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    • 专利摘要:
    PURPOSE: A therapeutic approach for the treatment of various pathologies is provided by effecting a mild depression in CNS activity without producing excessive sedation, muscle weakness, fatigue, or hepatotoxicity. CONSTITUTION: Use of a compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, and a pharmaceutically acceptable amide of isovaleric acid in the preparation of a pharmaceutical formulation, is provided for use in a method of treating a pathology that is ameliorated by a mild depression of CNS activity, whereby at least one symptom of the pathology is alleviated.
    公开号:KR20000038194A
    申请号:KR1019990701716
    申请日:1997-08-29
    公开日:2000-07-05
    发明作者:린다 디 아트맨；마누엘에프 발란드린
    申请人:젠센, 제임스 유；엔피에스 파마슈티칼즈, 인코포레이티드；
    IPC主号:
    专利说明:

    TREATMENT OF SPASTICITY, CONVULSIONS BY ISOVALERIC ACID DERIVATIVES CNS DEPRESSANTS}
    The present invention relates to pathological conditions such as spasticity and stiffness that can alleviate the symptoms by mildly inhibiting the activity of the central nervous system (CNS), in animals including humans. To treatment without undesirable excessive sedation or muscle weakness. More specifically, the present invention relates to the therapeutic use of isovaleramide, isovaleric acid, and related compounds in patients suffering from pathologies having these characteristics.
    Many of the drugs currently being used to treat pathologies such as cramps and competition have painful side effects that limit long-term clinical use. For example, among these drugs, benzodiazepines are ones that can decrease the cognitive ability. The other two agents are valproate and baclofen, the former showing hepatotoxicity, and the latter causing excessive muscle weakness and sedation, all of which are their treatment. The scientific potential is limited.
    Summary of the Invention
    It is therefore an object of the present invention to provide a therapeutic approach to treat various pathologies by mildly inhibiting CNS activity without causing excessive sedation, muscle weakness, fatigue or hepatotoxicity.
    Another object of the present invention is to provide a method for alleviating one or more symptoms associated with conditions such as spasms that can be alleviated by centrally mediated decrease through central control.
    Another object of the present invention is to provide a novel anticonvulsant therapy.
    According to one aspect of the present invention, in order to achieve the above and other objects, isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid and isovaleric acid Provided for the use of a compound selected from the group consisting of pharmaceutically acceptable amides to prepare a pharmaceutical formulation for use in a method of alleviating at least one symptom of the pathology by treating a pathology that is alleviated by weakly inhibiting CNS activity. do. That is, the present invention comprises the steps of administering to a patient with a pathology that is alleviated by weakly inhibiting CNS activity, a therapeutically effective amount of a pharmaceutical formulation containing a pharmaceutically acceptable carrier and a component selected from the aforementioned pharmaceutical groups. It includes a treatment method comprising a.
    According to one embodiment of the present invention, the pathology to be treated is affective mood disorder, convulsion, central nervous pain syndrome, headache, headache, Or restlessness syndromes. In another embodiment, the pathology is alleviated by reducing muscle tension through the center, an example of which is spasm.
    According to another embodiment of the invention, the bark of the Valerianaceae, the cramp bark of the Viburnum opulus, the black haw bark or hop of the Viburnum prunifolium tree A compound is provided for use in the manufacture of a pharmaceutical formulation for use in a method of treating spasms, wherein the extract is hydrolyzed in vivo to produce isovaleric acid or isovaleramide. It contains at least one. The present invention also provides a method for alleviating cramps in a subject in need of such treatment, comprising administering a therapeutically effective amount of the extract described above.
    Other objects, features and advantages of the present invention can be seen by the following detailed description. However, it will be apparent to those skilled in the art that various changes and modifications can be made within the spirit and scope of the present invention from the detailed description, that the following detailed description and specific examples are presented by way of example only, for purposes of illustration. It must be understood.
    Figure 1 shows the structure of several compounds including isovaleramide.
    FIG. 2 shows the effect of isovaleramide (300 mg / kg, intraperitoneal administration) on gross observational spasticity scores caused by metal probes applied to the abdomen of long-term spinal anesthesia rats.
    FIG. 3 shows that in long-term spinal anesthesia, flexor reflex, an electrophysiological measure of convulsions, is dose- and time-dependently reduced. Before and after the effects of isovaleramide (300, 600 and 1200 mg / kg, oral administration), baclofen (10 mg / kg, subcutaneous administration) and excipients (water, 12 mg / kg, oral administration), and Observations were made 30, 60, 90 and 120 minutes after dosing and the results are shown. At all ranges of dose, isovaleramide significantly reduced flexor reflexes, comparable to that observed with baclofen. Statistical significance was determined by one-way analysis of variance (ANOVA) and post-hoc Dunnett's t-test: p <0.05 (*); p <0.01 (**); NS: no significance).
    Figure 4 shows that isovaleramide and the known anticonvulsant baclofen have reduced flexor reflexes to comparable levels in mice anesthetized for long periods of time. The reaction obtained in FIG. 3 was converted to total-area-under-the-curve below the curve for the 2 hour measurement. All drug-related groups differed significantly from excipients (p <0.05, ANOVA).
    1. Overview
    We weakly inhibit isovaleric acid and its pharmaceutically acceptable salts, amides (eg isovaleramide) and alcohol esters (eg ethyl isovalerate and beta-sitostearyl isovalerate) in order to weakly inhibit CNS activity. It has been found that can be administered in vivo. That is, these agents can centrally enhance (or reduce excitatory neurotransmission) without completely inhibiting all activity. Thus, according to the present invention, patients receiving these reagents do not openly soothe or become numb or are paralyzed, for example, in connection with a sudden seizure reduction (no numbness) or in connection with alleviation of muscle tone. There is no paralysis (no paralysis), no paralysis (no soothing action) in connection with causing a sedative effect, or paralysis (relative to weakness or lethargy) in alleviating foreign symptoms such as spasms.
    Numerous pathologies exemplified by affective mood disorders, headaches (chronic, complex, migraine), inactivity, neuropathic pain, impairment, convulsions and stiffness have symptoms alleviated by mild CNS inhibition. Thus, individuals suffering from these pathologies are, according to the present invention, candidates for the treatment of the invention receiving a pharmaceutical formulation of isovaleramide, isovaleric acid or related compounds.
    It is believed that the compounds of the present invention act through GABA metabolism and are therefore pharmacologically similar to existing agents known to enhance central GABA neurotransmission. As with many existing agents such as barbiturates, benzodiazepines, gabapentin, valproate, vigabatrin, and progabides, the compounds of the present invention are inhibitory (GABA- and / or glycine-associated) neurons. It is effective in treating pathological conditions such as those mentioned above, which are thought to be caused by regulatory defects in delivery. Such regulation may occur by direct or mediating effects on the CNS receptor or by impacting metabolic pathways that increase GABA or glycine concentrations and / or reduce the levels of excitatory neurotransmitters such as glutamate. Ruggero et al., In ANTIEPILEPTIC DRUGS (4th ed.), Pages 581-88 (Raven Press 1995); Nogrady, MEDICINAL CHEMISTRY: A BIOCHEMICL APPROACH (2d ed.), Pages 225-39 (Oxford University Press 1988); Fonnum and Morselli, respectively PSYCHOPHARMACOLOGY: THE THIRD GENERATION OF PROGRESS, pages 173-82 and 183-95 (Raven Press 1987). However, despite having pharmacological similarities to the existing drugs mentioned above, the compounds of the present invention surprisingly have adverse side effects associated with known drug therapies in the art, such as hepatotoxicity that occurs with the administration of valproate. Does not cause
    2. Examples of pathologies alleviated by weakly inhibiting CNS activity
    SPASTICITY: "Spasm is an upper part characterized by a rate-dependent increase in tension reflexes (muscle length), often accompanied by exaggerated tendon reflexes due to overexcitence of stretch reflexes. (Eg CNS) motor neuron disorder. " Lance, Symposia synopsis in SPASTICITY-DISORDERED MOTOR CONTROL, Feldman et al., (Eds.) (1980). However, increased tension reflexes are just one of many symptoms found in motor dysfunction caused by upper nerve damage in various neuropathic disorders; In other words, these motor disorders show a wide variety of causes and types of onset.
    The conditions and symptoms of the major diseases associated with cramps include multiple sclerosis, cerebral palsy, seizures, trauma or injury to the spinal cord, and obstructive head trauma. To occur with convulsions, such as the Wabinsky reaction, painful flexor spasm or extensor spasm, increased or excessive deep tendon reflexes and clonus There are possible "positive symptoms". Other symptoms called "negative symptoms" include weakness, fatigue, lack of alertness and paralysis. Clinically defined as "spastic paresis" is a combination of these positive and negative signs and symptoms.
    The pathological conditions observed in convulsions range from spontaneous external seizures to certain muscles, ie, sprains, strains and acute muscular aches that occur outside or around the CNS. It is fundamentally different at the enemy level. The pathological condition of spasms is also different from the involuntary spasms of smooth muscles, which occur quite often, such as vasospasm, gallbladder spasm and bronchial spasm. These non-spastic (non-CNS) distal symptoms or symptoms that are biased at specific sites are usually treated with so-called "antispasmodic" or "spasmolytic" drugs. They are usually not useful for treating spasticity. Cedarbaum & Schleifer, "Drugs for Parkinson's Disease, Spasticity and Acute Muscle Spasms." in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed. [GOODMAN AND GILMAN'S], pages 463-484 (Pergamon Press 1990).
    The pharmaceutical compositions used in accordance with the present invention can centrally reduce muscle tension and are therefore useful for acutely or chronically relieving one or more symptoms associated with spasms. In this regard, "spasticity" refers to painful flexor spasms or extensors, increased or excessively occurring deep tendon reflexes, hyperreflectiveness, loss of agility, Refers to heightened tension in skeletal muscle, manifested by, but not limited to, muscle weakness, exaggerated tendon jerks, and clonus. "Antispasticity agent" is used herein to refer to the following symptoms of convulsions: painful flexor spasm or extensor spasm, increased or excessively Compositions useful for the symptomatic therapy of convulsions in which at least one of the resulting deep tendon reflexes, hyperacidity, loss of agility, muscle weakness, exaggerated tendon jerks and clonus is proven to be alleviated Means. Thus, “alleviation” of convulsions is herein referred to as painful flexor or extensor spasm, increased or excessively occurring deep tendon reflex, hyperplasia. By alleviating one or more of the symptoms of cramps, including but not limited to acidosis, loss of agility, muscle weakness, exaggerated tendon jerks and clonus.
    Cramps are associated with multiple sclerosis, seizures, head trauma, spinal cord injury, cerebral palsy, and other neurodegenerative diseases, and conditions. Convulsions are distinguished from acute muscle spasms, which may be associated with several different conditions than the condition causing the convulsions. This acute muscle spasm-induced condition includes trauma, inflammation, anxiety and / or pain.
    The difference between convulsions and acute muscle spasms also emerges from the fact that drugs useful for the treatment of muscle spasms are not useful for treating spasms associated with chronic neurological diseases. Cedarbaum & Schleifer (1990), published above. Similarly, agents used to treat cramps associated with chronic neuropathy have been diazepam (Valium). Except for benzodiazepines such as), it has not been used to treat acute muscle spasms. The diazepines are known to have anabolic and analgesic as well as muscle-relaxing activity. On the other hand, the present invention is characterized in that the mycelial strain is reduced through the central mass, whereby certain convulsive symptoms are then alleviated.
    Convulsive Disorders: Because of the wide availability of reasonably predictable and experimentally accessible animal models for stiffness, many clinically useful antistiff agents have been manufactured and developed. For example, Cereghino et al., "Introduction," in "ANTIEPILEPTIC DRUGS, 4th ed., Pages 1-11 (Raven Press 1995)." For many patients, sudden seizures are available using drugs currently available. Although adjustable, 25-30% of patients continue to have seizures despite optimal treatment, and many others experience unacceptable side effects. "Dichter et al., Drug Therapy 334: 1583 (1996) .
    Thus, due to the development of serious side effects including troubled daytime seation, muscle weakness, tolerance, gingival hyperplasia, hematologic abnormalities and potentially fatal liver toxicity, the clinical manifestations of many anticonvulsants The use is in trouble. Many of these side effects are particularly relevant for the clinical control of pediatric epilepsy.
    The present invention can be used to treat rigid disorders such as epilepsy. In other words, the pharmaceutical compositions of the present invention show "anticonvulsant activity" which is demonstrated to be reduced in severity, recovery or duration of stiffness in epileptic animal models. Accordingly, the compositions of the present invention may be used to treat conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures that occur following head injury or head surgery. Will be useful. However, seizures in which the composition of the present invention exhibits antistiff activity are not limited to the above examples.
    Epilepsy is a common disorder that has a variety of causes and is very difficult to control, and often requires several years of treatment to control a seizure. "At the present time, there is no therapy that satisfactorily treats epilepsy in a substantial number of patients. Clinical trials indicate that even when patients present similar types of seizures and drugs have similar mechanisms of action, some patients may The frequency and severity of adverse reactions vary greatly, that is, until epilepsy is cured or a new, powerful and safe drug is discovered and developed, with a wide range of activities. Combination regimens with mechanisms of action and side effects are inevitable. " Dichter et al. (1996), supra.
    AFFECTIVE MOOD DISORDERS: This title covers everything from depression to dysphoric mania, ie mania, schizoaffective disorders, traumatic brain injury-induced aggression. conditions such as aggression, post-traumaic stress disorder, panic states, and behavioral dyscontrol syndromes. Affective mood disorders have been mainly prevented with lithium salts since 1950 in Europe and in the 1970s in the United States. Emrich et al., J. Affective Disorders 8: 243-50 (1985). Recently, due to some problems with lithium therapy, alternative therapies have been developed to replace this therapy. New alternatives to lithium to treat affective mood disorders are therapies using antistiff agents such as carbamezepine, benzodiazepines, valpromide and valproate. Bernasconi et al., In ANTICONVULSANTS IN AFFECTIVE DISORDERS, pages 14-32 (Excerpta Medica 1984). Valproate has less tendency to lower arousal and mental action, memory impairment and cognitive ability than benzodiazepines.
    Although valproate has been shown to be effective in a number of affective disorders, there is a need for new therapeutics and therapies with improved side effects profiles due to the hepatotoxicity, mutagenicity, and gastrointestinal disorders observed with this drug. Stand out. The pharmaceutical compositions according to the invention are effective in this respect, especially in terms of improved side effects. For example, despite the structural similarities between valpromide and isovaleramide (see FIG. 1), it is expected that there will be no side effects associated with valproate. If there were side effects, the efficacy of the present invention to treat various affective mood disorders would have been impaired.
    CENTRAL NEUROPATHIC PAIN SYNDROMES: Conditions in this category include "neural pain," which affects a significant number of patients with brain or spinal cord disorders such as seizures, trauma, multiple sclerosis, and diabetes. give. Casey, in PAIN and CENTRAL NERVOUS SYSTEM DISEASE (Raven 1991). Many GABAergic compounds have shown efficacy in a variety of analgesia models associated with identifying therapeutic candidates for the treatment of neuropathic pain. Lloyd & Morselli, in PSYCHOPHARMACOLOGY: THE THIRD GENERATION OF PROGRESS (Raven Press 1987). In the same vein, the use of antistiff agents such as valproate to treat pore pain is described in a wide range of literature. Swendlow, J. Clin. Neuropharmacol. 7: 51-82 (1984). That is, the pharmaceutical composition of the present invention can be used in a similar aspect to alleviate neuropathic pain.
    HEADCHES: Migraine Headaches (Hering & Kuritzky, Cephalalgia 12: 81-84 (1992)), Complex Headaches (Hering & Kuritzky, loc. Cit. 9: 195-98 (1989)) Headaches (Mathew & Sabiha, Headache 31: 71-74 (1991)) have been treated with valproate therapy. Interaction with the GABA-like system is believed to play an important role in the cause of these headaches and related valproate therapies. For this reason, the present invention can alleviate the symptoms associated with these three types of headaches without the adverse side effects of valproate therapy.
    RESTLESSNESS SYNDROME: The term "restlessness syndrome", distinct from the mood itself, is independent of the mood itself, as well as physical (rather than mental) disturbances. Meaning that the limbs are not physically (non-mentally) for a while, characterized by involuntary movement. Sachdev et al., Austral. new Zealand J. Psychiatry 30: 38-53 (1996).
    Numerous signs, as well as signs of inactivity, can be found in connection with many organic and inorganic psychotic illnesses. For example, symptoms such as drug-induced extrapyramidal syndrome that do not stop the drug-induced time-lapse (long-term, chronic and atrophic long-term dyspepsia) )) Is one of the most common side effects found in neuroleptic medications. This time limit falls under the category of symptoms that are not associated with so-called "restless leg syndrome" and "sleep-related periodic leg movements", head and / or spinal cord trauma. There are also pathologies that may be associated with lesions of the spinal cord. Spontaneous leg tremor symptoms are common chromosomal dominant inheritance and express a variety of clinical symptoms.
    The neurochemical basis for symptoms that do not stand still is associated with decreased GABA neurotransmission. Consistent with this, benzodiazepines, baclofen, valproate and gabapentin show efficacy in the treatment of tremor symptoms. O'Keefe, Arch. Intern. Med. 156: 243-48 (1996): Danek et al., NEUROLOGICAL DISORDERS: COURSE AND TREATMENT, pages 819-23 (Academic Press 1996); Mellick & Mellick, Neurology 45 (suppl): 285-86 (1995). More generally, the present invention provides effective therapies for symptoms that have minimal side effects and do not stop for a while.
    MOVEMENT DISORDERS: Many GABA drugs are used to reduce dyskinesia, which is characterized by motor disturbances such as Parkinson's disease, Huntington's correa, late-onset dyskinesia, and stiff-man syndrome. Known. This fact highlights the role that central GABA functions play in the regulation and regulation of CNS excitability and movement. Lloyd & Morselli (1987), homology. For the same reason, the therapies of the present invention may alleviate one or more of the symptoms of exercise disorder, possibly by decreasing CNS activity via GABA-like mechanisms.
    3. Manufacturing method of pharmaceutical preparation
    Roots and roots of Valeriana spp. (Commonly known as Gilcho root; Valerianaceae family) have been used for medicinal purposes since ancient times. The most commonly used gilt root preparations include aqueous and hydroalcoholic extracts, such as tinctures for oral administration. In addition, ammonia-treated tinctures have been used in medicine since the early 17th century. Over the past 30 years, the sedative and hardening action of the herbaceous root preparations originates primarily from the chemically fragile monoterpenoid iridoid triester compounds called valepotraiates ("valerian-epoxy-triesters (-ates)"). It was.
    The most common and abundant valerian lysates, Valrate and Didrorovaltrate, each have two isovalerate moieties esterified to the "central" iridoid nucleus. . Lin et al., Pharm. Res. 8: 1094-02 (1991). However, these substances, which are weak to acids and heat, reach the stomach after oral administration and do not remain intact, and easily produce two moles of isovaleric acid per mole of valeric ate. Furthermore, the aqueous extracts of roots and roots of Giloba root retain their biological properties despite the valence hydrate triester being water-insoluble. Bos et al., Phytochem. Anal. 7: 143-51 (1996).
    The water-soluble main active ingredients of commonly used citrus root extracts, such as aqueous extracts, hydroalcoholic extracts or tinctures, and other agents, have been identified as isovaleric acid, an ester hydrolysis product. In the ammonia treated tincture, ammonium isovalerate and isovaleramide are produced. Balandrin et al., J. Toxicol. -Toxin Rev. 14: 165 (1995). The structure of isovaleramide and related compounds is shown in FIG. 1. In this way, chemically fragile valforportate and other ciliary root-derived monoterpenoid isovalerate esters such as bornyl, avaldulyl and ethyl isovalerate are obtained from isovaleric acid, its salts and isovaler It acts as a chemical precursor and "pro-drugs" of amides.
    Isovaleramide has been isolated from herbaceous root plants, most of which have since been isolated as a separation product that is subjected to ammonia treatment. Buckova et al., Ce. Farm. 26: 308 (1977); Chem. Abstr. 88: 86063z (1978); Bos et al. and Fuzzati et al., Phytochem. Anal. 7: 143, 76 (1996). More recently, it has been found that isovaleramide exhibits low acute toxicity in vivo, is not mutagenic and has clinically useful decontamination properties. U.S. Patent 5,506,268 and PCT Application WO 94 / 28,888.
    Medicinal plant extracts useful for treating convulsions and spastic symptoms can be prepared by aqueous, hydroalcoholic or alcoholic extraction, or by extraction with other suitable solvents using methods well known to those skilled in the art. In the context of the present invention, useful extracts include at least one of the following components: isovaleric acid, salts or complexes thereof, ethyl isovalerate, isovaleramide, N-ethyl isovaleramide, and chemical precursors thereof. Useful extracts also have a common property of releasing isovaleric acid and / or isovaleramide when hydrolyzed in vivo. Standard methods for preparing such extracts are U.S. PHARMACOPOEIA (U.S.P) and NATIONAL FORMULARY (N.F.) earlier than 1950 and other well-known references [Gennaro (Ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed. (Mack Publishing Co. 1990), Tyler et al., PHARMACOGNOSY, 9th ed. (Lea and Febiger 1988), Hera et al., THE NATIONAL STANDARD DISPENSATORY (Lea Brothers 1905). See also US Pat. No. 5,506,268 and PCT application WO 94 / 28,888.
    The main historical sources of isovaleric acid in nature were closely related plants belonging to the root and root of the herbaceous root and the Valerianaceae family. As discussed by Hobbs (1990, homologous), these plants include Valeriana officinalis L., East Indian vinegar V. wallichii DC, and biblical spikenard Nardstachys jatamansi (Roxb). .) DC, etc. In addition to the roots and roots of the herbaceous roots, there are other plants traditionally known as sedatives or "allergic" herbs known to contain or produce isovaleric acid. These plants are hops (Humulus lupulus L., Moraceae family often used in herbal preparations), cramp bark, or Viburnum opulus L., Caprifoliaceae) and American bark (Viburnum prunifolium L. root bark). Hare et al., THE NATIONAL STANDARD DISPENSATORY, pages 93, 94, 159, 160, 169, 256, 642, 692-694, 766, 767, 932, 1031, 1383, 1384, 1426, 1479, 1480, 1571, 1572 1619, 1620, 1631-1633, 1661, 1662 (Lea Brothers 1905); Heyl et al., J. Am. Chem. Soc. 42: 1744 (1920); Grier, Pharm. J. Pharm. 68: 302 (1929); Grier, Chem. Drug. (London) 110: 420 (1929); Grieve, A MODERN HERBAL, pages 35-40, 265-276, 381, 382, 411-415, 744-746, 781, 782 and 824-830 (Hafner 1959); Holbert, J. Am. Pharm. Assoc., Sco. Ed. 35: 315 (1946); Hoffmann, THE HERBAL HANDBOOK: A USER'S GUIDE TO MEDICAL HERBALISM, pages 38, 39, 83 and 84 (Healing Arts Press 1989).
    In the roots and roots of the herbaceous roots, hops produce isovaleric acid from more chemically complex precursors upon oxidation or enzymatic degradation. Millspaugh, AMERICAN MEDICINAL PLANTS, AN ILLUSTRATED AND DESCRIPTIVE GUIDE TO THE AMERICAN PLANTS USED AS HOMEOPATHIC REMEDIES, pages 622-626 (Dover 1974); Hare et al., THE NATIONAL STANDARD DISPENSATORY, pages 766-767 (Lea Brothers 1905); Grier, Chem. Drug. (London) 110: 420 (1929); Stevens, CHem. Rev. 67: 19 (1967); Duke, CRC HANDBOOK OF MEDICINAL HERBS, page 557 (CRC Press 1985).
    Pharmaceutically acceptable salts of organic acids, such as isovaleric acid, which have been licensed for sale by the U.S. Food and Drug Administration include sodium, potassium, lithium, zinc, aluminum, calcium or magnesium salts. REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed., Page 1445 (Mack Publishing Co. 1990). Salts of isovaleric acid commercially available in the United States include ammonium, sodium, potassium and zinc salts of isovaleric acid.
    Pharmaceutically acceptable alcohols can form esters with isovaleric acid via the corresponding isovaleric chloride and / or anhydride by methods well known in the art. For example, March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS AND STRUCTURE, fourth ed. (John Wiley and Sons 1992). These alcohols contain at least one hydroxyl moiety or phenyl moiety and exhibit good tolerance in vivo. Examples of suitable alcohols include certain carbohydrates and related compounds such as ethanol, glucose, fructose, sucrose, xylose and lactose, sugar alcohols such as dulcitol, mannitol and sorbitol, sugar acids such as gluconic acid and glucuronic acid, polyols Inositol glycerol, benzyl alcohol, phenol, salicylic acid, salginine, salicyamide, vanillin, p-hydroxycinnamman (p-coumarinic acid), caffeic acid, ferulic acid, gallic acid, elaginic acid, guercetin and Specific phenols such as eugenol are included. Examples of other suitable alcohols include bioderived amines and alkaloids such as deferdrine, pseudoephedrine, phenylpropanolamine, tyramine and dopamine, ascorbic acid (vitamin C), thiamine (vitamin B1), riboflavin (vitamin B2), pyridoxine (vitamin) B6), vitamins such as cyanocobalamin (vitamin B12), tocopherol (vitamin E), choline, folic acid, and pantothenic acid, monoterpenoid alcohols such as geraniol, nerol and linalool, alpha- And natural triterpenoid alcohols such as beta-amirin, lupeol, oleanolinic acid and ursolic acid, bile acids such as choline acid, deoxycholine acid and taurocholine acid, and beta-sitosterol, stigmasterol, Commonly occurring plant sterols (phytosterols), such as camphorsterol and brassicasterol, are included. Tyler et al., PHARMACOGNOSY, 9th ed. (Lea and Febiger 1988). Those skilled in the art can readily identify other well-tolerated hydroxyl- and phenol-containing compounds by reference (see, eg, THE MERK INDEX and REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed., (Mack Publishing Co. 1990)). Esters of isovaleric acid commercially available in the United States include bornyl esters, ethyl esters, n-butyl esters, isoamyl esters and geranyl esters of isovaleric acid.
    Among the isovaleric acid, ammonium isovalerate, and other isovalerate esters, ethyl isovalerate, isoamyl isovalerate, 2-methylbutyl isovalerate, cinnamil isovalerate, methyl isovalerate, bornyl iso Esters, such as valerate, isobornyl isovalerate and menthyl isovalerate, are described in the Code of Federal Regulation by the FDA as acceptable flavoring agents that can be used in food. 21 CFR §172.515 (1991). Root and root of Valerian officinalis L. and bark of Viburnum prunifolium L. (black haw) are listed in 21 CFR §172.510 (1991) as acceptable natural flavors and natural supplements. have. Hope and "lupulin" are listed as generally considered to be safe ("GRAS"). 21 CFR §182.20 (1991).
    In general, esters of isovaleric acid are expected to be hydrolyzed by esterase enzymes that are widely present in vivo to release isovaleric acid and the alcohol or phenol component. Particularly preferred isovalerate esters are glyceryl mono-, di- and especially tri-isovalerate ("triisovalerine"), isovaleryl salicylic acid or salicylate (salicylic acid isovalerate), ethyl isovalerate And beta-sitosteryl isovalerate. See FIG. 1. When these isovalerate esters are hydrolyzed in vivo, isovaleric acid and glycerol (glycerine), salicylic acid (anesthetic, anti-inflammatory, and antipyretic action), ethanol (ethyl alcohol or ordinary "alcohol", CNS inhibitor), respectively. Releases beta-sitosterol (harmless phytosterol). Except for ethyl isovalerate, these esters are nonvolatile or only slightly volatile, thus minimizing an unpleasant odor. In refined form, these esters also have the advantage of having a neutral to pleasant odor, whereas isovaleric acid and isovaleric acid salts such as ammonium, sodium, potassium and zinc isovalerate salts have an extremely unpleasant odor. Has In addition, ethyl isovalerate is a liquid, while glyceryl mono-, di- and tri-isovalerate, isovaleryl salicylate and beta-sitosteryl isovalerate are expected to be solid at room temperature, thus A wide variety of standard solid forms well known in the art such as tablets (e.g. uncoated tablets, enteric tablets, film-coated tablets), capsules, gelcaps, powders, thickeners (drops, drops), elixirs, tinctures and syrups And oral formulations in liquid form.
    In addition to isovaleramide, various variously substituted isovaleric acid amides can be prepared by methods well known in the art. For example, March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, AND STRUCTURE, 4 th ed. (John Wiley and sons 1992). Preferred amides include N-ethyl isovaleramide, N-methyl isovaleramide, N, N-dimethyl isovaleramide, N-methyl, N-ethyl isovaleramide, N-isovaleryl GABA, and N-isovaleryl Glycine is included. For example, Tanaka et al., J. Biol. Chem. 242: 2966 (1967). N, N-diethyl isovaleramide (“valyl”) was intended to have CNS inhibitor (sedative) activity, but has recently been reported to have CNS stimulant (hardener) properties. See US Pat. No. 5,506,268 and PCT Application WO 94 / 28,888. Amides of isovaleric acid and p-aminophenol can also be prepared by standard methods and "isovaleraminophen" is obtained. This compound is acetaminophen (Tylenol ; Structurally related). These substituted amides are also hydrolyzed in vivo in a manner similar to isovalerate esters to release isovaleramide or isovaleric acid (in this case via hepatic amidase enzymes).
    The compounds and compositions described above represent alternative forms for delivering isovaleric acid or isovaleramide in vivo. In certain cases, such as isovaleryl salicylic acid and ethyl isovalerate, it is expected that the pharmacologically active moiety corresponding to the alcohol or phenol moiety will exhibit its own pharmacological effect. Compounds such as, for example, "isovaleraminophen" may not only have the effect expected from isovaleric acid or isovaleramide sites, but also "tylenol." -Like "effects are also expected. Chemically known combinations of pharmaceutically effective alcohols, phenols or primary or secondary amines with isovaleric acid are within the scope of the present invention.
    Pharmaceutical formulations of the present invention may be prepared according to known methods for preparing pharmaceutically useful compositions, wherein the active ingredient is mixed and combined with a pharmaceutically acceptable carrier. See, for example, REGIMSTON'S PHARMACEUTICAL SCIENCES and GOODMAN AND GILLMAN'S published above. The composition is said to be in a “pharmaceutically acceptable carrier” if it can be tolerated by the patient receiving it. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier. Other suitable carriers (eg saline and Ringer's solution) are well known to those skilled in the art. See, eg, REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
    In general, the doses of anticonvulsants and antispasmodics described herein will vary depending on factors such as the age, weight, height, sex, general medical condition and prior medical history of the patient. When for the purpose of treatment, a compound of the invention and a pharmaceutically acceptable carrier are administered in a therapeutically effective amount to a subject in need of such treatment. If the amount administered is physiologically significant, the combination of active agent and carrier is said to be administered in a “therapeutically effective amount”. If the pathology of a patient receiving the drug is changed to a detectable level due to the presence of the active agent, the drug is said to be physiologically significant. For example, in the context of the present invention, if the spasm is relieved by the presence of an antispasticity agent, the drug is physiologically significant, while the anticonvulsant agent is stiff by the presence of the drug. The drug is physiologically significant if the result is a reduction in severity, recall or duration.
    Isovaleramide and related compounds can be administered orally using solid oral dosage forms such as enteric tablets, caplets, gelcaps or capsules, or liquid oral dosage forms such as syrups or elixirs. The dose of isovaleramide and related compounds as an anticonvulsant is in the range of 100-1000 mg per dose, preferably 300-600 mg per dose. Unit dosage forms in solid oral dosage forms contain about 200-350 mg per tablet or capsule, which is typically administered 1-2 times a day, up to 4 times, in an amount of 1-20 mg per kg of body weight. . Liquid formulations may also have an active ingredient composition to administer an amount of 1-2 teaspoons per dose. In addition, a pediatric chewing agent and a liquid oral dosage form may be administered. These compounds may also be added in the form of drops to food or beverages (using a dropper from a "concentrated" formulation) for oral administration. Furthermore, compounds such as isovaleramide can be formulated with chewing gum to enable oral delivery and absorption.
    Alternatively, isovaleramide and related compounds can be administered by infusion or through other systemic routes such as transdermal or mucosal routes of administration, such as rectal routes of administration using nasal, cheek or suppositories. But oral administration is much simpler and therefore advantageous.
    For use in oral dosage forms, the dosage level of the active ingredient is 100-1000 mg, preferably 200-600 mg, or 1-20 mg / kg body weight per active unit.
    In addition to use in humans, isovaleramide and related compounds can be used in animals, such as cats, dogs, birds, horses, cattle, mink, poultry and fish, for example as anticonvulsants or anticonvulsants. In such cases, the active compounds may be administered by systemic route or infusion, such as by transdermal or mucosal route of administration (eg rectal administration with suppositories), or may be administered orally in addition to food or beverages. When used as an anticonvulsant, the dosage for isovaleramide and / or related compounds is about 1-1000 mg / kg body weight of the animal, depending on the type and route of administration. Preferred oral dosages are about 200-600 mg per kg body weight.
    When used as an antistiff agent, the dosage for isovaleramide and / or related compounds is about 1-1000 mg / kg per kg body weight of the animal, depending on the type and route of administration of the animal. Preferred oral dosages are about 100-600 mg / kg body weight.
    Thus, the present invention provides isovaleramide, isovaleric acid, and / or pharmaceutically acceptable salts, substituted amides, and alcohol esters thereof as active ingredients suitable for oral, parenteral, transdermal, mucosal, nasal, buccal or rectal administration. It includes various pharmaceutical compositions containing. While such compounds may exist as by-products of certain pharmaceutical formulations beyond the scope of the present invention, features of the present invention are isovaleramide, isovaleric acid, and / or pharmaceutically acceptable salts, substituted amides thereof. , And alcohol esters are present in standardized amounts. In other words, the pharmaceutical formulation includes at least one of these compounds in any chemically defined quantitative amount that allows to determine the amount of the particular composition required to achieve the dosages described herein.
    It is further understood that isovaleramide and / or related compounds may be used in combination with other pharmaceutically active ingredients.
    4. Demonstration of treatment-related activity
    The suitability and efficacy of pharmaceutical formulations for alleviating the pathologies described above can be demonstrated using animal models such as, but not limited to, those described below.
    (a) Mutant Spastic Mouse
    Spastic mutant mice are homozygous mice with autosomal recessive traits of genetic spasms. These mice are normal at birth and begin to show coarse tremor, abnormal gait, skeletal muscle rigidity and abnormal right reflexes from 2-3 weeks of age. No structural abnormalities are found. Rather, these mice lack glycine receptors throughout the central nervous system. Drugs that enhance the binding or synthesis of GABA, such as valproate and benzodiazepines, have the effect of alleviating some of the symptoms of cramping in humans as well as in this rat model.
    Evaluation of convulsions in convulsive mutant mice can be performed by an electrophysiological evaluation similar to the EMG record described below. If it is measured on a less delicate scale, righting can also be evaluated. These mice show abnormal and delayed stereotactic reflection when they are laid straight on the floor. All stereotactic reflections greater than 1 second are considered abnormal. Most normal mice do not even lay straight. Tremor grabs the tail of the mouse and can assess progress with a rating of "None", "Minor", "Medium" or "Severe". Softness can be assessed by placing the mouse on a glass object with flat, round grooves and edges. Lift the glass about 12 inches above the table and tilt it slowly until it is almost vertical. Normal mice try to climb on glass for one minute or longer before their legs fall. Spastic mice usually remain stiff in one position and soon fall back to the floor. Chai et al., Proc. Soc. Exptl. Biol. Med. 109: 491 (1962).
    (b) The Acute / Chronic Spinally Transected Rat And The Acute Decerebrate Rat
    There are several models of convulsions, including acute cerebral deceased mice, acute or chronic spinal cord truncated mice, and mice with chronic spinal cord-lesion lesions. Acute models have proven useful for elucidating the mechanisms involved in the development of seizures, but have been criticized for their acuteness. Experimental animals usually die or fully recover from cramps. Unlike convulsions, which usually occur in the state of spasticity in humans, most of which are initially manifested as relaxation paralysis, convulsions in animal models develop convulsions as soon as the cause is given. In humans, convulsions develop weeks and months later. Some models of convulsions with longer-term lesions or amputations of the spinal cord may show postoperative relaxation paralysis. Approximately four weeks after the lesion / transection, the laxity changes to seizures of different severity. Although all of these models have their own shortcomings and do not express the state of human convulsions, they still provide a great deal of information about the nature of convulsions. These models have also provided a way to test multiple treatment paradigms that can lead to similar treatments to be tested in humans. Many of these models are made using different species such as cats, dogs, and primates. In these models baclofen, diazepam and tizanidine are effective for several seizure parameters (EMG recording, H-reflection, H / M ratio, mono- and polysynaptic reflex, hepatic convulsion, hyperreflection).
    (c) Primary Observation Irwin Test In The Rat
    This method is based on the method described by Irwin (Psychopharmacologia 13: 222-57 (1968)). This test detects the physiological, behavioral and toxic effects of the test substance and dictates the range of dosage that can be used for subsequent experiments. Typically, three rats per group are administered compared to the control group administered the test substance and administered with excipients. Changes in behavior, symptoms of neurotoxicity, pupil diameter, and rectal temperature are recorded according to a standardized observation grid induced by Irwin. This grid is designed for lethality, soothing, excitement, aggression, straub tail, twisting, stiffness, tremor, exophthalmos, excessive saliva, tearing, napping, bowel movements, fear, contraction, and contact. Responsiveness, loss of stereotactic reflexes, sleep, ataxia, muscle tone, stereotypies, head shaking, catalepsy, grasping, ptosis, respiration, Corneal reflection, anesthesia, abnormal gait, forepaw treading of the forefoot, loss of balance, head distortion, rectal temperature, and pupil diameter. Observations are made 15, 30, 60, 120, and 180 minutes and 24 hours after administration of the test substance. Test substances are usually administered via the intraperitoneal (i.p.) route.
    (d) Rotarod Test In The Rat and Mouse
    This test is to test for neurological deficiency using the method described by Dunham et al., J. Am. Pharm. Assoc. 46: 208-09 (1957). Place the rat or mouse on a spinning rod at 8 revolutions per minute. Count the animals falling off the rods within three minutes and record the time of fall (up to 180 seconds). Ten rats per group are tested and this test is blindfolded. The test compound is administered intraperitoneally 60 minutes before the test. Diazepam, a type of benzodiazepine, is administered intraperitoneally in an amount of 8 mg / kg as a reference. The control group receiving the excipient also participates in the trial.
    (e) Antiticvulsant Activity
    There are a number of in vivo animal models of epilepsy, including clinically distinct behavioral effects and several types of seizures. Therefore, it is prudent to test the effects on different models, since the same mechanisms may be involved in all types of seizure activity and extrapolate.
    One useful model is provided by the Frings audiogenic seizure-susceptible mouse model, which is a model of reflex epilepsy. For testing, each mouse is placed in a rounded plexiglass chamber and subjected to sound decibels of 110 decibels and 11 kHz for 20 seconds. Animals that do not exhibit tonal hindlimb kidneys are considered protected. In addition, the seizure score for each mouse was (1) running for less than 10 seconds, (2) running for more than 10 seconds, (3) long-term activity of the limbs and / or vibrissae, (4) forefoot kidney / back paw flexion ; And (5) hind foot extension.
    Average seizure scores can be calculated for each group of mice used in the dose-response study. For each dose, mice can be tested on a spinning rod to test motor impairment (toxicity). The damage test on a rotating rod can be carried out by placing a mouse on a rod 1 inch in diameter for 6 minutes, with a test time of 3 minutes. If the mouse falls off the spinning rod within 3 minutes, it is considered a toxic response.
    (f) Anti-manic Activity
    To assess the possibility of using the compound in treating emotional mood disorders, an amphetamine-induced overactivity model (rat) can be used. In addition to testing traditional and atypical antipsychotic activity, this model has been proposed as a simple animal model for testing manic behavior. Costall et al., Brain Res. 123: 89-111 (1977).
    (g) Neurogenic Inflammations Of The Meninges
    Neurological inflammation of the meninges has been suggested as an event in the pathology underlying migraine headaches. Lee et al., Brit. J. Pharmacol. 116: 1661-67 (1995). For each test compound, the ability to prevent leakage of radiolabeled bovine serum albumin in the epidural after trigeminal nerve stimulation was tested.
    (h) Analgesic Properties
    Many pre-animals for assessing anesthesia characteristics, such as Bennett or Chung models of warping, hotplates, tail flicks, joint pain, foot pressure tests, and neuropathic pain ( whole animal) method. Albe-Fessard et al., 13 ADVANCES IN PAIN RESEARCH AND THERAPY, pages 11-27 (Raven Press 1990).
    (i) Therapeutic Benefit Relative To Movement Disorders and Restlessness Syndormes
    For example, animal models exist for dyskinesia and dysfunction, such as drug-induced ataxia, serotonin symptoms, rotation induced by unilateral black matter lesions. Lloyd & Morselli (1987), published above. In addition, reports of individual cases of anecdotal efficacy of compounds in humans have also supported this suggestion. Mellick & Mellick (1995), published above; Olson et al., Am. J. Med. 102: 60-66 (1997).
    The therapeutic effects of isovaleramide, isovaleric acid and related compounds shown in the various assays described above are generally not toxic, so that the compounds of the present invention, as described above, include convulsions and stiffness / seizure. Make it an ideal medicine to treat them. With this background, the present invention will be more readily understood through the following examples, which are presented for purposes of illustration and do not limit the scope of the invention.
    Example 1
    Use of myelin herb preparations to relieve spasms associated with multiple sclerosis
    A 42-year-old female patient with one or more symptoms of multiple sclerosis was under significant stress, had difficulty falling asleep and used to fall asleep late at night. Once I was asleep, I was disturbed by sleep because of my stressful dreams and used to wake up often. The patient also frequently experienced painful extensor contractions in the lower extremities at night, which often caused her to wake up. The next day, this painful extensor contraction used to cause muscle / joint stiffness and severe muscle pain (a bruise).
    This patient decided to take a herbicide formulation that was recognized to have sleep-assisted properties. The gilcho root formulation "Baldriparan stark N" consists of tablets made in Germany, which includes gilcho root, hops and lemon balm extract. The coated and compressed tablets consisted of 70% (v / v) ethanol extract 95 mg (dry weight) of ginko root root, 15% (m / m) methanol extract of hops and water extract of lemon balm 85 mg (dry weight). Surprisingly, the herbicide formulation was recognized to not only enable the onset of sleep and improve sleep quality, but also alleviated painful extensor contraction. The patient did not experience painful extensor contractions when waking up to go to the toilet at night, even when he got up in bed, and the usual legs did not even feel stiff. The patient continued to take these preparations to relieve these symptoms as needed (prn or pro re nata) and continued to experience the symptoms.
    Example 2
    Use of biliary tract preparations to relieve spinal cord injury and associated spasms
    A 38-year-old male patient suffered from convulsions (hyperreflective, tendon reflex and extensor contraction) caused by a previous spinal cord injury. All of these symptoms lowered and disturbed the sleep quality of the patient. Ingesting the same German formulation as described in Example 1, the patient experienced not only a marked improvement in sleep quality but also a significant decrease in nocturnal contraction at night. This patient continued to take the formulation as needed (prn) to alleviate the symptoms as described above.
    Example 3
    Isovaleramide Antispasmodic Test
    (1) Evaluation of spasms in long-term spinal cords
    In this study, male S. albino Holzmann-induced rats (Harlan Sprague-Dawley Laboratories) weighing 270-530 g were used as test subjects. Each of these animals was placed in a cage and fed with food and water continuously throughout the experiment. All procedures were under the supervision and approval of the Institutional Animal Care and Use Committee. Animals were anesthetized by injecting a mixture of isoflurane and oxygen at a flow rate of 4 liters / minute. The rats were then placed in stereostereoscopic frames to maintain anesthesia. A laminectomy was performed between T6-T9 to remove the muscles around the spinal cord. The spinal cord of 1 to 2 millimeters size was removed by aspiration and instead gel foam was used to reduce bleeding and layered sections were layered.
    After cutting, the rats were placed in one room to maintain the body temperature by raising the room temperature to about 80 ° F using a heater. The next day after the procedure, the hind limbs of the spinal cord-cut mice were bathed and urinated in the bladder to urinate. The experiment was conducted between 21 and 28 days after the procedure. During the first two weeks, to prevent bladder inflammation, rats were orally administered 0.25 ml of Sulfatrim Pediatric Suspension, an antibiotic. Anti-bacterial creams were applied to skin areas with signs of pressure sores. Within approximately two weeks, all animals restored bladder control and no longer needed antibiotics. Advokat, Brain Res. 684: 8 (1995). Cramps were evaluated before and after drug treatment so that each animal could be its own control.
    Initial evaluation of convulsions was performed by an objective scoring method that assessed harmless stimuli, namely the convulsive response induced by pressing a specific four (4) site of the lower abdomen with a metal probe. Four experiments were performed and scores ranged from 0 (if there was no convulsive response in all four experiments) to 4 (if the best tonic-clonic reaction occurred in all four experiments). The spastic response was evaluated for each experiment by grading method. All convulsion scores were converted to percent spasticity such that 0/4 = 0%, 1/4 = 25%, and the like before and after treatment. The original and normalized scores thus obtained were analyzed by one-way repeated measures ANOVA.
    As shown in Figure 2, isovaleramide is effective at reducing spasticity scores (45-65%) at 15, 30, 60 and 120 minutes post-dose, intraperitoneally, at a dose of 300 mg / kg. It was. The next day, 1440 minutes (24 hours), the convulsion scores were essentially restored to their original baseline. No excessive behavioral toxicity or motor impairment was observed at this dose. Mice could grab using the unparalyzed paws as well as the untreated rats (control group) and were mentally intact.
    Referring to FIG. 3, in order to test the stimulus that activates high-threshold afferents, the multiple synebs flexor-reflective response was recorded as EMG activity from the ipsilateral hamstring muscle. . A biphasic electric stroke was applied to the biceps, and a recording electrode was installed on the biceps femoris semitendinosus muscle. Five sets of stimuli were given at each time point. Over both predrug and postdose periods, flexor reflexes were recorded every 30 minutes once a stable baseline reaction was achieved. Hao et al., Eur. J., Pharmocol. 191: 407 (1990).
    That is, before treatment and isovaleramide (300, 600 and 1200 mg / kg, oral), baclofen (10 mg / kg, subcutaneous) and excipients (water, 12 ml / kg, oral) After 30, 60, 90 and 120 minutes, the response in the spinal corded rats was measured by observing the flexor-reflective response (FIG. 3), respectively.
    Isovaleramide reduced the magnitude of the flexor-reflective response at all doses and at all time points performed in constricted, long-term spinal corded mice. In this model neither baclofen nor isovaleramide caused changes in H / M reflection.
    In FIG. 4, the reaction shown in FIG. 3 was converted to the form of total-area-under-the-curve over the two hours of measurement time. Based on a one-way analysis of the variance, all drug-treated groups differed significantly from the groups that prescribed the excipient (p <0.05). There was no difference in the total reduction in flexor reflexes over the two hour period between groups prescribed the drug (compound comparison of mating, Student-Newman-Cowls method).
    (2) First observation Irwin test in rat
    Isovaleramide administered intraperitoneally to rats showed no difference compared to the control group injected with saline, at a dose of up to 256 mg / kg. At 512 mg / kg, mild sedation was observed between 60-120 minutes, loss of contraction (only observed in one of three rats) at 120 minutes, and muscle tension decreased between 60-120 minutes. . At 1024 mg / kg, noticeable sedation was observed up to 30 minutes, gradually becoming normal by 120 minutes and becoming mild at 180 minutes. At this dose, fear reduction was observed up to 30 minutes, and one of the three animals showed reduced fear up to 120 minutes. Reduced contact reactivity up to 120 minutes, reduced muscle tone up to 180 minutes, mild hypothermia up to 120 minutes, and abnormal gait (rolling) between 60-80 minutes were observed at this dose. At this dose, at 15 minutes, one of the three mice showed a loss of grasping and loss of stereotactic reflection.
    (3) Spinning rod test in rats and Frings Mouse
    Isovaleramide administered in amounts of 128, 256 and 512 mg / kg (intraperitoneal) 60 minutes prior to testing on the spinning rod had no significant effect on rat spinning performance. See Table 1. Diazepam, on the other hand, dose-dependently reduced spin rod performance.
    Effect of Isovaleramide and Diazepam on Rat Spinning Test Dosage of isovaleramide (mg / kg) a Number b of fallen miceFall time (seconds) Mean ± S.E.M.t value% Change compared to control 05135.5 ± 18.0-- 1286134.5 ± 20.7 c 0.036-One% 256798.4 ± 23.3 c 1.261-27% 5127115.9 ± 20.5 c 0.717-14% Diazepam (mg / kg) a4955.8 ± 20.6 d 2.909-59% 810+ c 16.3 ± 6.4 f 6.222-88% a. Isovaleramide and diazepam were administered intraperitoneally 60 minutes prior to the spin rod test.b 10 mice per group.c Test not significant according to Student's test.p <0.01e Fisher's eject test (Fisher's) P <0.05f according to the Exact Test) p <0.001
    Isovaleramide did not have a significant effect on spin rod performance when administered to Frings mice at an amount of up to 150 mg / kg (intraperitoneal) 15 minutes before the spin rod test. On the other hand, the doses of 300 mg / kg, 600 mg / kg and 1000 mg / kg (intraperitoneal) decreased the rotator rod performance in 1, 4 and 8 of 8 Frings mice, respectively.
    Example 4
    Antistiffness Activity in the Epilepsy Model of Frings Auditory Seizure-sensitive Mice
    The results in Table 2 demonstrate that isovaleramide exhibits antistiff activity in this epileptic animal model. Isovaleramide also has a rapid onset of action and relatively short duration. Antistiffness activity begins to appear as fast as 15 minutes, but decreases substantially in 2 hours. All quantitative studies were therefore conducted at the 15 minute time point. At this point, the median effective dose (ED 50 ) indicating protection from tonic dilation was 126 mg / kg upon intraperitoneal administration. It was also observed at this point that the seizure scores were dose-dependently reduced. At doses significantly higher than those that provide antistiffness activity (> 300 mg / kg), animals prescribed isovaleramide exhibited zoological toxicity characterized by inability to balance on the spinning rod. No appreciable toxicity was observed at doses below 300 mg / kg. The median toxic dose (TD 50 ) for spinning rod injury was 531 mg / kg upon intraperitoneal administration. In other words, the calculated protection index (TD 50 / ED 50 ) was about 4.2.
    Thus, although isovaleramide shows a relatively low titer in this model, isovaleramide shows a relatively good separation between activity and toxicity. Thus isovaleramide is surprising and remarkable for reflex epilepsy in a model of Frings audiogenic seizure-susceptible mouse, based on the structure-activity relationship present in the amide and the corresponding acid. It also has an efficacy as an anticonvulsant that was not predicted.
    The activity profile of isovaleramide is similar to that of sodium valproate, an antistiff agent with a broad spectrum. Isovaleric acid as well as compounds structurally similar to valproate have been reported in the literature to increase GABA concentrations throughout the CNS. Although other mechanisms have been suggested, it is primarily the function mentioned above that contributes to the antistiff activity of valproate. Isovaleric acid, on the other hand, has been reported to be inactive as an anticonvulsant, although it has been reported to slightly increase GABA levels in the brain of mice. See, eg, Locher et al., Neuropharmacology 24: 427 (1985); Keane et al., Loc. cit. 22: 875 (1983); Keane et al., Pharmacol. Res. Commun. 17: 547 (1985).
    Effect of Isovaleramide on Auditory Seizure Susceptibility in Frings Mice after Intraperitoneal Administration Dosage of isovaleramide (mg / kg, intraperitoneal)Seizure score ± S.E.M.Number of protected mice among the eight mice provided for the test a Number a of the toxic mice out of the eight mice provided for the test 754.4 ± 0.6One0 112.54.0 ± 0.620 1502.0 ± 0.660 3001.0 ± 08One 600- 4 1000- 8 ED 50 with protection: 126 mg / kg (98.8-168 b ) TD 50 : 531 mg / kg (372-711 b ) a measured at 15 minutes b 95% confidence interval
    In general, historical papers on the structure-activity relationship of antistiffness activity around compounds similar to valproate have no teaching on simple, unsubstituted compounds such as isovaleramide. Thus, it is surprisingly and unexpectedly predicted that isovaleramide exhibits a similar efficacy profile to valproate in the Frings auditory seizure-sensitive mouse model and similar activity separation between efficacy and toxicity as measured by spin rod performance. The result was not. These observations suggest that isovaleramide is an effective treatment as an antistiff agent with a broad spectrum. Isovaleramide is known to be relatively nontoxic in the mutagenicity and cytotoxicity tests. U.S. Patent 5,506,268 and PCT Application WO 94 / 28,888. Valproate, on the other hand, has long been known to have a hepatotoxic-induced profile. See, eg, Locher et al., Neuropharmacology 24: 427 (1985).
    While specific reference has been made to certain preferred embodiments, it should be understood that the invention is not limited to these examples. Those skilled in the art can make various modifications to the implementations disclosed above, and such changes are intended to encompass the present invention as defined in the following claims.
    All publications and patent applications mentioned in the specification are indicative of the technical level of the technical field to which the present invention belongs. All publications and patent applications are incorporated herein by reference in their entirety to the same extent that each is specifically and individually described.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] A compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid and a pharmaceutically acceptable amide of isovaleric acid, weakly inhibits CNS activity. Use to prepare a pharmaceutical formulation for use in a method of treating a condition that relieves mild depression and alleviating at least one symptom of the pathology.
    [2" claim-type="Currently amended] The pathology of claim 1, wherein the pathology is affective mood disorder, convulsions, central neuropathic pain syndrome, headache, and restlessness. syndrome).
    [3" claim-type="Currently amended] 3. Use according to claim 2, characterized in that the pathology is rigid.
    [4" claim-type="Currently amended] Use according to claim 1, characterized in that the pathology is ameliorated by centrally decreasing the muscle tension through the center.
    [5" claim-type="Currently amended] 5. Use according to claim 4, characterized in that the pathology is spasticity.
    [6" claim-type="Currently amended] Use according to claim 1, characterized in that the compound is isovaleramide.
    [7" claim-type="Currently amended] Extracts of the Valerianaceae, the cramp bark of the Viburnum opulus, the black haw bark or the hop of the Viburnum prunifolium tree are used to treat convulsive symptoms. Use in the manufacture of a pharmaceutical formulation for use, wherein said extract comprises at least one compound hydrolyzed in vivo to produce isovaleric acid or isovaleramide.
    [8" claim-type="Currently amended] Alleviating at least one symptom of the pathology to a patient having a pathology that is alleviated by weakly inhibiting CNS activity by administering a therapeutically effective amount of a pharmaceutical formulation containing a pharmaceutically acceptable carrier and the components described below A method of treatment comprising: the ingredient is in the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, and a pharmaceutically acceptable amide of isovaleric acid The treatment method selected.
    [9" claim-type="Currently amended] As a method of alleviating the convulsive symptoms of patients in need of alleviation of convulsive symptoms, the bark of the Valerianaceae, the bark of Viburnum opulus and the black haw of the Viburnum prunifolium tree administering a therapeutically effective amount of an extract of bark or hop, said extract comprising at least one compound that is hydrolyzed in vivo to produce isovaleric acid or isovaleramide. How to feature.
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    同族专利:
    公开号 | 公开日
    BR9713188A|1999-11-03|
    KR100594400B1|2006-07-03|
    PT938304E|2005-04-29|
    AT284683T|2005-01-15|
    HK1023725A1|2005-03-24|
    RU2232016C2|2004-07-10|
    CN1152677C|2004-06-09|
    IL128724D0|2000-01-31|
    IL128724A|2003-05-29|
    EP0938304B1|2004-12-15|
    CN1235541A|1999-11-17|
    JP2000504035A|2000-04-04|
    EP0938304A1|1999-09-01|
    AU728765B2|2001-01-18|
    CN1531924A|2004-09-29|
    AU4330297A|1998-03-19|
    DK0938304T3|2005-03-14|
    ES2235251T3|2005-07-01|
    WO1998008498A1|1998-03-05|
    DE69731968D1|2005-01-20|
    DE69731968T2|2005-12-22|
    CA2264577A1|1998-03-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-08-30|Priority to US2505096P
    1996-08-30|Priority to US60/025,050
    1996-08-30|Priority to US60/25,050
    1997-08-29|Application filed by 젠센, 제임스 유, 엔피에스 파마슈티칼즈, 인코포레이티드
    2000-07-05|Publication of KR20000038194A
    2006-07-03|Application granted
    2006-07-03|Publication of KR100594400B1
    优先权:
    申请号 | 申请日 | 专利标题
    US2505096P| true| 1996-08-30|1996-08-30|
    US60/025,050|1996-08-30|
    US60/25,050|1996-08-30|
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