitrozo urea|

---

JPH0717518B2|1985-11-28|1995-03-01|湧永製薬株式会社|Antitumor action regulator|

---

JPH0723308B2|1985-12-12|1995-03-15|旭電化工業株式会社|Radiosensitizer|

---

EP0232693A3|1985-12-16|1988-04-06|La Region Wallonne|Conjugates of vinblastine and its derivatives, process for their preparation and pharmaceutical compositions containing them|

---

WO1987004078A1|1986-01-06|1987-07-16|The University Of Melbourne|Precipitation of collagen in tactoid form|

---

US4774227A|1986-02-14|1988-09-27|Collagen Corporation|Collagen compositions for bone repair containing autogeneic marrow|

---

US4983580A|1986-04-04|1991-01-08|Allergan, Inc.|Methods and materials for use in corneal wound healing|

---

US4745180A|1986-06-27|1988-05-17|Cetus Corporation|Solubilization of proteins for pharmaceutical compositions using heparin fragments|

---

US4841085A|1986-06-30|1989-06-20|Board Of Regents, University Of Texas System|Aldophosphamides|

---

US5013649A|1986-07-01|1991-05-07|Genetics Institute, Inc.|DNA sequences encoding osteoinductive products|

---

US6432919B1|1986-07-01|2002-08-13|Genetics Institute, Inc.|Bone morphogenetic protein-3 and compositions|

---

FR2601675B1|1986-07-17|1988-09-23|Rhone Poulenc Sante|TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR2601676B1|1986-07-17|1988-09-23|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL|

---

US5004606A|1986-09-24|1991-04-02|Hybritech Incorporated|Non-covalent antibody-anthracycline immunocomplexes|

---

US5175287A|1986-09-25|1992-12-29|S R I International|Process for preparing 1,2,4-benzotriazine oxides|

---

US5624925A|1986-09-25|1997-04-29|Sri International|1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents|

---

US4979959A|1986-10-17|1990-12-25|Bio-Metric Systems, Inc.|Biocompatible coating for solid surfaces|

---

JPS63170375A|1987-01-07|1988-07-14|Pola Chem Ind Inc|Heterocyclic compound derivative, its production and radiosensitizer containing said derivative as active component|

---

US5047528A|1987-01-22|1991-09-10|University Of Bristish Columbia|Process of synthesis of vinblastine and vincristine|

---

GB8701381D0|1987-01-22|1987-02-25|Erba Farmitalia|Antitumor agent|

---

FR2611203B1|1987-02-20|1989-06-09|Sturtz Georges|GEM-DIPHOSPHONIC ANALOGS OF AMETHOPTERIN AND DEAZA-N-10 AMETHOPTERINE DERIVATIVES. THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

US4877864A|1987-03-26|1989-10-31|Genetics Institute, Inc.|Osteoinductive factors|

---

US5034320A|1987-03-31|1991-07-23|Allelix, Inc.|Vinblastine synthesis|

---

US4921963A|1987-04-13|1990-05-01|British Columbia Cancer Foundation|Platinum complexes with one radiosensitizing ligand|

---

FI87572C|1987-05-08|1993-01-25|Sankyo Co|Process for the preparation of platinum complexes with therapeutic effect|

---

JPS63310873A|1987-06-09|1988-12-19|Taiho Yakuhin Kogyo Kk|4,5-dinitroimidazole derivative|

---

JP2602887B2|1987-06-10|1997-04-23|京都大学長|New fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizer containing the same|

---

US5304654A|1987-06-10|1994-04-19|Yasunori Nishijima|Fluorine-containing nitroimidazole compounds|

---

CA1329206C|1987-06-10|1994-05-03|Tsutomu Kagiya|Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same|

---

US4797397A|1987-07-31|1989-01-10|Warner-Lambert Company|2-nitroimidazole derivatives useful as radiosensitizers for hypoxic tumor cells|

---

US5532220A|1987-08-31|1996-07-02|The Regents Of The University Of California|Genetic mechanisms of tumor suppression|

---

JPH01139596A|1987-11-25|1989-06-01|Pola Chem Ind Inc|Heterocyclic compound derivative, production thereof and radiosensitizer, antiviral and anticancer agent containing said derivative as active ingredient|

---

US5364622A|1987-12-04|1994-11-15|Dr. Karl Thomae Gmbh|Methods for preventing adhesions to organs and parts of organs by application of tissue plasminogen activator and hydroxyethylcellulose hydrogel|

---

US4996152A|1987-12-04|1991-02-26|The United States Of America, As Represented By The Secretary Of Agriculture|Avian herpesvirus amplicon as a eucaryotic expression vector|

---

US4950699A|1988-01-11|1990-08-21|Genetic Laboratories, Inc.|Wound dressing incorporating collagen in adhesive layer|

---

US4847325A|1988-01-20|1989-07-11|Cetus Corporation|Conjugation of polymer to colony stimulating factor-1|

---

US5192316A|1988-02-16|1993-03-09|Allergan, Inc.|Ocular device|

---

US5024742A|1988-02-24|1991-06-18|Cedars-Sinai Medical Center|Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers|

---

US4942184A|1988-03-07|1990-07-17|The United States Of America As Represented By The Department Of Health And Human Services|Water soluble, antineoplastic derivatives of taxol|

---

US6133029A|1988-03-21|2000-10-17|Chiron Corporation|Replication defective viral vectors for infecting human cells|

---

US5716826A|1988-03-21|1998-02-10|Chiron Viagene, Inc.|Recombinant retroviruses|

---

US5591624A|1988-03-21|1997-01-07|Chiron Viagene, Inc.|Retroviral packaging cell lines|

---

US4923876A|1988-04-18|1990-05-08|Cetus Corporation|Vinca alkaloid pharmaceutical compositions|

---

US5290552A|1988-05-02|1994-03-01|Matrix Pharmaceutical, Inc./Project Hear|Surgical adhesive material|

---

US4908356A|1988-05-25|1990-03-13|Research Corporation Technologies, Inc.|Aldophosphamide derivatives useful as antitumor agents|

---

US5190929A|1988-05-25|1993-03-02|Research Corporation Technologies, Inc.|Cyclophosphamide analogs useful as anti-tumor agents|

---

US4950483A|1988-06-30|1990-08-21|Collagen Corporation|Collagen wound healing matrices and process for their production|

---

US5167960A|1988-08-03|1992-12-01|New England Deaconess Hospital Corporation|Hirudin-coated biocompatible substance|

---

US4906460A|1988-08-05|1990-03-06|Sorenco|Additive for hair treatment compositions|

---

US5665583A|1988-08-12|1997-09-09|Arch Dev Corp|Methods and materials relating to IMPDH and GMP production|

---

US5066658A|1988-11-10|1991-11-19|Ortho Pharmaceutical Corporation|Substituted hydroxyureas|

---

US5162430A|1988-11-21|1992-11-10|Collagen Corporation|Collagen-polymer conjugates|

---

US5264214A|1988-11-21|1993-11-23|Collagen Corporation|Composition for bone repair|

---

AU677789B2|1992-07-02|1997-05-08|Collagen Corporation|Biocompatible polymer conjugates|

---

US5936035A|1988-11-21|1999-08-10|Cohesion Technologies, Inc.|Biocompatible adhesive compositions|

---

US5475052A|1988-11-21|1995-12-12|Collagen Corporation|Collagen-synthetic polymer matrices prepared using a multiple step reaction|

---

US5614587A|1988-11-21|1997-03-25|Collagen Corporation|Collagen-based bioadhesive compositions|

---

US5306500A|1988-11-21|1994-04-26|Collagen Corporation|Method of augmenting tissue with collagen-polymer conjugates|

---

US5304595A|1988-11-21|1994-04-19|Collagen Corporation|Collagen-polymer conjugates|

---

US5109112A|1989-01-19|1992-04-28|Merck & Co., Inc.|FK-506 cytosolic binding protein|

---

CA2045129A1|1989-02-01|1990-08-02|Alfred I. Geller|Herpes simplex virus type i expression vector|

---

US5457183A|1989-03-06|1995-10-10|Board Of Regents, The University Of Texas System|Hydroxylated texaphyrins|

---

US5703055A|1989-03-21|1997-12-30|Wisconsin Alumni Research Foundation|Generation of antibodies through lipid mediated DNA delivery|

---

DE69033982T2|1989-03-21|2002-10-24|Us Health|Matrix metalloproteinase inhibitor peptides|

---

EP0390530B1|1989-03-31|1995-05-17|CANJI, Inc.|Retinoblastoma gene product antibodies and uses therefor|

---

US5641764A|1989-03-31|1997-06-24|Peter Maccallum Institute|Halogenated DNA ligand radiosensitizers for cancer therapy|

---

US5122614A|1989-04-19|1992-06-16|Enzon, Inc.|Active carbonates of polyalkylene oxides for modification of polypeptides|

---

US5324844A|1989-04-19|1994-06-28|Enzon, Inc.|Active carbonates of polyalkylene oxides for modification of polypeptides|

---

US5141747A|1989-05-23|1992-08-25|Minnesota Mining And Manufacturing Company|Denatured collagen membrane|

---

US5200411A|1989-06-14|1993-04-06|Sandoz, Ltd.|Heteroatoms-containing tricyclic compounds|

---

DE3924424A1|1989-07-24|1991-01-31|Boehringer Mannheim Gmbh|NUCLEOSIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS A MEDICINAL PRODUCT AND THEIR USE IN THE SEQUENCING OF NUCLEIC ACID|

---

US5100885A|1989-08-01|1992-03-31|Johnson Matthey, Inc.|Copper radiosensitizers|

---

NZ234718A|1989-08-11|1992-05-26|Saint Gobain Isover|Decomposable glass fibres|

---

US5166149A|1989-09-08|1992-11-24|Chemex Pharmaceuticals, Inc.|Methotrexate compositions and methods of treatment using same|

---

AT143023T|1989-12-19|1996-10-15|Pharmacia Spa|CHIRALE 1,5-DIIODO-2-METHOXY OR BENZYLOXY INTERMEDIATE PRODUCTS|

---

KR927003539A|1990-01-26|1992-12-18|스즈끼 쯔네시|2-nitro imidazole derivatives, preparation method thereof and radiosensitizer using the same|

---

US5104957A|1990-02-28|1992-04-14|Autogenesis Technologies, Inc.|Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom|

---

US5201764A|1990-02-28|1993-04-13|Autogenesis Technologies, Inc.|Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom|

---

US5989894A|1990-04-20|1999-11-23|University Of Wyoming|Isolated DNA coding for spider silk protein, a replicable vector and a transformed cell containing the DNA|

---

US5688678A|1990-05-16|1997-11-18|Genetics Institute, Inc.|DNA encoding and methods for producing BMP-8 proteins|

---

US5594158A|1990-06-22|1997-01-14|The Board Of Regents Of The University Of Nebraska|Processes for producing doxorubicin, daunomycinone, and derivatives of doxorubicin|

---

US5210030A|1990-06-25|1993-05-11|Merck & Co., Inc.|Process for selectively acylating immunomycin|

---

JPH06500688A|1990-06-29|1994-01-27|||

---

US5147652A|1990-07-03|1992-09-15|Cell Research Corporation|Autobiotics and their use in eliminating nonself cells in vivo|

---

US5219564A|1990-07-06|1993-06-15|Enzon, Inc.|Poly amino acid copolymers and drug carriers and charged copolymers based thereon|

---

US5209776A|1990-07-27|1993-05-11|The Trustees Of Columbia University In The City Of New York|Tissue bonding and sealing composition and method of using the same|

---

US5278324A|1990-08-28|1994-01-11|Virginia Tech Intellectual Properties, Inc.|Water soluble derivatives of taxol|

---

US5059699A|1990-08-28|1991-10-22|Virginia Tech Intellectual Properties, Inc.|Water soluble derivatives of taxol|

---

SE466754B|1990-09-13|1992-03-30|Berol Nobel Ab|COVALENT BINDING POLYMERS TO HYDROPHILIC SURFACES|

---

PT98990A|1990-09-19|1992-08-31|American Home Prod|PROCESS FOR THE PREPARATION OF CARBOXYLIC ACID ESTERS OF RAPAMICIN|

---

US5817491A|1990-09-21|1998-10-06|The Regents Of The University Of California|VSV G pseusdotyped retroviral vectors|

---

US5380536A|1990-10-15|1995-01-10|The Board Of Regents, The University Of Texas System|Biocompatible microcapsules|

---

US5410016A|1990-10-15|1995-04-25|Board Of Regents, The University Of Texas System|Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers|

---

US5626863A|1992-02-28|1997-05-06|Board Of Regents, The University Of Texas System|Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers|

---

US5169754A|1990-10-31|1992-12-08|Coulter Corporation|Biodegradable particle coatings having a protein covalently immobilized by means of a crosslinking agent and processes for making same|

---

US5189178A|1990-11-21|1993-02-23|Galardy Richard E|Matrix metalloprotease inhibitors|

---

US5892112A|1990-11-21|1999-04-06|Glycomed Incorporated|Process for preparing synthetic matrix metalloprotease inhibitors|

---

US5268384A|1990-11-21|1993-12-07|Galardy Richard E|Inhibition of angiogenesis by synthetic matrix metalloprotease inhibitors|

---

US5183900A|1990-11-21|1993-02-02|Galardy Richard E|Matrix metalloprotease inhibitors|

---

US5239078A|1990-11-21|1993-08-24|Glycomed Incorporated|Matrix metalloprotease inhibitors|

---

WO1993013663A1|1992-01-17|1993-07-22|Abbott Laboratories|Method of directing biosynthesis of specific polyketides|

---

US5116756A|1991-01-28|1992-05-26|Merck & Co., Inc.|Process for producing FK-506|

---

US5219895A|1991-01-29|1993-06-15|Autogenesis Technologies, Inc.|Collagen-based adhesives and sealants and methods of preparation and use thereof|

---

US5294715A|1991-02-01|1994-03-15|University Of Pittsburgh|Acridine-intercalator based hypoxia selective cytotoxins|

---

US5156613A|1991-02-13|1992-10-20|Interface Biomedical Laboratories Corp.|Collagen welding rod material for use in tissue welding|

---

GB9103430D0|1991-02-19|1991-04-03|Smithkline Beecham Plc|Novel compound|

---

TW197439B|1991-04-04|1993-01-01|Ueno Pharmaceutics Applic Res Co Ltd||

---

US5147877A|1991-04-18|1992-09-15|Merck & Co. Inc.|Semi-synthetic immunosuppressive macrolides|

---

US5093338A|1991-04-23|1992-03-03|Merck & Co., Inc.|Lipophilic macrolide useful as an immunosuppressant|

---

US5091389A|1991-04-23|1992-02-25|Merck & Co., Inc.|Lipophilic macrolide useful as an immunosuppressant|

---

US5198421A|1991-04-26|1993-03-30|Merck & Co., Inc.|Phosphorylated cyclic lipopeptide|

---

US5140018A|1991-05-07|1992-08-18|Abbott Laboratories|1,3,2-benzodithiazole-1-oxide compounds|

---

US5889169A|1991-05-16|1999-03-30|Cold Spring Harbor Laboratory|Cell cycle regulatory protein p16 gene|

---

DK0592562T3|1991-06-25|1999-08-30|Genetics Inst|BMP-9 compositions|

---

US5225403A|1991-06-25|1993-07-06|Merck & Co., Inc.|C-21 hydroxylated FK-506 antagonist|

---

CA2071160A1|1991-07-31|1993-02-01|Vittorio Farina|Asymmetric synthesis of taxol side chain|

---

US5256657A|1991-08-19|1993-10-26|Sterling Winthrop, Inc.|Succinamide derivative matrix-metalloprotease inhibitors|

---

US5561137A|1991-09-05|1996-10-01|Abbott Laboratories|Thio-heterocyclic macrolactam immunomodulators|

---

US5541193A|1991-09-05|1996-07-30|Abbott Laboratories|Heterocycle-containing macrocyclic immunomodulators|

---

US5534632A|1991-09-05|1996-07-09|Abbott Laboratories|Macrocyclic carbamate immunomodulators|

---

ES2179823T3|1991-09-05|2003-02-01|Abbott Lab|MACROLIDO IMMUNOSUPRESOR.|

---

US5604234A|1991-09-05|1997-02-18|Abbott Laboratories|Substituted thiol macrolactam immunomodulators|

---

US5563172A|1991-09-05|1996-10-08|Abbott Laboratories|Macrocyclic amide and urea immunomodulators|

---

US5208241A|1991-09-09|1993-05-04|Merck & Co., Inc.|N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity|

---

US5247076A|1991-09-09|1993-09-21|Merck & Co., Inc.|Imidazolidyl macrolides having immunosuppressive activity|

---

US5252732A|1991-09-09|1993-10-12|Merck & Co., Inc.|D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity|

---

US5350866A|1991-09-23|1994-09-27|Bristol-Myers Squibb Company|10-desacetoxytaxol derivatives|

---

US5283253A|1991-09-23|1994-02-01|Florida State University|Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them|

---

JPH07503943A|1991-10-29|1995-04-27|||

---

FR2683529B1|1991-11-12|1994-02-04|Bretagne Occidentale Universite|PHARMACEUTICAL COMPOUNDS GEM-DIPHOSPHONATES ANALOGUE OF CIS-PLATINUM.|

---

US5164399A|1991-11-18|1992-11-17|American Home Products Corporation|Rapamycin pyrazoles|

---

AU3140093A|1991-11-22|1993-06-15|University Of Mississippi, The|Synthesis and optical resolution of the taxol side chain and related compounds|

---

NZ240785A|1991-11-28|1995-08-28|Cancer Res Campaign Tech|Substituted nitro aniline derivatives and medicaments|

---

GB9125660D0|1991-12-03|1992-01-29|Smithkline Beecham Plc|Novel compound|

---

US5221625A|1992-01-10|1993-06-22|Merck & Co., Inc.|Cyclcic FR-900520 microbial biotransformation agent|

---

CA2100808A1|1992-10-01|1994-04-02|Vittorio Farina|Deoxy paclitaxels|

---

US5272171A|1992-02-13|1993-12-21|Bristol-Myers Squibb Company|Phosphonooxy and carbonate derivatives of taxol|

---

WO1993018043A1|1992-03-05|1993-09-16|American Home Products Corporation|Novel rapamycin 42-sulfonates and 42-sulfamates useful as immunosuppressive agents|

---

US5200534A|1992-03-13|1993-04-06|University Of Florida|Process for the preparation of taxol and 10-deacetyltaxol|

---

US5324634A|1992-03-31|1994-06-28|The Research Foundation Of State University Of New York|Diagnostic tests measuring gelatinase/inhibitor complexes for detection of aggressive and metastatic cancer|

---

US5440056A|1992-04-17|1995-08-08|Abbott Laboratories|9-deoxotaxane compounds|

---

AU4267293A|1992-05-01|1993-11-29|British Biotech Pharmaceuticals Limited|Use of MMP inhibitors|

---

AU4242993A|1992-05-21|1993-12-13|Penn State Research Foundation, The|Cultured tissues as a source of taxol, related taxanes and other novel anti-tumor/anti-viral compounds|

---

US5587308A|1992-06-02|1996-12-24|The United States Of America As Represented By The Department Of Health & Human Services|Modified adeno-associated virus vector capable of expression from a novel promoter|

---

WO1993024476A1|1992-06-04|1993-12-09|Clover Consolidated, Limited|Water-soluble polymeric carriers for drug delivery|

---

WO1993025533A1|1992-06-05|1993-12-23|Abbott Laboratories|Methods and reagents for the determination of immunosuppressive agents|

---

US5248796A|1992-06-18|1993-09-28|Bristol-Myers Squibb Company|Taxol derivatives|

---

GB9213077D0|1992-06-19|1992-08-05|Erba Carlo Spa|Polymerbound taxol derivatives|

---

US5274137A|1992-06-23|1993-12-28|Nicolaou K C|Intermediates for preparation of taxols|

---

US5294637A|1992-07-01|1994-03-15|Bristol-Myers Squibb Company|Fluoro taxols|

---

US5385606A|1992-07-06|1995-01-31|Kowanko; Nicholas|Adhesive composition and method|

---

ZA935110B|1992-07-17|1994-02-04|Smithkline Beecham Corp|Rapamycin derivatives|

---

ZA935112B|1992-07-17|1994-02-08|Smithkline Beecham Corp|Rapamycin derivatives|

---

ZA935111B|1992-07-17|1994-02-04|Smithkline Beecham Corp|Rapamycin derivatives|

---

GB9215665D0|1992-07-23|1992-09-09|British Bio Technology|Compounds|

---

US5324644A|1992-07-28|1994-06-28|Merck & Co., Inc.|Process for producing immunosuppressant agent|

---

MX9304399A|1992-07-31|1994-02-28|Warner Lambert Co|NOVEL PROCESS TO PREPARE [[2-BROMOETHYL) -AMINO] METHYL] -2-NITRO-1H-IMIDAZOL-1-ETHANOL CHIRAL AND RELATED COMPOUNDS.|

---

US5514379A|1992-08-07|1996-05-07|The General Hospital Corporation|Hydrogel compositions and methods of use|

---

MX9304868A|1992-08-13|1994-05-31|American Home Prod|27-HYDROXYRAPAMICINE, DERIVED FROM THE SAME AND PHARMACEUTICAL COMPOSITION THAT CONTAINS IT.|

---

US5202448A|1992-08-14|1993-04-13|Napro Biotherapeutics, Inc.|Processes of converting taxanes into baccatin III|

---

US5614549A|1992-08-21|1997-03-25|Enzon, Inc.|High molecular weight polymer-based prodrugs|

---

WO1994005282A1|1992-09-04|1994-03-17|The Scripps Research Institute|Water soluble taxol derivatives|

---

FR2696463B1|1992-10-05|1994-11-25|Rhone Poulenc Rorer Sa|Process for obtaining 10-deacetyl baccatin III.|

---

FR2696462B1|1992-10-05|1994-11-25|Rhone Poulenc Rorer Sa|Process for obtaining 10-deacetyl baccatin III.|

---

US5318895A|1992-10-05|1994-06-07|Merck & Co., Inc.|Aspergillus niger mutants|

---

FR2696464B1|1992-10-05|1994-11-10|Rhone Poulenc Rorer Sa|New esterification process for baccatin III and 10-deacetyl baccatin III.|

---

FR2696461B1|1992-10-05|1994-11-10|Rhone Poulenc Rorer Sa|New derivatives of taxol analogs, their preparation and compositions containing them.|

---

GB9221220D0|1992-10-09|1992-11-25|Sandoz Ag|Organic componds|

---

US5411984A|1992-10-16|1995-05-02|Virginia Tech Intellectual Properties, Inc.|Water soluble analogs and prodrugs of taxol|

---

US5552156A|1992-10-23|1996-09-03|Ohio State University|Liposomal and micellular stabilization of camptothecin drugs|

---

US5258389A|1992-11-09|1993-11-02|Merck & Co., Inc.|O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives|

---

ZA938349B|1992-11-10|1994-08-01|Smithkline Beecham Corp|Rapamycin derivatives.|

---

AU5605994A|1992-11-12|1994-06-08|Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The|Methods for determining the presence of functional p53 in mammalian cells|

---

GB9223904D0|1992-11-13|1993-01-06|British Bio Technology|Inhibition of cytokine production|

---

US5661033A|1992-11-25|1997-08-26|The Board Of Trustees Of The Leland Stanford Junior University|Gene transfer using herpes virus vectors as a tool for neuroprotection|

---

US5380751A|1992-12-04|1995-01-10|Bristol-Myers Squibb Company|6,7-modified paclitaxels|

---

US5279949A|1992-12-07|1994-01-18|Board Of Trustees Operating Michigan State University|Process for the isolation and purification of taxol and taxanes from Taxus spp|

---

US5298643A|1992-12-22|1994-03-29|Enzon, Inc.|Aryl imidate activated polyalkylene oxides|

---

JPH06203767A|1992-12-28|1994-07-22|Matsushita Electron Corp|Deflection yoke|

---

US5254580A|1993-01-19|1993-10-19|Bristol-Myers Squibb Company|7,8-cyclopropataxanes|

---

US5349001A|1993-01-19|1994-09-20|Enzon, Inc.|Cyclic imide thione activated polyalkylene oxides|

---

US5321095A|1993-02-02|1994-06-14|Enzon, Inc.|Azlactone activated polyalkylene oxides|

---

GB9302016D0|1993-02-02|1993-03-17|Sandoz Ltd|Compounds|

---

US6284513B1|1993-02-03|2001-09-04|Warner-Lambert Company|Process for the production of stromelysin catalytic domain protein|

---

GB9302569D0|1993-02-10|1993-03-24|Smithkline Beecham Plc|Novel compound|

---

CA2215309C|1995-03-23|2008-11-25|Focal, Inc.|Redox and photoinitiator systems for priming for improved adherence of gels to substrates|

---

US5310901A|1993-03-05|1994-05-10|Merck & Co., Inc.|O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives|

---

US5310903A|1993-03-05|1994-05-10|Merck & Co., Inc.|Imidazolidyl rapamycin derivatives|

---

AU6361294A|1993-03-09|1994-09-26|Enzon, Inc.|Taxol-based compositions with enhanced bioactivity|

---

WO1994021253A1|1993-03-17|1994-09-29|Abbott Laboratories|Substituted aliphatic amine-containing macrocyclic immunomodulators|

---

US5457194A|1993-03-17|1995-10-10|Abbott Laboratories|Substituted aliphatic amine-containing macrocyclic immunomodulators|

---

US5594006A|1993-03-18|1997-01-14|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivatives as matrix metalloproteinases inhibitors|

---

US5382582A|1993-03-26|1995-01-17|Chan; Carcy L.|Methotrexate analogs and methods of using same|

---

GB9307956D0|1993-04-17|1993-06-02|Walls Alan J|Hydroxamic acid derivatives|

---

US5412092A|1993-04-23|1995-05-02|Bristol-Myers Squibb Company|N-substituted 2-azetidinones|

---

DE69430060T2|1993-04-23|2002-11-07|Abbott Lab|RAPAMYCINE ANTIBODIES WITH OPEN RING|

---

US5306727A|1993-04-30|1994-04-26|Research Corporation Technologies, Inc.|Phosphoramidates useful as antitumor agents|

---

US5380897A|1993-05-25|1995-01-10|Hoeschele; James D.|Tri complexes|

---

FR2705686B1|1993-05-28|1995-08-18|Transgene Sa|New defective adenoviruses and corresponding complementation lines.|

---

US5549904A|1993-06-03|1996-08-27|Orthogene, Inc.|Biological adhesive composition and method of promoting adhesion between tissue surfaces|

---

US5910488A|1993-06-07|1999-06-08|Vical Incorporated|Plasmids suitable for gene therapy|

---

EP1413585A3|1993-06-15|2004-08-04|E.I. Du Pont De Nemours And Company|Novel, recombinantly produced spider silk analogs|

---

JPH07107058B2|1993-06-22|1995-11-15|旭電化工業株式会社|Nitrotriazole compound|

---

US6140087A|1993-06-24|2000-10-31|Advec, Inc.|Adenovirus vectors for gene therapy|

---

US6080569A|1993-06-24|2000-06-27|Merck & Co., Inc.|Adenovirus vectors generated from helper viruses and helper-dependent vectors|

---

ES2139746T3|1993-07-20|2000-02-16|Pfizer|HETEROARIL CICLOALQUENIL HIDROXIUREAS.|

---

GB9315914D0|1993-07-31|1993-09-15|Smithkline Beecham Plc|Novel compound|

---

US5773428A|1993-08-05|1998-06-30|Syntex Inc.|Matrix metalloprotease inhibitors|

---

US6013792A|1993-08-05|2000-01-11|Syntex , Inc.|Matrix metalloprotease inhibitors|

---

US5387680A|1993-08-10|1995-02-07|American Home Products Corporation|C-22 ring stabilized rapamycin derivatives|

---

GB9318612D0|1993-09-08|1993-10-27|Sandoz Ltd|An assay|

---

US5409915A|1993-09-14|1995-04-25|The University Of Vermont And State Agricultural College|Bis-platinum complexes as chemotherapeutic agents|

---

US6015686A|1993-09-15|2000-01-18|Chiron Viagene, Inc.|Eukaryotic layered vector initiation systems|

---

US5455262A|1993-10-06|1995-10-03|Florida State University|Mercaptosulfide metalloproteinase inhibitors|

---

US5470834A|1993-10-06|1995-11-28|Florida State University|Sulfoximine and suldodiimine matrix metalloproteinase inhibitors|

---

WO1995010267A1|1993-10-08|1995-04-20|The United States Of America, Represented By The Secretary, Department Of Health And Human Services|Use of nitric oxide-releasing compounds as hypoxic cell radiation sensitizers|

---

US6210939B1|1993-10-25|2001-04-03|Canji, Inc.|Recombinant adenoviral vector and methods of use|

---

US5643575A|1993-10-27|1997-07-01|Enzon, Inc.|Non-antigenic branched polymer conjugates|

---

US6037472A|1993-11-04|2000-03-14|Syntex Inc.|Matrix metalloprotease inhibitors|

---

WO1995013375A1|1993-11-10|1995-05-18|The Johns Hopkins University|Tumor suppressor waf1|

---

GB9323165D0|1993-11-10|1994-01-05|Chiros Ltd|Compounds|

---

WO1995014023A1|1993-11-19|1995-05-26|Abbott Laboratories|Semisynthetic analogs of rapamycin being immunomodulators|

---

US5527907A|1993-11-19|1996-06-18|Abbott Laboratories|Macrolide immunomodulators|

---

WO1995015328A1|1993-11-30|1995-06-08|Abbott Laboratories|Macrocyclic immunomodulators with novel cyclohexyl ring replacements|

---

US5484799A|1993-12-09|1996-01-16|Abbott Laboratories|Antifungal dorrigocin derivatives|

---

ES2146741T3|1993-12-17|2000-08-16|Novartis Ag|RAPAMICINE DERIVATIVES USEFUL AS IMMUNOSUPPRESSANTS.|

---

GB9401129D0|1994-01-21|1994-03-16|British Bio Technology|Hydroxamic acid derivatives as metalloproteinase inhibitors|

---

JP3827324B2|1994-01-22|2006-09-27|ブリテッシュバイオテックファーマシューティカルズリミテッド|Metalloproteinase inhibitor|

---

US5457182A|1994-02-15|1995-10-10|Merck & Co., Inc.|FK-506 cytosolic binding protein, FKBP12.6|

---

US5444072A|1994-02-18|1995-08-22|Syntex Inc.|6-substituted mycophenolic acid and derivatives|

---

US5362735A|1994-02-23|1994-11-08|Smithkline Beecham Corporation|Rapamycin derivatives|

---

US5514716A|1994-02-25|1996-05-07|Sterling Winthrop, Inc.|Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof|

---

FR2716893B1|1994-03-03|1996-04-12|Rhone Poulenc Rorer Sa|Recombinant viruses, their preparation and their therapeutic use.|

---

US5395850A|1994-03-10|1995-03-07|Bristol-Myers Squibb Company|6,7-epoxy paclitaxels|

---

GB9405076D0|1994-03-16|1994-04-27|Inst Of Ophtalmology|A medical use of matrix metalloproteinase inhibitors|

---

FI951367A|1994-03-28|1995-09-29|Japan Energy Corp|Purine derivatives and suppressants for infectious diseases|

---

CA2187626C|1994-04-13|2009-11-03|Michael G. Kaplitt|Aav-mediated delivery of dna to cells of the nervous system|

---

US6013517A|1994-05-09|2000-01-11|Chiron Corporation|Crossless retroviral vectors|

---

US5641636A|1994-05-20|1997-06-24|University Of Pennsylvania|Method of predicting fetal membrane rupture based on matrix metalloproteinase-9 activity|

---

US6140099A|1994-05-20|2000-10-31|The Trustees Of The University Of Pennsylvania|Method of delaying fetal membrane rupture by inhibiting matrix metalloproteinase-9 activity|

---

GB9411088D0|1994-06-03|1994-07-27|Hoffmann La Roche|Hydroxylamine derivatives|

---

CA2192442C|1994-06-10|2007-09-25|Imre Kovesdi|Complementary adenoviral vector systems and cell lines|

---

EP0766664B1|1994-06-22|2000-04-05|British Biotech Pharmaceuticals Limited|Metalloproteinase inhibitors|

---

US5622866A|1994-06-23|1997-04-22|Merck & Co., Inc.|Expression cassettes useful in construction of integrative and replicative expression vectors for Streptomyces|

---

ES2142490T3|1994-07-27|2000-04-16|Novartis Ag|CYCLOPEPTOLIDS.|

---

US5583114A|1994-07-27|1996-12-10|Minnesota Mining And Manufacturing Company|Adhesive sealant composition|

---

GB9416897D0|1994-08-20|1994-10-12|British Biotech Pharm|Metalloproteinase inhibitors|

---

BR9509237A|1994-10-05|1997-10-21|Chiroscience Ltd|Peptidyl compounds and their therapeutic use as metalloprotease inhibitors|

---

DE69534166T2|1994-10-28|2006-03-09|Trustees Of The University Of Pennsylvania|RECOMBINANT ADENOVIRUS AND METHODS OF USE THEREOF|

---

US5856152A|1994-10-28|1999-01-05|The Trustees Of The University Of Pennsylvania|Hybrid adenovirus-AAV vector and methods of use therefor|

---

AR002945A1|1994-11-15|1998-05-27|Bayer Corp|ACIDOS 4-BIARILBUTIRICO OR 5-BIARILPENTANOICO SUBSTITUTED AND ITS DERIVATIVES AS INHIBITORS OF MATRIX METALOPROTEASES, COMPOSITION CONTAINING THEM, AND METHODS FOR THE PREPARATION OF SUCH COMPOUNDS|

---

US5789434A|1994-11-15|1998-08-04|Bayer Corporation|Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors|

---

EP0713707A1|1994-11-23|1996-05-29|Collagen Corporation|In situ crosslinkable, injectable collagen composition for tissue augmention|

---

GB9423914D0|1994-11-26|1995-01-11|British Biotech Pharm|Polyether derivatives as metalloproteinase inhibitors|

---

US5532265A|1994-11-30|1996-07-02|The Board Of Trustees Of The Leland Stanford Junior University|Treatment of central nervous system inflammatory disease with matrix metalloprotease inhibitors|

---

US5602142A|1994-12-21|1997-02-11|Evanston Hospital Corporation|DNA-affinic hypoxia selective cytotoxins|

---

JP2902318B2|1994-12-28|1999-06-07|呉羽化学工業株式会社|Esculetin derivatives, their production method and matrix metalloprotease inhibitors|

---

US5639746A|1994-12-29|1997-06-17|The Procter & Gamble Company|Hydroxamic acid-containing inhibitors of matrix metalloproteases|

---

US6033847A|1995-02-06|2000-03-07|St. Jude Children's Research Hospital|InK4c-p18 and InK4d-p19, inhibitors of cyclin-dependent kinases CDK4 and CDK6, and uses thereof|

---

US5672598A|1995-03-21|1997-09-30|The Procter & Gamble Company|Lactam-containing hydroxamic acids|

---

EP0871755A1|1995-03-23|1998-10-21|Cantab Pharmaceuticals Research Limited|Vectors for gene delivery|

---

US5900245A|1996-03-22|1999-05-04|Focal, Inc.|Compliant tissue sealants|

---

US6025480A|1995-04-03|2000-02-15|Sloan-Kettering Institute For Cancer Research|Isolated nucleic acid molecules encoding P57KIP2|

---

US5691381A|1995-04-18|1997-11-25|The Dupont Merck Pharmaceutical Company|Hydroxamic and carbocyclic acids as metalloprotease inhibitors|

---

AT198326T|1995-04-20|2001-01-15|Pfizer|ARYLSULFONAMIDO-SUBSTITUTED HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF MMP AND TNF|

---

US6147114A|1995-04-25|2000-11-14|Fuji Yakuhin Kogyo Kabushiki Kaisha|Highly water-soluble metalloproteinase inhibitors|

---

US5698706A|1995-05-10|1997-12-16|Chiroscience Limited|Heterocyclic amides and methods of use|

---

WO1996035711A1|1995-05-10|1996-11-14|Chiroscience Limited|Peptide compounds which inhibit metalloproteinase and tnf liberation, and their therapeutic use|

---

AU710502B2|1995-05-10|1999-09-23|Darwin Discovery Limited|Peptidyl compounds which inhibit metalloproteinase and TNF liberation and their therapeutic use|

---

ES2184861T3|1995-05-10|2003-04-16|Darwin Discovery Ltd|PEPTIDIC COMPOUNDS INHIBITING THE LIBERATION OF METALOPROTEINASE AND TNF AND ITS THERAPEUTIC USE.|

---

GB9509631D0|1995-05-12|1995-07-05|Sandoz Ltd|Antifungal combination|

---

US5605976A|1995-05-15|1997-02-25|Enzon, Inc.|Method of preparing polyalkylene oxide carboxylic acids|

---

JP3133642B2|1995-05-19|2001-02-13|花王株式会社|Hair cosmetics|

---

US5627206A|1995-06-02|1997-05-06|Warner-Lambert Company|Tricyclic inhibitor of matrix metalloproteinases|

---

US5665764A|1995-06-02|1997-09-09|Warner-Lambert Company|Tricyclic inhibitors of matrix metalloproteinases|

---

US5886022A|1995-06-05|1999-03-23|Bayer Corporation|Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors|

---

US6093570A|1995-06-07|2000-07-25|The University Of North Carolina At Chapel Hill|Helper virus-free AAV production|

---

US6040183A|1995-06-07|2000-03-21|University Of North Carloina At Chapel Hill|Helper virus-free AAV production|

---

US5677282A|1995-06-07|1997-10-14|Proscript, Inc.|Amino acid amides of 1,3,4-thiadiazoles as matrix metalloproteinase|

---

AT228135T|1995-06-09|2002-12-15|Novartis Erfind Verwalt Gmbh|rapamycin derivatives|

---

IL160406D0|1995-06-15|2004-07-25|Crucell Holland Bv|A cell harbouring nucleic acid encoding adenoritus e1a and e1b gene products|

---

US5917090A|1995-06-30|1999-06-29|British Biotech Pharmaceuticals Ltd.|Matrix metalloproteinase inhibitors|

---

GB9514867D0|1995-07-20|1995-09-20|British Biotech Pharm|Metalloproteinase inhibitors|

---

KR980009238A|1995-07-28|1998-04-30|우에노 도시오|Sulfonyl amino acid derivative|

---

AUPN477695A0|1995-08-14|1995-09-07|Commonwealth Scientific And Industrial Research Organisation|Gene therapy|

---

WO1997010502A1|1995-09-15|1997-03-20|Merck & Co., Inc.|A high throughput assay using fusion proteins|

---

US5723313A|1995-09-27|1998-03-03|St. Jude Children's Research Hospital|ARF-p19, a novel regulator of the mammalian cell cycle|

---

US5684152A|1995-09-28|1997-11-04|Merck & Co., Inc.|Preparation of carboxyalkyl derivatives as inhibitors of matrix metalloproteinases|

---

US6458889B1|1995-12-18|2002-10-01|Cohesion Technologies, Inc.|Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|

---

US5665777A|1995-11-14|1997-09-09|Abbott Laboratories|Biphenyl hydroxamate inhibitors of matrix metalloproteinases|

---

CZ291659B6|1995-11-17|2003-04-16|Warner-Lambert Company|Sulfonamide inhibitors of matrix metalloproteinases|

---

US5830727A|1995-11-18|1998-11-03|Human Gene Therapy Research Institute|Herpes simplex virus amplicon mini-vector gene transfer system|

---

JP2000500761A|1995-11-23|2000-01-25|ブリティッシュバイオテックファーマシューティカルズリミテッド|Metalloproteinase inhibitors|

---

US5843903A|1995-11-27|1998-12-01|The Administrators Of The Tulane Educational Fund|Targeted cytotoxic anthracycline analogs|

---

US6117633A|1995-12-08|2000-09-12|University Technologies International Inc.|DNA sequence encoding the tumor suppressor gene ING1|

---

JP4193917B2|1995-12-18|2008-12-10|アンジオデバイスインターナショナルゲーエムベーハー|Crosslinked polymer composition and method of use thereof|

---

US5752974A|1995-12-18|1998-05-19|Collagen Corporation|Injectable or implantable biomaterials for filling or blocking lumens and voids of the body|

---

DE69624081T2|1995-12-20|2003-06-12|Hoffmann La Roche|Matrix metalloprotease inhibitors|

---

DE69619865T2|1995-12-22|2002-11-07|Warner Lambert Co|AROMATIC KETO ACID AND THEIR DERIVATIVES AS INHIBITORS OF THE MATRIX METALLOPROTEINASE|

---

DE19548624A1|1995-12-23|1997-06-26|Boehringer Mannheim Gmbh|New barbituric acid derivatives, processes for their preparation and medicaments containing these compounds|

---

ES2217386T3|1996-01-02|2004-11-01|Aventis Pharmaceuticals Inc.|ACID COMPOUNDS REPLACED HYDROXAMIC.|

---

US5744349A|1996-03-05|1998-04-28|Washington University|DNA sequences encoding human Myt1 kinase|

---

CA2266478C|1996-09-23|2002-11-12|Focal, Inc.|Polymerizable biodegradable polymers including carbonate or dioxanone linkages|

---

GB9607120D0|1996-04-04|1996-06-12|Chiroscience Ltd|Compounds|

---

GB9607249D0|1996-04-04|1996-06-12|Chiroscience Ltd|Compounds|

---

GB9607119D0|1996-04-04|1996-06-12|Chiroscience Ltd|Compounds|

---

WO1997038091A1|1996-04-10|1997-10-16|Sloan-Kettering Institute For Cancer Research|METHODS FOR ENHANCING ANIMAL GROWTH AND CELL PROLIFERATION BY ELIMINATION OF FUNCTIONAL p27?Kip1¿|

---

US6054472A|1996-04-23|2000-04-25|Vertex Pharmaceuticals, Incorporated|Inhibitors of IMPDH enzyme|

---

US5807876A|1996-04-23|1998-09-15|Vertex Pharmaceuticals Incorporated|Inhibitors of IMPDH enzyme|

---

CN1116288C|1996-04-23|2003-07-30|沃泰克斯药物股份有限公司|Urea derivatives as inhibitors of IMPDH enzyme|

---

US6128582A|1996-04-30|2000-10-03|Vertex Pharmaceuticals Incorporated|Molecules comprising an IMPDH-like binding pocket and encoded data storage medium capable of graphically displaying them|

---

US5968795A|1996-05-15|1999-10-19|Bayer Corporation|Biaryl acetylenes as inhibitors of matrix metalloproteases|

---

US5863915A|1996-05-15|1999-01-26|Bayer Corporation|Substituted 4-arylbutyric acid derivatives as matrix metalloprotease|

---

US5932577A|1996-05-15|1999-08-03|Bayer Corporation|Substituted oxobutyric acids as matrix metalloprotease inhibitors|

---

AU736316B2|1996-05-20|2001-07-26|Signal Pharmaceuticals, Inc.|Mitogen-activated protein kinase p38-2 and methods of use therefor|

---

PT1021424E|1996-06-21|2003-06-30|Upjohn Co|TIADIAZOLO AMIDES AS MATRIX METALOPROTEINASE INHIBITORS|

---

US6300514B1|1997-06-25|2001-10-09|Ono Pharmaceutical Co., Ltd.|Aryl derivatives and drugs containing the same as the active ingredient|

---

US5852213A|1996-07-10|1998-12-22|American Cyanamid Company|Mercaptoketones and mercaptoalcohols and a process for their preparation|

---

WO1998002441A2|1996-07-12|1998-01-22|Ariad Pharmaceuticals, Inc.|Non immunosuppressive antifungal rapalogs|

---

SK3799A3|1996-07-18|2000-03-13|Pfizer|Phosphinate compounds, pharmaceutical compositions, method for inhibiting of matrix metalloproteases or of producing tnf and method of treatment|

---

IL128079D0|1996-07-22|1999-11-30|Monsanto Co|Thiol sulfone metalloprotease inhibitors|

---

IT1284876B1|1996-08-07|1998-05-22|Applied Research Systems|HCG AS A COLLAGENASE INHIBITOR|

---

AU730464B2|1996-08-07|2001-03-08|Darwin Discovery Limited|Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity|

---

US6566384B1|1996-08-07|2003-05-20|Darwin Discovery Ltd.|Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity|

---

GB9616643D0|1996-08-08|1996-09-25|Chiroscience Ltd|Compounds|

---

WO1998006711A1|1996-08-16|1998-02-19|Warner-Lambert Company|Butyric acid matrix metalloproteinase inhibitors|

---

JP3539736B2|1996-08-28|2004-07-07|ザプロクターアンドギャンブルカンパニー|Phosphinamides as substrate metalloprotease inhibitors|

---

EP0927156A1|1996-09-04|1999-07-07|Warner-Lambert Company|Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases|

---

US6624177B1|1996-09-04|2003-09-23|Warner-Lambert Company|Matrix metalloproteinase inhibitors and their therapeutic uses|

---

JP2002514180A|1996-09-04|2002-05-14|ワーナー―ランバート・コンパニー|Compounds for inhibiting matrix metalloproteinases and methods thereof|

---

US6022948A|1996-09-17|2000-02-08|Washington University|Method of cell surface activation and inhibition|

---

AT289590T|1996-09-27|2005-03-15|Upjohn Co|BETA-SULFONYL-HYDROXAMIC ACIDS AS MATRIX-METALOPROTEINASEINHIBITORS|

---

US5977408A|1996-10-16|1999-11-02|American Cyanamid Company|Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors|

---

US5962481A|1996-10-16|1999-10-05|American Cyanamid Company|Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors|

---

US6228869B1|1996-10-16|2001-05-08|American Cyanamid Company|Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors|

---

US5929097A|1996-10-16|1999-07-27|American Cyanamid Company|Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors|

---

US6548524B2|1996-10-16|2003-04-15|American Cyanamid Company|Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors|

---

GB9621814D0|1996-10-19|1996-12-11|British Biotech Pharm|Metalloproteinase inhibitors|

---

CA2268418A1|1996-10-22|1998-04-30|Pharmacia & Upjohn Company|.alpha.-amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors|

---

US5994132A|1996-10-23|1999-11-30|University Of Michigan|Adenovirus vectors|

---

MY117687A|1996-10-31|2004-07-31|Bayer Corp|Substituted 4-biphenyl-4-hydroxybutric acid derivatives as matrix metalloprotease inhibitors|

---

JPH10130217A|1996-11-01|1998-05-19|Kotobuki Seiyaku Kk|Carboxylic acid, its derivative, its production and pharmaceutical composition containing the acid|

---

US5965441A|1996-11-13|1999-10-12|The General Hospital Coporation|HSV/AAV hybrid amplicon vectors|

---

ES2278399T3|1996-11-20|2007-08-01|Introgen Therapeutics, Inc.|IMPROVED METHOD FOR THE PRODUCTION AND PURIFICATION OF ADENOVIRAL VECTORS.|

---

NZ334897A|1996-12-09|2001-02-23|Warner Lambert Co|Medicaments for treating and preventing heart failure and ventricular dilatation|

---

ZA9711121B|1996-12-13|1998-06-23|Handelman Joseph H|Reduction of hair growth.|

---

WO1998026773A1|1996-12-17|1998-06-25|Warner-Lambert Company|Use of matrix metalloproteinase inhibitors for treating neurological disorders and promoting wound healing|

---

EP0948489A1|1996-12-17|1999-10-13|Fujisawa Pharmaceutical Co., Ltd.|Piperazine compounds as inhibitors of mmp or tnf|

---

US5952320A|1997-01-07|1999-09-14|Abbott Laboratories|Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion|

---

US5985911A|1997-01-07|1999-11-16|Abbott Laboratories|C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion|

---

US6153436A|1997-01-10|2000-11-28|The Board Of Trustees Of The University Of Arkansas|Method of gene delivery using wildtype adeno associated viral vectors with insertions|

---

JP2001509810A|1997-01-17|2001-07-24|ファルマシア・アンド・アップジョン・カンパニー|Bis-sulfonamidohydroxamic acids as MMP inhibitors|

---

GB9702088D0|1997-01-31|1997-03-19|Pharmacia & Upjohn Spa|Matrix metalloproteinase inhibitors|

---

AU6144498A|1997-02-06|1998-08-26|Osiris Therapeutics, Inc.|P21cip1 or p27kip1 effects on the regulation of differentiation of human mesenchymal stem cells|

---

DE69828620T2|1997-02-25|2005-12-01|The Regents Of The University Of Michigan, Ann Arbor|METHOD AND COMPOSITIONS FOR PREVENTING AND TREATING THE CHRONOLOGICAL AGING OF HUMAN SKIN|

---

US6172057B1|1997-02-27|2001-01-09|American Cyanamid Company|N-Hydroxy-2--3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors|

---

US6197791B1|1997-02-27|2001-03-06|American Cyanamid Company|N-hdroxy-2--3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors|

---

WO1998039316A1|1997-03-04|1998-09-11|Monsanto Company|N-hydroxy 4-sulfonyl butanamide compounds|

---

WO1998039326A1|1997-03-04|1998-09-11|Monsanto Company|Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds|

---

DE69827940T2|1997-03-04|2005-06-09|Pharmacia Corp.|THIARYLSULFONAMID-hydroxamic acid|

---

JP2002515900A|1997-03-04|2002-05-28|モンサントカンパニー|Aromatic sulfonyl alpha-hydroxyhydroxamic acid compound|

---

US6087359A|1997-03-04|2000-07-11|Getman; Daniel P.|Thioaryl sulfonamide hydroxamic acid compounds|

---

US6638952B1|1997-03-04|2003-10-28|Pharmacia Corporation|Aromatic sulfonyl alpha-cycloamino hydroxamic acid compounds|

---

US5932600A|1997-03-14|1999-08-03|Vertex Pharmaceuticals Incorporated|Inhibitors of IMPDH enzyme|

---

ES2201452T3|1997-03-14|2004-03-16|Vertex Pharmaceuticals Incorporated|INHIBITORS OF THE IMPDH ENZYME.|

---

US20020111495A1|1997-04-04|2002-08-15|Pfizer Inc.|Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes|

---

GB9707333D0|1997-04-11|1997-05-28|British Biotech Pharm|Metalloproteinase inhibitors|

---

US6020191A|1997-04-14|2000-02-01|Genzyme Corporation|Adenoviral vectors capable of facilitating increased persistence of transgene expression|

---

US5756545A|1997-04-21|1998-05-26|Warner-Lambert Company|Biphenysulfonamide matrix metal alloproteinase inhibitors|

---

FR2762315B1|1997-04-22|1999-05-28|Logeais Labor Jacques|AMINO ACID DERIVATIVES INHIBITOR OF EXTRACELLULAR MATRIX METALLOPROTEASES AND TNF ALPHA RELEASE|

---

WO2000000600A2|1997-09-22|2000-01-06|Chang Lung Ji|Lentiviral vectors, comprising modified major donor splice sites and major packaging signals|

---

US6277633B1|1997-05-13|2001-08-21|The University Of North Carolina At Chapel Hill|Lentivirus-based gene transfer vectors|

---

US5932763A|1997-05-15|1999-08-03|Bayer Corporation|Inhibition of matrix metalloproteases by 2--4-biaryl-4-oxobutyric acids|

---

US5804581A|1997-05-15|1998-09-08|Bayer Corporation|Inhibition of matrix metalloproteases by substituted phenalkyl compounds|

---

US5925637A|1997-05-15|1999-07-20|Bayer Corporation|Inhibition of matrix metalloproteases by substituted biaryl oxobutyric acids|

---

GB9710490D0|1997-05-21|1997-07-16|British Biotech Pharm|Metalloproteinase inhibitors|

---

TWI234467B|1997-06-04|2005-06-21|Univ Michigan|Composition for inhibiting photoaging of skin|

---

US6156303A|1997-06-11|2000-12-05|University Of Washington|Adeno-associated virus isolates and AAV vectors derived therefrom|

---

GB9713726D0|1997-06-30|1997-09-03|Ciba Geigy Ag|Organic compounds|

---

WO1999002704A2|1997-07-08|1999-01-21|Cold Spring Harbor Laboratory|Dual specifically phosphatase and methods of use|

---

US6482827B1|1997-07-10|2002-11-19|Pharmacia & Upjohn S.P.A.|Matrix metalloproteinase inhibitors|

---

GB9714971D0|1997-07-16|1997-09-24|Cancer Res Campaign Tech|Assays,therapeutic methods and means|

---

GB9715030D0|1997-07-18|1997-09-24|British Biotech Pharm|Metalloproteinase inhibitors|

---

US6221646B1|1997-07-31|2001-04-24|Chiron Corporation|Materials and methods for simplified AAV production|

---

US6235786B1|1997-08-06|2001-05-22|Abbott Laboratories|Reverse hydroxamate inhibitors of matrix metalloproteinases|

---

US6294573B1|1997-08-06|2001-09-25|Abbott Laboratories|Reverse hydroxamate inhibitors of matrix metalloproteinases|

---

US6162241A|1997-08-06|2000-12-19|Focal, Inc.|Hemostatic tissue sealants|

---

US5854382A|1997-08-18|1998-12-29|Meadox Medicals, Inc.|Bioresorbable compositions for implantable prostheses|

---

EP0897908A1|1997-08-19|1999-02-24|Roche Diagnostics GmbH|3-Aryl-succinamido-hydroxamic acids, process for their preparation and medicaments containing them|

---

US6342507B1|1997-09-05|2002-01-29|Isotechnika, Inc.|Deuterated rapamycin compounds, method and uses thereof|

---

US6448058B1|1997-09-12|2002-09-10|Versicor, Inc.|Methods for solid phase synthesis of mercapto compounds and derivatives, combinatorial libraries thereof and compositions obtained thereby|

---

GB9719426D0|1997-09-13|1997-11-12|Johnson Matthey Plc|Novel process|

---

US5997895A|1997-09-16|1999-12-07|Integra Lifesciences Corporation|Dural/meningeal repair product using collagen matrix|

---

WO1999015641A1|1997-09-24|1999-04-01|The Regents Of The University Of California|Non-primate lentiviral vectors and packaging systems|

---

US6080874A|1997-09-25|2000-06-27|Abbott Laboratories|Synthesis and isolation of N--alkyl-N-hydroxyurea|

---

JPH11106775A|1997-10-03|1999-04-20|Taiho Kogyo Co Ltd|Solid lubricating film composition and plain bering material prepared therefrom|

---

AU9663798A|1997-10-06|1999-04-27|Warner-Lambert Company|Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases|

---

CN1282319A|1997-10-09|2001-01-31|小野药品工业株式会社|Aminobutanoic acid derivatives|

---

PL340412A1|1997-10-20|2001-01-29|Hoffmann La Roche|Bicyclic kinase inhibitors|

---

WO1999024464A1|1997-11-10|1999-05-20|Dana-Farber Cancer Institute, Inc|Glycosylated modified primate lentivirus envelope polypeptides|

---

WO1999024419A1|1997-11-12|1999-05-20|Darwin Discovery Limited|Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity|

---

US6187924B1|1997-11-12|2001-02-13|Darwin Discovery, Ltd.|Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity|

---

US6063786A|1997-11-12|2000-05-16|Darwin Discovery, Ltd.|Heterocyclic compounds having MMP and TNF inhibitory activity|

---

AT232192T|1997-11-21|2003-02-15|Upjohn Co|ALPHA HYDROXY, AMINO AND FLUORO DERIVATIVES OF BETA SULFONYL HYDROXAMIC ACIDS AS MATRIX METAL OPROTEIN NOSE INHIBITORS|

---

GB9725782D0|1997-12-05|1998-02-04|Pfizer Ltd|Therapeutic agents|

---

KR20010033062A|1997-12-12|2001-04-25|루이기 낼다이니|Therapeutic use of lentiviral vectors|

---

US6335156B1|1997-12-18|2002-01-01|The Johns Hopkins University School Of Medicine|14-3-3σ arrests the cell cycle|

---

BR9814422A|1997-12-23|2000-10-10|Warner Lambert Co|Ace inhibitor combinations - mmp inhibitor|

---

US5994099A|1997-12-31|1999-11-30|The University Of Wyoming|Extremely elastic spider silk protein and DNA coding therefor|

---

EA002971B1|1998-01-09|2002-12-26|Пфайзер Инк.|Matrix metalloprotease inhibitors, processes making thereof, use and method of treatment|

---

GB9801690D0|1998-01-27|1998-03-25|Pfizer Ltd|Therapeutic agents|

---

US6071903A|1998-01-27|2000-06-06|American Cyanamid Company|2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-hydroxyamic acids|

---

US6169103B1|1998-03-03|2001-01-02|Warner-Lambert|Fluorine-substituted biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases|

---

GB9804504D0|1998-03-03|1998-04-29|Leo Pharm Prod Ltd|Matrix metalloproteinase inhibitors|

---

US6037361A|1998-03-09|2000-03-14|Warner-Lambert Company|Fluorinated butyric acids and their derivatives as inhibitors of matrix metalloproteinases|

---

IL131217D0|1998-03-10|2001-01-28|Napro Biotherapeutics Inc|Novel methods and compositions for delivery of taxanes|

---

US6100032A|1998-03-13|2000-08-08|Johns Hopkins University|Human Smad3 and Smad4 are sequence-specific transcription activators|

---

FI980604A0|1998-03-18|1998-03-18|Univ Helsinki Licensing|New matrix metalloprotein inhibitors and regulators|

---

US6524850B1|1998-03-27|2003-02-25|The Scripps Research Institute|Kinase wee1 fusion protein compositions, nucleotide sequences, expression systems, and methods of use|

---

US6277061B1|1998-03-31|2001-08-21|The Research Foundation Of State University Of New York|Method of inhibiting membrane-type matrix metalloproteinase|

---

WO1999051754A1|1998-04-02|1999-10-14|Dana-Farber Cancer Institute, Inc.|Infectious pseudotyped lentiviral vectors lacking matrix protein and uses thereof|

---

EP0952148B1|1998-04-10|2004-05-12|Pfizer Products Inc.|Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives|

---

GT199900044A|1998-04-10|2000-09-14||PROCEDURES FOR PREPARING PHENOXYPHENYL SULFONYL HALIDES.|

---

PA8469601A1|1998-04-10|2000-09-29|Pfizer Prod Inc|PROCEDURE FOR RENTING STERICALLY IMPAIRED SULFONAMIDES|

---

JP2002512997A|1998-04-29|2002-05-08|バーテックスファーマシューティカルズインコーポレイテッド|Inhibitor of IMPDH enzyme|

---

JPH11313675A|1998-04-30|1999-11-16|Hoechst Marion Roussel Kk|Human bmp-7 promotor and screening of bone-related substance using the same|

---

US6316466B1|1998-05-05|2001-11-13|Syntex Llc|Pyrazole derivatives P-38 MAP kinase inhibitors|

---

US6376527B1|1998-05-05|2002-04-23|Syntex Llc|Pyrazole derivatives-p38 map kinase inhibitors|

---

US20020156114A1|1998-05-05|2002-10-24|Goldstein David Michael|Pyrazole derivatives - p38 MAP kinase inhibitors|

---

CA2331878A1|1998-05-14|1999-11-18|G.D. Searle & Co.|1,5-diaryl substituted pyrazoles as p38 kinase inhibitors|

---

US6509361B1|1999-05-12|2003-01-21|Pharmacia Corporation|1,5-Diaryl substituted pyrazoles as p38 kinase inhibitors|

---

US6288063B1|1998-05-27|2001-09-11|Bayer Corporation|Substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives as matrix metalloprotease inhibitors|

---

US6113913A|1998-06-26|2000-09-05|Genvec, Inc.|Recombinant adenovirus|

---

US6168807B1|1998-07-23|2001-01-02|Les Laboratoires Aeterna Inc.|Low molecular weight components of shark cartilage, processes for their preparation and therapeutic uses thereof|

---

BR9912600A|1998-07-30|2001-05-02|Warner Lambert Co|Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases|

---

WO2000006560A1|1998-07-30|2000-02-10|Warner-Lambert Company|Tricyclic heteroaromatics and their derivatives as inhibitors of matrix metalloproteinases|

---

US6117869A|1998-08-04|2000-09-12|Warner-Lambert Company|Compounds for and methods of inhibiting matrix metalloproteinases|

---

US6514534B1|1998-08-14|2003-02-04|Incept Llc|Methods for forming regional tissue adherent barriers and drug delivery systems|

---

JP2002523492A|1998-08-29|2002-07-30|ブリティッシュバイオテックファーマシューティカルズリミテッド|Hydroxamic acid derivatives as protease inhibitors|

---

US6509337B1|1998-09-17|2003-01-21|Pfizer Inc.|Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF inhibitors|

---

CA2344412A1|1998-09-21|2000-03-30|Takeda Chemical Industries, Ltd.|Thiol compound, their production and use|

---

WO2000024725A1|1998-10-26|2000-05-04|Vertex Pharmaceuticals Incorporated|Pentacyclic compounds useful as inhibitors of hepatitis c virus ns3 helicase|

---

US6596747B2|1998-10-29|2003-07-22|Bristol-Myers Squibb Company|Compounds derived from an amine nucleus and pharmaceutical compositions comprising same|

---

CA2348234A1|1998-10-29|2000-05-11|Chunjian Liu|Compounds derived from an amine nucleus that are inhibitors of impdh enzyme|

---

US6420403B1|1998-10-29|2002-07-16|Edwin J. Iwanowicz|Inhibitors of IMPDH enzyme|

---

JP2002528533A|1998-10-29|2002-09-03|ブリストル−マイヤーズスクイブカンパニー|Novel inhibitors of the enzyme IMPDH|

---

US6210922B1|1998-11-30|2001-04-03|National Research Council Of Canada|Serum free production of recombinant proteins and adenoviral vectors|

---

CA2353642C|1998-12-04|2009-11-10|Amarpreet S. Sawhney|Biocompatible crosslinked polymers|

---

EP1147189A2|1998-12-04|2001-10-24|Immusol, Inc.|Ribozyme therapy for the treatment and/or prevention of restenosis|

---

US6288261B1|1998-12-18|2001-09-11|Abbott Laboratories|Inhibitors of matrix metalloproteinases|

---

US6328229B1|1998-12-18|2001-12-11|Cohesion Technologies, Inc.|Low volume mixing spray head for mixing and dispensing of two reactive fluid components|

---

US6262080B1|1998-12-31|2001-07-17|Avantis Pharmaceuticals Inc.|3--lactams useful as inhibitors of matrix metalloproteinase|

---

US6329550B1|1998-12-31|2001-12-11|Aventis Pharmaceuticals Inc.|Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase|

---

US6544980B2|1998-12-31|2003-04-08|Aventis Pharmaceuticals Inc.|N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase|

---

US6352976B1|1998-12-31|2002-03-05|Aventis Pharmaceuticals Inc.|Selective inhibitors of MMP-12|

---

US6486193B2|1998-12-31|2002-11-26|Aventis Pharmaceuticals Inc.|3-substituted pyrrolidines useful as inhibitors of matrix metalloproteinases|

---

US6294539B1|1999-01-19|2001-09-25|Advanced Syntech, Llc|Heterocyclic hydroxamic acid derivatives as MMP inhibitors|

---

CN1178915C|1999-01-27|2004-12-08|惠氏控股有限公司|Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase inhibitors/TNF-alpha converting enzyme inhibitors|

---

SK11352001A3|1999-02-08|2002-09-10|G. D. Searle & Co.|Sulfamato hydroxamic acid metalloprotease inhibitor|

---

GB9903598D0|1999-02-18|1999-04-07|Univ Manchester|Connective tissue healing|

---

US6514979B1|1999-03-03|2003-02-04|University Of Maryland Biotechnology Institute|Synergistic combinations of guanosine analog reverse transcriptase inhibitors and inosine monophosphate dehydrogenese inhibitors and uses therefor|

---

KR100652535B1|1999-03-19|2006-12-01|버텍스 파마슈티칼스 인코포레이티드|Inhibitors of impdh enzyme|

---

CA2361848A1|1999-04-02|2000-10-12|Dupont Pharmaceuticals Company|Novel lactam inhibitors of matrix metalloproteinases, tnf-.alpha., and aggrecanase|

---

JP2002541138A|1999-04-02|2002-12-03|デュポンファーマシューティカルズカンパニー|Novel amide derivatives as inhibitors of matrix metalloproteases, TNF-α and aggrecanase|

---

KR20020002419A|1999-04-06|2002-01-09|우에노 도시오|4-aminobutanoic acid derivatives and drugs containing these derivatives as the active ingredient|

---

CO5170501A1|1999-04-14|2002-06-27|Novartis Ag|USEFUL REPLACED BLUES FOR THE TREATMENT OF DISEASES MEDIATED BY TNFa eIL-1 AND DISEASES OF THE OSEO METABOLISM|

---

US6312725B1|1999-04-16|2001-11-06|Cohesion Technologies, Inc.|Rapid gelling biocompatible polymer composition|

---

WO2000063194A1|1999-04-19|2000-10-26|Shionogi & Co., Ltd.|Sulfonamide derivatives having oxadiazole rings|

---

US6287588B1|1999-04-29|2001-09-11|Macromed, Inc.|Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof|

---

AT528406T|1999-04-29|2011-10-15|Gbp Ip Llc|METHOD AND DEVICE FOR PRODUCING SAFE, RECOMBINANT HIGH TITAN LENTIVIRUS VECTORS|

---

US6583299B1|1999-05-20|2003-06-24|G.D. Searle & Co.|α-amino-β-sulfonyl hydroxamic acid compounds|

---

TWI223599B|1999-05-24|2004-11-11|Shionogi & Co|Evaluation method of matrix metalloprotease inhibitory activity|

---

AU5031200A|1999-05-28|2000-12-18|Vertex Pharmaceuticals Incorporated|Method for preparing 5-substituted oxazoles|

---

US6511993B1|1999-06-03|2003-01-28|Kevin Neil Dack|Metalloprotease inhibitors|

---

JP3362778B2|1999-06-03|2003-01-07|独立行政法人農業生物資源研究所|Method for producing ultrafine crystalline silk powder|

---

US6294694B1|1999-06-04|2001-09-25|Wisconsin Alumni Research Foundation|Matrix metalloproteinase inhibitors and method of using same|

---

CA2377278C|1999-06-25|2010-03-23|Vertex Pharmaceuticals Incorporated|Prodrugs of carbamate inhibitors of impdh|

---

US6541521B1|1999-07-12|2003-04-01|Warner-Lambert Company|Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases|

---

KR20010010393A|1999-07-20|2001-02-05|김윤|Biodegradable Block Copolymer of Hydrophobic and Hydrophilic Polymers, and Composition for Drug Delivery Comprising Same|

---

EP1211240A4|1999-09-01|2003-02-12|Ajinomoto Kk|Biscyclopropanecarboxylic acid amide compounds and medicinal use thereof|

---

IL138686D0|1999-10-01|2001-10-31|Pfizer Prod Inc|α- SULFONYLAMINO HYDROXAMIC ACID INHIBITORS OF MATRIX METALLOPROTEINASES FOR THE TREATMENT OF PERIPHERAL OR CENTRAL NERVOUS SYSTEM DISORDERS|

---

SE9904177D0|1999-11-18|1999-11-18|Astra Ab|Novel compounds|

---

GB9929979D0|1999-12-17|2000-02-09|Darwin Discovery Ltd|Hydroxamic acid derivatives|

---

US6380253B1|2000-01-05|2002-04-30|Efa Sciences Llc|Method of stabilizing and potentiating the action of anti-angiogenic substances|

---

PL357995A1|2000-01-31|2004-08-09|Pfizer Products Inc.|Nicotinamide benzofused-heterocyclyl derivatives useful as selective inhibitors of pde4 isozymes|

---

ES2223772T3|2000-01-31|2005-03-01|Pfizer Products Inc.|PYRIMIDINCARBOXAMIDS USED AS INHIBITORS OF THE ISOZIMAS PDE4.|

---

MXPA02007938A|2000-02-17|2003-02-10|3M Innovative Properties Co|Delivery systems using preformed biodegradable polymer compositions and methods.|

---

US6867299B2|2000-02-24|2005-03-15|Hoffmann-La Roche Inc.|Oxamide IMPDH inhibitors|

---

US6465508B1|2000-02-25|2002-10-15|Wyeth|Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors|

---

AU4161001A|2000-03-03|2001-09-17|Human Genome Sciences Inc|Protein tyrosine phosphatase polynucleotides, polypeptides, and antibodies|

---

US6458822B2|2000-03-13|2002-10-01|Pfizer Inc.|2-oxo-imidazolidine-4-carboxylic acid hydroxamide compounds that inhibit matrix metalloproteinases|

---

CA2400168A1|2000-03-17|2001-09-27|Thomas P. Maduskuie, Jr.|Beta-amino acid derivatives as inhibitors of matrix metalloproteases and tnf-alpha|

---

US7495018B2|2000-03-30|2009-02-24|Takeda Pharmaceutical Company Limited|Substituted 1,3-thiazole compounds, their production and use|

---

US20020019539A1|2000-03-31|2002-02-14|Bailey Anne E.|Process for the preparation of matrix metalloproteinase inhibitors|

---

CN1366524A|2000-04-07|2002-08-28|三星电子株式会社|Sulfonamide derivative as matrix metalloproteinase inhibitor|

---

WO2001079246A2|2000-04-13|2001-10-25|Pharmasset, Ltd.|3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections|

---

WO2001081340A2|2000-04-24|2001-11-01|Bristol-Myers Squibb Company|Heterocycles that are inhibitors of impdh enzyme|

---

US6503892B2|2000-04-26|2003-01-07|New England Medical Center Hospitals Inc.|Method of using matrix metalloproteinase inhibitors in filtering blebs following glaucoma filtering surgery and in the treatment of ischemic damage to the retina and optic nerve|

---

CA2408921A1|2000-05-10|2001-11-15|Bristol-Myers Squibb Company|Modified inosine 5'-monophosphate dehydrogenase polypeptides and uses thereof|

---

EP1286994A1|2000-05-15|2003-03-05|Darwin Discovery Limited|Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity|

---

HU0302904A3|2000-07-18|2005-02-28|Leo Pharma As|Matrix metalloproteinase inhibitors|

---

MXPA03001528A|2000-08-22|2004-04-02|Ribapahrm Inc|Improved specificity in treatment of diseases.|

---

AU1214702A|2000-08-31|2002-03-13|Hoffmann La Roche|7-oxo pyridopyrimidines|

---

SV2003000617A|2000-08-31|2003-01-13|Lilly Co Eli|INHIBITORS OF PROTEASA PEPTIDOMIMETICA REF. X-14912M|

---

US6455570B1|2000-10-06|2002-09-24|The Trustees Of The University Of Pennsylvania|Polypyrrolinone based inhibitors of matrix metalloproteases|

---

US20020151491A1|2000-11-28|2002-10-17|Jian-Dong Li|Composition and method for treating the over-production of mucin in diseases such as otitis media using an inhibitor of MUC5AC|

---

EP1363704A2|2000-12-15|2003-11-26|Triangle Pharmaceuticals Inc.|Dapd combination therapy with inosine monophosphate dehydrogenase inhibitor|

---

DE10064997A1|2000-12-23|2002-06-27|Merck Patent Gmbh|New 1-benzoyl-3-phenyl-tetrahydropyridazine derivatives, useful for treating e.g. allergy, are selective inhibitors of phosphodiesterase IV, and new intermediates|

---

US6600057B2|2000-12-29|2003-07-29|Kimberly-Clark Worldwide, Inc.|Matrix metalloproteinase inhibitors|

---

US6642255B2|2001-01-11|2003-11-04|Bristol-Myers Squibb Pharma Company|1,2,-Disubstituted cyclic inhibitors of matrix metalloproteases and TNF-alpha|

---

DK1355916T3|2001-01-22|2007-05-07|Merck & Co Inc|Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase|

---

HU0302891A2|2001-01-31|2003-12-29|Pfizer Products Inc.|Ether derivatives useful as inhibitors of pde4 isozymes, their use and pharmaceutical compositions containing them|

---

WO2002060898A1|2001-01-31|2002-08-08|Pfizer Products Inc.|Thiazolyl-, oxazolyl-, pyrrolyl-, and imidazolyl-acid amide derivatives useful as inhibitors of pde4 isozymes|

---

MXPA03006887A|2001-01-31|2003-11-13|Pfizer Prod Inc|Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes.|

---

YU63703A|2001-02-12|2006-05-25|F. Hoffmann-La Roche Ag.|6-supstituted pyrido-pyrimidines|

---

MXPA01013171A|2001-02-14|2004-05-21|Warner Lambert Co|Tricyclic biphenyl sulfonamide matrix metalloproteinase inhibitors.|

---

MXPA01013172A|2001-02-14|2002-08-21|Warner Lambert Co|Sulfonamide matrix metalloproteinase inhibitors.|

---

WO2002072150A2|2001-03-13|2002-09-19|Angiotech Pharmaceuticals Inc.|Micellar drug delivery vehicles and uses thereof|

---

AU2002338286A1|2001-04-10|2002-10-28|Leo Pharma A/S|Novel aminophenyl ketone derivatives|

---

CA2681952A1|2001-04-25|2002-10-31|Eidgenoessische Technische Hochschule Zurich|Drug delivery matrices to enhance wound healing|

---

US20030166201A1|2001-04-30|2003-09-04|Jensen Michael C.|Selection systems for genetically modified cells|

---

AU2002257456A1|2001-05-24|2002-12-03|University Of Western Ontario|Control of myogenesis by modulation of p38 map kinase activity|

---

JP2004535411A|2001-05-25|2004-11-25|ブリストルーマイヤーズスクイブカンパニー|Hydantoins and related heterocyclic compounds as inhibitors of matrix metalloproteinases and / or TNF-α convertases |

---

EP1407005A4|2001-06-11|2006-05-31|Interleukin Genetics Inc|Integrative assays for monitoring molecular assembly events|

---

EP1399542A2|2001-06-15|2004-03-24|National Research Council of Canada|Methods for modulating gap junctions|

---

GB0117506D0|2001-07-18|2001-09-12|Bayer Ag|Imidazopyridinones|

---

US6770647B2|2001-08-17|2004-08-03|Bristol-Myers Squibb Pharma Company|Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme |

---

US6824769B2|2001-08-28|2004-11-30|Vertex Pharmaceuticals Incorporated|Optimal compositions and methods thereof for treating HCV infections|

---

CN1281603C|2001-08-30|2006-10-25|霍夫曼-拉罗奇有限公司|Aminopyrrole compounds as antiinflammatory agents|

---

AU2002341715A1|2001-09-17|2003-04-01|Bristol-Myers Squibb Company|Cyclic hydroxamic acids as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme |

---

WO2003031431A1|2001-10-09|2003-04-17|Bristol-Myers Squibb Company|Cyclic sulfone derivatives as inhibitors of matrix metalloproteinases and/or tnf-$g converting enzyme |

---

WO2003035066A1|2001-10-23|2003-05-01|Celltech R & D Limited|2-aminoquinolone derivatives for use as impdh inhibitors|

---

CA2462525A1|2001-10-31|2003-05-08|Merck Patent Gesellschaft Mit Beschraenkter Haftung|Type 4 phosphodiesterase inhibitors and uses thereof|

---

US20030212056A1|2001-11-02|2003-11-13|Jingwu Duan|Beta-sulfone derivatives as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme |

---

CN1585641A|2001-11-05|2005-02-23|默克专利有限公司|Hydrazono-malonitriles|

---

WO2003063573A2|2001-11-09|2003-08-07|Intarcia Therapeutics, Inc.|Method for treating diseases with omega interferon|

---

WO2003053958A1|2001-12-20|2003-07-03|Celltech R & D Limited|Quinazolinedione derivatives|

---

AU2002346729A1|2001-12-20|2003-07-09|Bristol-Myers Squibb Company|Barbituric acid derivatives as inhibitors of tnf-$g converting enzyme and/or matrix metalloproteinases|

---

AU2002357312A1|2001-12-20|2003-07-09|Bristol-Myers Squibb Company|Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme and/or matrix metalloproteinases|

---

TW200301698A|2001-12-21|2003-07-16|Squibb Bristol Myers Co|Acridone inhibitors of IMPDH enzyme|

---

KR20040094413A|2002-02-01|2004-11-09|오메로스 코포레이션|Compositions and methods for systemic inhibition of cartilage degradation|

---

US7101883B2|2002-03-18|2006-09-05|Bristol-Myers Squibb Company|Uracil derivatives as inhibitors of TNF-α converting enzyme and matrix metalloproteinases|

---

ES2302925T3|2002-03-20|2008-08-01|Elan Pharma International Limited|COMPOSITIONS OF NANOPARTICULES OF PROTEIN QUINASA INHIBITORS ACTIVATED BY MYTHOGEN .|

---

WO2003082287A1|2002-03-22|2003-10-09|Bristol-Myers Squibb Company|Dpc 333 formulation having unique biopharmaceutical characteristics|

---

GB0208223D0|2002-04-10|2002-05-22|Celltech R&D Ltd|Chemical compounds|

---

GB0208224D0|2002-04-10|2002-05-22|Celltech R&D Ltd|Chemical compounds|

---

US6620813B1|2002-06-21|2003-09-16|Medinox, Inc.|Hydroxamate derivatives of non-steroidal anti-inflammatory drugs|

---

US7462687B2|2002-11-12|2008-12-09|Enzon Pharmaceuticals, Inc.|Prodrugs of vancomycin with hydrolysis resistant polymer linkages|

---

CA2511521C|2002-12-30|2012-02-07|Angiotech International Ag|Drug delivery from rapid gelling polymer composition|CA2511521C|2002-12-30|2012-02-07|Angiotech International Ag|Drug delivery from rapid gelling polymer composition|

---

US7883500B2|2003-03-26|2011-02-08|G&L Consulting, Llc|Method and system to treat and prevent myocardial infarct expansion|

---

WO2004087045A2|2003-03-28|2004-10-14|Kosan Biosciences, Inc.|Devices, methods, and compositions to prevent restenosis|

---

US20050208095A1|2003-11-20|2005-09-22|Angiotech International Ag|Polymer compositions and methods for their use|

---

CA2536041A1|2003-11-10|2005-05-26|Angiotech International Ag|Medical implants and fibrosis-inducing agents|

---

JP2007516742A|2003-11-20|2007-06-28|アンジオテックインターナショナルアーゲー|Electrical devices and anti-scarring agents|

---

US8277831B2|2004-02-17|2012-10-02|Advanced Technologies And Regenerative Medicine, Llc.|Drug-enhanced adhesion prevention|

---

WO2005089472A2|2004-03-17|2005-09-29|Genzyme Corporation|Anti-adhesion spraying|

---

WO2005116086A2|2004-04-07|2005-12-08|The University Of Georgia Research Foundation, Inc.|Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods|

---

US8034796B2|2004-04-07|2011-10-11|The University Of Georgia Research Foundation, Inc.|Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods|

---

US20050244367A1|2004-05-03|2005-11-03|Ilypsa, Inc.|Phospholipase inhibitors localized in the gastrointestinal lumen|

---

US7879361B2|2005-01-04|2011-02-01|Gp Medical, Inc.|Nanoparticles for drug delivery|

---

US7201918B2|2004-11-16|2007-04-10|Microvention, Inc.|Compositions, systems and methods for treatment of defects in blood vessels|

---

US8071574B2|2005-02-22|2011-12-06|John Dennis Bobyn|Implant improving local bone formation|

---

US20080125745A1|2005-04-19|2008-05-29|Shubhayu Basu|Methods and compositions for treating post-cardial infarction damage|

---

US9539410B2|2005-04-19|2017-01-10|Abbott Cardiovascular Systems Inc.|Methods and compositions for treating post-cardial infarction damage|

---

WO2006122414A1|2005-05-17|2006-11-23|Matregen Corp.|Depot for sustained and controlled delivery of methotrexate|

---

US20070100199A1|2005-11-03|2007-05-03|Lilip Lau|Apparatus and method of delivering biomaterial to the heart|

---

WO2007123993A2|2006-04-19|2007-11-01|University Of South Florida|Niosome-hydrogel drug delivery|

---

AU2007260924A1|2006-06-21|2007-12-27|The Board Of Trustees Of The Leland Stanford Junior University|Compositions and methods for joining non-conjoined lumens|

---

US9192697B2|2007-07-03|2015-11-24|Hemoteq Ag|Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis|

---

US7732190B2|2006-07-31|2010-06-08|Advanced Cardiovascular Systems, Inc.|Modified two-component gelation systems, methods of use and methods of manufacture|

---

US9242005B1|2006-08-21|2016-01-26|Abbott Cardiovascular Systems Inc.|Pro-healing agent formulation compositions, methods and treatments|

---

US20090148502A1|2006-10-23|2009-06-11|Hemo Nanoscience, Llc|Compositions and methods for treating lacerations, abrasions, avulsions, burns, ulcers, and cases of excessive bleeding|

---

US9005672B2|2006-11-17|2015-04-14|Abbott Cardiovascular Systems Inc.|Methods of modifying myocardial infarction expansion|

---

US8414909B2|2006-11-20|2013-04-09|Lutonix, Inc.|Drug releasing coatings for medical devices|

---

US8998846B2|2006-11-20|2015-04-07|Lutonix, Inc.|Drug releasing coatings for balloon catheters|

---

US8414910B2|2006-11-20|2013-04-09|Lutonix, Inc.|Drug releasing coatings for medical devices|

---

US20080276935A1|2006-11-20|2008-11-13|Lixiao Wang|Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs|

---

US8414525B2|2006-11-20|2013-04-09|Lutonix, Inc.|Drug releasing coatings for medical devices|

---

US8414526B2|2006-11-20|2013-04-09|Lutonix, Inc.|Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids|

---

US8425459B2|2006-11-20|2013-04-23|Lutonix, Inc.|Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent|

---

US9700704B2|2006-11-20|2017-07-11|Lutonix, Inc.|Drug releasing coatings for balloon catheters|

---

US9737640B2|2006-11-20|2017-08-22|Lutonix, Inc.|Drug releasing coatings for medical devices|

---

US8192760B2|2006-12-04|2012-06-05|Abbott Cardiovascular Systems Inc.|Methods and compositions for treating tissue using silk proteins|

---

WO2008076383A2|2006-12-18|2008-06-26|Med Institute Inc.|Stent graft with releasable therapeutic agent|

---

CA2743022C|2007-01-21|2012-10-09|Hemoteq Ag|Methods for coating catheter balloons with a defined quantity of active agent|

---

ES2381639T3|2007-04-13|2012-05-30|Kuros Biosurgery Ag|Polymeric fabric sealant|

---

US20080287633A1|2007-05-18|2008-11-20|Drumheller Paul D|Hydrogel Materials|

---

US20080293910A1|2007-05-24|2008-11-27|Tyco Healthcare Group Lp|Adhesive formulatiions|

---

CN101338036B|2007-07-06|2010-11-03|常州百瑞吉生物医药有限公司|Biocompatible quick-gelatinizing hydrogels and method for preparing spray thereof|

---

US8101371B2|2007-10-18|2012-01-24|Musc Foundation For Research Development|Methods for the diagnosis of genitourinary cancer|

---

US8232402B2|2008-03-12|2012-07-31|Link Medicine Corporation|Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications|

---

US10046081B2|2008-04-11|2018-08-14|The Henry M Jackson Foundation For The Advancement Of Military Medicine, Inc.|Electrospun dextran fibers and devices formed therefrom|

---

EP2276879B1|2008-04-11|2015-11-25|Virginia Commonwealth University|Electrospun dextran fibers and devices formed therefrom|

---

US9072727B2|2008-04-18|2015-07-07|Warsaw Orthopedic, Inc.|Alpha adrenergic receptor agonists for treatment of degenerative disc disease|

---

US8956641B2|2008-04-18|2015-02-17|Warsaw Orthopedic, Inc.|Alpha adrenergic receptor agonists for treatment of inflammatory diseases|

---

US8883768B2|2008-04-18|2014-11-11|Warsaw Orthopedic, Inc.|Fluocinolone implants to protect against undesirable bone and cartilage destruction|

---

US20090263456A1|2008-04-18|2009-10-22|Warsaw Orthopedic, Inc.|Methods and Compositions for Reducing Preventing and Treating Adhesives|

---

WO2010024898A2|2008-08-29|2010-03-04|Lutonix, Inc.|Methods and apparatuses for coating balloon catheters|

---

AU2009313927A1|2008-11-13|2010-05-20|Astrazeneca Ab|Azaquinolinone derivatives and uses thereof|

---

JP5706691B2|2008-12-19|2015-04-22|株式会社ネクスト２１|Method for producing hydrogel and hydrogel|

---

EP3064230B1|2009-07-10|2019-04-10|Boston Scientific Scimed, Inc.|Use of nanocrystals for a drug delivery balloon|

---

WO2011008393A2|2009-07-17|2011-01-20|Boston Scientific Scimed, Inc.|Nucleation of drug delivery balloons to provide improved crystal size and density|

---

CA2730598C|2010-03-16|2018-03-13|Confluent Surgical, Inc.|Modulating drug release rate by controlling the kinetics of the ph transition in hydrogels|

---

EP2611476B1|2010-09-02|2016-08-10|Boston Scientific Scimed, Inc.|Coating process for drug delivery balloons using heat-induced rewrap memory|

---

JP5886749B2|2010-09-02|2016-03-16|日本化薬株式会社|Drug-block copolymer complex and method for producing medicament containing the same|

---

KR101255337B1|2010-10-04|2013-04-16|한국과학기술연구원|Nitric oxide delivery system using thermosensitive synthetic polymers|

---

KR20140023372A|2011-04-20|2014-02-26|카르빌란 바이오서저리, 인코포레이티드|In-situ gel forming compositions|

---

EP2541547A1|2011-06-30|2013-01-02|Thomson Licensing|Method and apparatus for changing the relative positions of sound objects contained within a higher-order ambisonics representation|

---

US8669360B2|2011-08-05|2014-03-11|Boston Scientific Scimed, Inc.|Methods of converting amorphous drug substance into crystalline form|

---

WO2013028208A1|2011-08-25|2013-02-28|Boston Scientific Scimed, Inc.|Medical device with crystalline drug coating|

---

US8936784B2|2011-10-17|2015-01-20|Poly-Med, Inc.|Absorbable in situ gel-forming system, method of making and use thereof|

---

US8697118B2|2011-10-18|2014-04-15|St. Teresa Medical, Inc.|Stabilizers for hemostatic products|

---

EP2768514B8|2011-10-19|2019-06-19|Mercator Medsystems, Inc.|Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation|

---

WO2013086419A1|2011-12-09|2013-06-13|California Institute Of Technology|Polymer scaffolds and their use in the treatment of vision loss|

---

CN104487093B|2012-07-31|2017-10-10|阿克伦大学|The crosslinking promoted via the strain of the hydrogel based on PEG of the cycloaddition of not cupric|

---

US10016454B2|2012-12-04|2018-07-10|Cohera Medical, Inc.|Silane-containing moisture-curable tissue sealant|

---

TWI624270B|2013-01-17|2018-05-21|財團法人工業技術研究院|Pharmaceutical composition|

---

US9987391B2|2013-03-13|2018-06-05|St. Jude Medical Coordination Center Bvba|Injectable hydrogels|

---

US9555157B2|2013-11-12|2017-01-31|St. Teresa Medical, Inc.|Method of inducing hemostasis in a wound|

---

JP2015137430A|2014-01-20|2015-07-30|国立大学法人福井大学|Gel fiber and nonwoven fabric thereof|

---

US9522114B1|2014-03-27|2016-12-20|University Of South Florida|Enhanced targeted drug delivery system via chitosan hydrogel and chlorotoxin|

---

WO2015159995A1|2014-04-17|2015-10-22|典穂 神谷|Method for producing hydrogel, method for enveloping envelopment target, and method for releasing envelopment target|

---

EP3240819A1|2015-01-02|2017-11-08|Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.|Biodegradable polymer|

---

WO2017019214A1|2015-07-29|2017-02-02|Musc Foundation For Research Development|Donor organ pre-treatment formulation|

---

US10080806B2|2015-08-19|2018-09-25|International Business Machines Corporation|Sulfur-containing polymers from hexahydrotriazine and dithiol precursors as a carrier for active agents|

---

US9550863B1|2015-10-05|2017-01-24|International Business Machines Corporation|Polymers from stabilized imines|

---

US9534084B1|2015-11-02|2017-01-03|International Business Machines Corporation|High molecular weight polythioaminals from a single monomer|

---

WO2017083050A1|2015-11-12|2017-05-18|St. Teresa Medical, Inc.|A method of sealing a durotomy|

---

US9862802B2|2015-11-30|2018-01-09|International Business Machines Corporation|Poly probe based lithography|

---

US10227444B2|2016-06-01|2019-03-12|International Business Machines Corporation|Degradable polyurethanes containing thioaminal groups|

---

US10953128B2|2017-11-02|2021-03-23|St. Teresa Medical, Inc.|Fibrin sealant products|

---

WO2019195728A1|2018-04-06|2019-10-10|University Of Notre Dame Du Lac|Refillable drug delivery by affinity homing|

法律状态:
2009-11-05| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 01 OCT 2009. |

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2010-03-04| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 01 OCT 2009 |

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2010-03-11| FGA| Letters patent sealed or granted (standard patent)|

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2017-07-27| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US43747102P| true| 2002-12-30|2002-12-30||

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US60/437,471||2002-12-30||

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US44087503P| true| 2003-01-17|2003-01-17||

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US60/440,875||2003-01-17||

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PCT/US2003/041580|WO2004060346A2|2002-12-30|2003-12-30|Drug delivery from rapid gelling polymer composition|

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