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    • 专利摘要:
    use of cannabidiol in the preparation of a medicament to treat a partial seizure and composition comprising cannabidiol the present invention relates to the use of one or more cannabinoids in the treatment of epilepsy and more particularly to the use of one or a combination of cannabinoids in the treatment of seizures generalized or partial. in one embodiment, it refers to the use of cannabinoid thcv, as a pure or isolated compound, or as a plant extract in which significant amounts of any naturally occurring thc have been selectively removed. in another modality the phytocarbinoid is cdb.
    公开号:BR112012000076A2
    申请号:R112012000076-4
    申请日:2010-06-29
    公开日:2020-06-02
    发明作者:Whalley Ben；Stephens Gary；Williams Claire；Guy Geoffrey；Wright Stephen；Kikuchi Tetsuro
    申请人:Gw Pharma Limited；Otsuka Pharmaceutical Co Limited；
    IPC主号:
    专利说明:

    USE OF CANABIDIOL IN THE PREPARATION OF A MEDICINE TO TREAT A PARTIAL CRISIS AND COMPOSITION UNDERSTANDING CANABIDIOL
    This invention relates to the use of one or a combination of phyto-cannabinoids in the treatment of epilepsy and more particularly to the use of tetrahydrocannabivarin (THCV) in the treatment of generalized crises and / or cannabidiol (CBD) in generalized crisis and / or partial crises (unlike temporal lobe crises).
    BACKGROUND
    Epilepsy is a chronic neurological disorder that presents a wide spectrum of diseases that affects approximately 50 million people worldwide (Sander, 2003). Advances in understanding the body's internal endocannabinoid system have led to the suggestion that some cannabis-based drugs may have the potential to treat hyperexcitability disorder.
    central nervous system (Mackie, 2006, Wingerchuk, 2004, Alger, 2006). Cannabis has been assigned so much with pro-effects convulsive (Brust et al., 1992) and anti-convulsants.
    Therefore, it remains to be determined whether cannabinoids represent a therapeutic anticonvulsant yet to be unmasked or, conversely, a potential risk factor for recreational and medicinal users of cannabis (Ferdinand et al., 2005).
    In 1975 Consroe et al. described the case of the young man whose standard treatment (phenobarbital and phenytoin) did not control his seizures. When he started smoking cannabis socially he had no seizures. However, when he used only cannabis the crises came back. They concluded that ««: macWha may have an anti-convulsive effect on human epilepsy »,
    A study by Ng (1990) involved a larger population - of 3Q§ epileptic patients who had been admitted to the hospital after their first crisis. They were compared to a control population of 294 patients who had not had seizures, and it was found that the use of eânabis appeared to reduce the likelihood of having a seizure, however, this study · was criticized in a report by the 10 Institute of Medicine (1599) that claimed it was "weak", a fact that * the study did not include measures of health status prior to hospital admissions and - differences in your health status may have influenced your drug use "rather than the other way around.
    I mentioned. WO'02 / OO.IO'S makes reference to the antiseptic effects of oanabí.nôide cannabldiol (CTB ·},
    WO 2004/054., 057 refers to the potential use of THCV-parent * for the treatment of epilepsy among a range of diseases.
    © W02009 / 007597 reveals formulations containing THCV and
    CBD.
    Three controlled clinical trials investigated the antlepileptic potential of uanabidial ♦ In each of them, caxiábidiol was given in a timely manner.1 to patients with 25 major mal-generalized c-u focal crises.
    Cunha- et al (19W) reported a study in IS patients with large type of epilepsy. who were not responding well to conventional medication. They were given their regular medication or either 20G-33mg of cannabidiol or a placebo. Of the 35 patients who received Ctó, 3 showed complete improvement, 2 parsial, 2 minor; while Wed 1 remained unchanged. The only compensated effect was moderate subjectivity. Of the patients who received the placebo, 1 improved and 7 remained unchanged.
    Ames (1388) reported a much less successful study in which 12 epileptic patients were administered 200300mg of canahidiol per day, in addition to standard antlepileptic drugs, there appeared to be no significant improvement. in the frequency of crises.
    Trembly et al (1WQ) reports an open clinical trial with: a single patient who received cannabidiol OOO-1100mg per day for 10 months. This trial showed that the frequency of seizures was markedly reduced in the patient.
    It is still meaningful that about 22 years after these trials there was no further development. This could be low due to a number of factors, including a »general prejudice against cannabis-based drugs * It is also possible that the doses used in the trials were not ideal and the applicant determined that cannabinoids can produce bell-shaped dose response curves.
    In addition to disclosures suggesting that CBD may be beneficial. There is a report (Davis and Ramsey) of tetrahydrocani.bino.1 (THC) being administered to 5 institutionalized children 25 who did not respond to standard treatment (phenobarbital and phenenoin). get rid of crises completely, one became almost totally crisis free, and the other three got worse than before.
    However, there are more than 40 recognizable types of 30 epileptic syndromes, partly due to the susceptibility of arise varying from patient to patient (MaÇçrmiek ç
    Contreras, 2001, Lutç, 2004) it was a challenge to find drugs to shoot against these different types.
    A. neuronal activity is a prerequisite for function
    It is appropriate for the brain- .. However, the perception of the excitatory-inhibitory balance of neuronal activity can induce epileptic seizures.- These seizures can be grouped into two basic categories: partial and general seizures. <. Partial seizures 10 originate in specific regions of the brain and remain localized - most commonly in the temporal lobes (containing the hippocampus) -, while general seizures - appear in the entire frontal part of the brain with a secondary generalization of one. partial crisis. (McCormic-A and Contreras, 15 2801., Lut-z, 2004). This concept of classification of partial and generalized crises did not become common practice until the international League Against Epilepsy published a scheme, of classification 'of epileptic seizures in 1955 (Merlis, 1970, 30 .Gastaut., 197Ü., Dreifuss et al <., 1981).
    A. International League against ipilepsi a-still classified partial crises, separating them into simple and complex, depending on the presence or the compromise of a state of consciousness (Dreifuss ei al., 1981).
    2S The league also categorized general seizures into various types of clinical seizures, some examples of which are described below:
    Absence crises occur frequently, - having a sudden start and an interruption of ongoing activities. M ‘In addition, the speech is delayed or prevented by crises that last only a few seconds (Greifuss st aX., 1.8.81}.
    The tonic-sciences are many fields known as t! great evil '' f are the most often. found from the generalized © rises (Dreifuss et al «, 1881) * This type 5 of generalized © rise has two phases; When muscle tunics are replaced by a clanic phase of convulsive movements, the patient remains unconscious during the rise and for one. variable top period afterwards.
    Atonic laughs; known as ** gout attacks% are the result of sudden loss of muscle tone for a specific muscle, muscle group or all body muscles (.Drei fuss et al,,: 11/81) ,.
    The onset of epileptic seizures can be fatal with patients also experiencing long-term health implications (Lutz, 2004} .. These implications can take many forms.
    mental health problems (for example, prevention of normal development of childhood glutamatergic synapse);
    cognitive deficits (eg, diminishing the ability of neuronal circuits in the hippocampus to learn and store memories)
    morphological changes (eg, selective loss of neurons in the CAI and CA.3 regions of the hippocampus in 25 patients who present mesial temporal lobe epilepsy as a result of. © xcitotoxicity) (Swann ,, 2004, Avoli et al ,, 2005í
    It is important to note that epilepsy also greatly affects the patient's life - potentially living with 10 fear of consequential damage (for example, head trauma)., Re suit before a major crisis on the inability to perform daily tasks or the inability driving .one car less and having a prolonged crisis-free period (Fisher et al>, 200 ΘΚ
    Three well-established and widely used in vdv models »of acute crisis, which mimic neuronal activity and consequent physical symptoms that manifest in a crisis suffered by someone with epilepsy, are;
    pentylenetetrazole-induced model of generalized seizures (übay et si., 2G07, Bauca et al M 2004);
    Pilocarpine-induced model of temporal lobe seizures, ie hippocampus) (Pereira et al, 2007) and penicillin-induced models of partial seizures (Bostanci and Bagiríci, 2, <W «j.
    These provide a range of models of seizures and epilepsy, assistance. therapeutic research in humansi
    It is an object of the present invention to identify fitO'-cannabindides or tape-cannabinoid combinations that they have. use in the treatment of specific forms of crisis in addition to epi1epsia,
    It is another object of the present invention the decaying of the dosage ranges, which are susceptible to efficacy and identification of: combinations of cannabindides (due to the presence of passivity in different chiTsiatypes or varieties of eânabis) which are more likely to benefit due to di .ferences in their mechanisms of action.
    BREVB SWÃBX0 DA PIWIíÕAÇKO
    According. a first aspect of the present invention there is provided one or one. plurality of fútúanabinõidss selscionadus from the group and »tetrabidrocanabívarina (THCVJ is cannabidiol (CDB) for the. use in the treatment of generalized crises and. / or partial crisis <
    Preferably the medicine is for the treatment of seizures çlêMaasí is / or tonic ..
    The preferred daily dose of THCV is from less than 1.5 mg, preferably less than 5 mg to 10 mg to 15 mg more.
    Preferably, THCV is used in combination with
    1.0 at least one second cannabindide, therapeutically effective, preferably C £ ®.
    g CBD is preferably present in an amount that is proportional to a daily dose of at least 400 mg, more preferably. at least € 'GG mg and as much as SOOmg 15 or more, but preferably less than 1200 mg,
    Cannabinoids can be present as pure or isolated cannabinoids or in the form of plant extracts. Whenever a plant extract is used, it is preferable that the TKC content is less than Si by weight of the 20 total cannabinoids, more preferably less than 41 to Ü, 3% and liu 0 THC can be selectively removed from extracts using techniques such as crematography.
    The invention also extends to the use of a canePinoids phyto25 in the manufacture of a medicine for the treatment of a specific form of epilepsy.
    In accordance with a second aspect of the present invention, there is provided a composition for use in the treatment of general seizures to / or partial seizures comprising THCV and or CDB.
    The deposition preferably powdered the form of a plant extract containing one. it was more phytocannabindideá: e. one or more excipients.
    In accordance with a third aspect of the present invention, THcv and / or CDB are proposed for use in the manufacture of a medicament for use in the treatment of general seizures and / or outbreaks, Z or partial seizures.
    According to an aspect of the present invention it is provided. a method of treating generalized seizures and / or partial seizures is surprising to administration a. a patient on a medication comprising an effective amount of THCV and / or CBD ..
    The combined use is based on different apparent mechanisms of action given the different results and õbservãdQS in different animal models and in different doses.
    BOVB SESCBIÇÃO DOS DBSE1SHOS
    The modalities of the invention are further described a. follow with reference to the attached drawings, in which
    Figure 1 shows the latencies for the initial severity® and posterlores of the crises. The average values for 'uipvuj jeiã mio-'ôntea itdd' and ac pcuLua r 'üec of 5 5 ± SEM are shown for the vehicle or for low, medium or high doses of THCV ΒΠ0 and 70mg / kg of PTÉ. n ~ ~ 10;
    Figure 2 shows the duration of seizures and time to death> The mean duration of seizures in Animis surviving s and the time the first sign of crisis even death in those somm, are masters t for the vehicle or low, medium or high doses of THCV SDS and 70mg / kg FTZ., ή 3-10 dependent on proportions of animals that died within the experimental groups>. The vehicle group had no deaths and thus no value is shown here;
    Figure 3 shows the median severity scores. Average severity rates for the group of animals treated with vehicle or with low, medium doses or the action of thcv BDS before 7mg / 'kg of ate. n. ® 10 for all groups;
    Figure 4 shows mortality rates »Expressed mortality rates - with percentage of animals treated 10 with vehicle or ccm. low, medium or high doses of THCV W and 7 & mg / kg of the m, n ~ 10 for all · groups »j» · vein group had no deaths and thus none, value is shown here ..
    Figure 5 shows the latencies for the gravity® 15 húcian · and posterior of the crisec, .- is medium latentia for the first myoclonic ^ erk (W) and the scores of 3.5 + SEM are shown for the vehicle or for low doses , medium or high of THCV BDS and 8amg./.kg of ΡΤΙ. n - 7 - lô;
    Figure 6 shows the duration of the crises and the time to death. The average duration of crises in animals that survived, and the time from the first sign of crisis to death in those that died, are shown ± : B. E »M. for the vehicle or for low, medium or high doses of THCV BDS is 8Q mg / kg FTi. n. ® 3-7 px-dependent on 25 animals that died within the experimental groups.
    Figure 7 shows the median severity scores.
    Severity scores measured, for groups, of animals treated with vehicle or with low, medium or high doses of TH.CV BDS before Steng / kg of PTB »n
    - io for all groups;
    Figure 8 shows mortality rates. Mortality rates expressed as a percentage of animals treated with vehicle or with low, medium or high doses of THÇV BDS and 8Qmg / kg FT1. n »10 for all the® groups;
    Figure 9 AD shows the development of PTS-induced seizures and duration with pure THCV. A, B ® C show the average latency (s) from the injection of 8Q mg / kg of FT2 to; first sign of crisis (A); development of myoclonic seizures (B) and become-clonic seizures (C) for the vehicle and groups dosed with THCV, n ^ S-wool, depending on the incidence of each marker within a specific group) x (D) shows the average duration of crises is) to animals that survived post-crisis. All values ± sEM, * indicate a significant difference in the vehicle group (F <£ hUS;
    1.5 * <> .-; * 'Mann-Whitney V);
    Figure 10 A-B shows the effect of CBB on crises induced by FIZ A:% of mortality experienced as a result of the XP injection of Orng / kg of FTf in vehicle animals and dosed by CDB- (1,
    2D la.ltp mg / kg Óe (n- »15 for all groups), B; >
    of vehicle animals and dosed by cdb (i # in, 100 mg / kg. of CBD) that undergo tannic-clonised erises, as a result of the IP injection of 80mg / kg of PTI. * indicates the significant result (p <Q f Gl);
    25 : Figure 11 shows the lack of effect of THCV on the percentage of mortality. Significance was assessed using a binomial test, by comparison with the control and the significance was accepted ®m Ρνϋ, δδ, No significant difference vs control was found at any dose
    Figure 1.2 shows THCV's lack of affection for «maximum average gravity of cria®. Significance was assessed by Wâlísfô d® Simple variance (1-way AW1A) with Tu.key's post hóè test; P> 0.5 for all comparisons vs control;
    Figure 1.3 A-D shows the percentage of animals in each group that reached crisis states specified when treated with. THCT. Mf significant vs control harangues were evaluated using a binomial test. P <t, G5.
    Figure 14 shows the effect of CB on the 10% mottality <Slgnificencia: assessed by the binomial forehead * shows a significant increase in mortality (P <3.05), Oota ~ if this effect only appeared at .10 mg / kg and was lost at 10: 0 & g / kg, suggestive of a bifasicu effect;
    Figure 15 shows the maximum average severity of the crisis.
    Significance. was evaluated by simple Analysis of Variance (l ~ way AKOVA) with Tukey's post hoc test; F> 0.5 for all comparisons vs control;
    A. Figure IS A-D shows the percentage of animai® in each group that reached states of crisis® is especially affected ...
    Significant differences w cour '* o'e were evaluated using a binomial test® <P V *); F <0.001. (***.);
    Figure 17 shows the effects of CB.D on the mean tonic-clonic frequency. Significance was assessed using an AI4OVA with a post-hoc test of 25 Tukey. P <0.05 (*) <p <0 ^ 1 (. **);
    The figure. .18 descrew the percentage duration of time spent in a tonic-clonic state compared to the total duration of the crisis period. Significance was assessed using one-way ANOVA. Tukey's post-hoc test. P <0.05 30 (*);
    Figure IS Ά-Β describes the effects of CBD on tonic-clinical crises without postural cantrol. A <f of animals that suffered tonic-electronic seizures without postural control, B: frequency with which the animals exhibited S tonic-clinical seizures without postural coatrole during the two-hour recording period (or until death) <A: test binomial statistic; B: Analysis of simple variance (one-way OOVA) followed by the Tukey test, **, *** and # indicate ρχ.Ο, ΟΙ, 0.001 and 0, X, respectively; and
    Figure 20 A ~ C describes the effect of CBD on the severity and mortality of crises induced by panaoiline. A: The median severity of the crises (gray line », is also shown bare 25 and 76 8 percentiles (horizontal black lines) and the maximum and minimum values (error bars up and down, respectively). Bt Percentage of animals that remained crisis-free from start to finish Cj Bercentual of mortality ... At Simple variance analysis (one-way AKGVA) followed by Tukey's test, B &C; binomial statistical test; *, *** and # 20 indicate. p <Q, tJS, 0.001 to 0.1.
    Betalh & da maeió PTB
    Srsmplos 1-3
    General Methodology for Animals model PTX
    Wistar rats with IP4-2; 7S-110g:) were used to evaluate the effects DGS oanabiuôídçs; wcv (BBS and pure) and CBB in the fti model of angry geieral crises, Qs animals were accustomed to the test environments, cages, injection protocol, and handling before experimentation <Animals were housed in a room a
    M * C in an Iw 12 hours; cycle. © souxo {lux ©uled in Q900) at 50%: 4and humidity ,. -with free I went to fe âguã ..
    Cfnfigum ^ So e ^ erimental
    Cinca Perspex tanks of §1 cam lids were placed on a single bench with dividers between them. Closed circuit television cameras (CCTV) were mounted on the dividers to observe the behavior of mice. The Sony Topical CCD cameras (Sluecherry, EGA) were connected by half of BNC cables to one. Low noise PC via cards.
    of digital capture Brooktree (Bluecherry, USA). The soneminder software (http - // wx> canemlader .. cam) was used to monitor mice, start and end records and manage video files. The in house du Linux scripts are used to encode video files in a format suitable for offline analysis useful Leando The Observer (Boldus Technologies),
    Does
    A track. of doses of PTE (SQ-ISOmg / kg body weight) fox used to determine the best dose for .20 induction of. seizures (see below). dome result f the doses of 70 and Btmg / kg injected intraperitoneally (IB; 5Cmg / ml of the reserve in 8.51 saline) are used to examine the cauabindides <
    Experimental sprouts
    Bo dia do taste, the animals received an injepcMa ip, with. cannabindides (low, medium or high dose) on a combined volume of cannabindides velculo (çlílê de atanuli Cxemofor: 0.9% w / v NaCl solution), which served as a negative control group. The animals were then observed for 30 minutes, after which time they received an IE injection of 70 or Sfmg / kg FTZ. Negative vehicle controls were performed® «parallel to the subjects dosed with òanabinaid®. After receiving a dose of FTf : < the animals were recorded and filmed at the end. to determine the severity of the crisis and the latency for various types of crisis transport (see in vivo analysis, below). The forum animals were filmed for half an hour after the last sign of crisis, and then returned to their cages.
    in vivo analysis
    The animals were observed during the experimental procedures., But all analyzes were performed offline using a recorded video file using the behavior analysis software The Observer (Moldus, Netherlands 15). The crisis severity scoring system was used to determine the levels of crisis experienced by the subjects (Fóhl a Mares, 1987). All of the signs of crisis were detailed for all animals,
    Table 1 Scale for the severity of the crisis, adapted from Pohl to Mares, 198'7.
    οη <:>.;.>> çáods Crisis Expressio GOí ‘; p <n ·;:» »κ Υ ·: Λ1 Refiax of«Ndd rs i>; asíera: » 0 There is no compose “t ^ wentc concurrent 0.5 Çpoporfcs ^ abnormal focus (sniff, hv3 < E »excessive, orientation; Cunsatvado 1 Isolated myoclonus spasms <Λ '. V. ' ^ '3'5 < 2 Sionic crisis «: í p ica Preserved 3 o! 6nus d® bilateral foreleg.fully developed C © »se.rvado
    IS
    3. & front paw ellipse sounds cmpojmstetóniec a- fcCKção s $ <j csqpo ponservade 4 Tonic-cXonic crisis with phase suppressionronic Ssrdido 5 ck i a «oncical- c 1 onc tionally desired; .wlvids Lost δ Dead
    dependence from the injection of PTS for «specific indicators of © rise's development
    The latency (in seconds) from the injection of W1 to the priwiró myoolonic spasm (FMJj score of 1) γ and S for the reach by the animal of the. ** clonus of the foreleg with tonic component & body twist ”(score of 3.5} were recorded. PMJ is an indicator of onset of seizure activity, whereas> 90% · of the animals in the development. scores of 3.5, and so it is a tone 10 marker of the development of more severe crises Q data are presented as mean ± SEM within an experimental group <.
    Maximum crisis severity
    This is given as the average value for each experimental group oõm hása on the scoring scale below.
    % of mortality 5
    The percentage of animals within an experimental group that died. as a result of industrial crises by PT1. note that the majority of animals that 2t developed tonic-lanic crises (scores of : 4 and S) in the THÇV (BhS) study died as a result, and that a score of 5 (death) automatically indicates that the animal also suffered tonic-ulonic crises.
    Crisis duration
    The time (in seconds) from the first sign of whooping © (natmalmeute FMd}, to the last sign of crisis ôü, in the case of subjects who died, the time of death separated in animals : who survived and those who did not , S Sse if the mean ± SSM is given for each experimental group.
    Bstathetic $
    The differences latânçias NAC and durations were evaluated by the May variâneia analysis (WOVA) © test with post hoc Tukey ·· ία, F <0 © f i signifiaativo considered,
    Bxámpl © 1-THCV (BDS)
    THCV BDS © comprised an entire extract of a chemiarip in which TtCV was the predominant cannabinoid. (that is, the main çanáhinõida presète m extract, αα%> 15 cm by weight, of the total content of caneMnoidee). TBC was the second prevalent oanahindide male ( and it presumes significant amounts, (this is, compound - greater than 10, · by weight, of the total cannabinoid content, being present in about 16%) f and there was a number of smaller cane.bindidec identified., each comprising less than 2%, by weight, of the total cannabindide content as measured by Split analysis. The ratio of WCV to THC in this extract is 5: 1 wax,
    In fact, the THCV content was 0.5% by weight of the 2S extract and the WC loom was 13.6% by weight of the extract, with the other rods identified in total, with a 3% head. by weight of extract, the remaining 15% does not include anabinoids.
    PT1 pilot study
    0 Erises induced by the range of concentrations of
    PTZ íSO-lOGmg / kg; range - present in the literature) in rats were investigated in order to determine the ideal dose before investigating the effect of cannabindides v FT2 sweets;
    Sõmg / kg and <ümg / kg induced: very little crisis-like activity (p «4);
    7hmg / kg typically induced clonic seizures (score of 3. <5; 8 of 13 subjects);
    80mg / kg regularly induced tonic-clonic seizures
    10. (scores of 4 and 5; δ of 10 subjects)
    Besides, it was verified that a. repeated administration with PT2 resulted in increased sensitivity over time, therefore, no experiments were performed on animals that had already received a dose of PT2,
    The effect of WCV BDS on PT2-induced seizures was first assessed against a dose of PT2 of 7 d mg / kg. As described below, this produced a control group · vehicle that did not normally suffer from severe seizure scores »Fortanto THCV BDS It was also.
    2t ver if leads, against a dose of 80mg / kg of PTfh It was considered that the severity of the increased seizures experienced by animals · control of the exposed vehicle <áOmg / kg of pTt was a more adequate test of the potential anti-convulsive activity
    Effect of the THCV BD8 in crises induced by moderate PT2 and ras ras (7 Qog / kg j
    Three doses of BUS THCV were evaluated against a PT2 coneent.raçlò known to induce moderate seizures in rats (10mg / kg; see pilot, above). The low, medium and low doses of THCV BDS used were Q.-3T.
    3.70 and 37 f 04mg / kg, and yielded actual doses of WCV of 0.25,
    2.5 and 25mg / kg, respectively. These doses were paired in thcv with those qua estlu being used for the screening of WCV purs centers induced crises per
    TtoV BBS does not have any significant effects on the latency of the first MaclBnica spasm or in latency for the attainment of a severity score of
    3.5 in the severity of the arises (Fig 1). It must be not ax qua, although both values for these variables
    They have upper sides for dogs treated with medium dose. high THCV BPS compared to the control, this does not cansegulu reach significance (Fto, 05), in the same way., no significant impact on the duration of the crisis was seen (Fig. 2},
    The effects of TH.CV BDS on the severity of crises (Fig.
    3) and mortality (Fig. 4) in animals that received 70mg / kg doses of FT2 did not follow a simple pattern, no animal injected with vehicle alone exceeded the average severity score of 3.5 for this group, and 20 none of the animals died (n ~ 10).
    In contrast, 10mg / kg of FTB induced severe tonic-clonic seizures and death in 50% of animals injected at a low dose. of THCV BPS, demonstrating a median severity score of 4.75> This increase in severity was not significant, however, were animals injected with doses medium and high THCV BPS scores had a median severity score tsener s lower mortality rates than those exposed to low doses (Figures 3 and 4h. Mortality rates of medium and high doses were higher than 30 than those of the vehicle group, but not significantly (F> 0.5S; Fig. 4). However, the median severity scores were the same between medium and high doses (Fig, 3). This pattern of results suggested that an additional set of experiments, in which THCV BbS was screened 5 against a dose of PTS that would induce severe arises in control animals (treated with vehicle} was necessary,
    Effect of THCV BBS in severe PTt-induced seizures (S0mg / kg)
    The effects of the same three doses of THCV BDS on
    Since crises induced by SOmg / kg of FTE were evaluated, it is interesting to note that SQmg / kg induced significantly more crises than 70 mg / kg in vehicle control groups (P »0.009), with mean severity scores of © vise of 6 and 3.5, respectively, THCV BDS in © had a significant effect on FMJ latencies or a severity scale of 3.5 (Fig, S) <Likewise, no effect was observed in crisis durations (Fig, 8):,
    One dose of THCV BDS decreases both the severity of attacks (Fig 7) and mortality (Fig, 8). 20 animals that received doses of Wmg / kg PTB, animals that received low thcv bds had a median severity score smaller (3.5 compared to 5) than vehicle controls, however, this difference was not significant W> 0.5)> The low-dose group of thCTH ass also had a 25% mortality rate. vehicle control group (30% to 80%)>
    The groups treated with medium and high doses of THCV
    BDS had a lower risk rating of 4.75 (>> 0.3 vs control ©), at a lower mortality rate of 50%. compared to 8 and 50% respectively.
    Resi-wd vivd conclusion
    A. TSCV BBS trisection in the BIB model does not seem to have any significant anti-on pro-convulsive effect on 5 moderate or severe crises induced by BTZ. However, a trend towards lower severity and mortality was observed in animals that received an. low dose of THCV BM before the induction of severe attacks (Sõmg / kg FT1), in comparison to vehicle controls.
    It is possible that this effect is masked with higher doses of THCV BBS by higher levels of other cannabinoid constituents (such as TMC) present in the non-THCV content of TKCV BDS. Higher doses of THCV BDS will contain increasing doses of non-THCV content> such as THC, which may oppose any potential positive effects of THCV.
    Example 2 - WW {pure
    Effect of pure THCV against PT.2-induced crises
    Low doses (0, G2S mg / kgj, medium (0.25 mg / kg) 'high (-2, -5 W / W at pure THCV were' evaluated for their effects on PTS-induced seizures. Male to penalty note at this point, by comparisons to Example 1 ÇTHCV BPS , that different doses of pure TBCV were used compared to THCV BBS, see Table 2 below.
    Table 2. Comparison of doses of THCV BD5 and TBQV pulls using the PT 2- Xo mode
    üosa ’‘ low- ’ U * «and Wd, 5 . · - Smsé altebag / kgj(ug / kg ·} TKCV sts «, 25 2, .5 25
    pure thcv 0, O2-5 O., SS i, s
    The values provided are for the THCV content of the doses (actual doses, therefore, of TO WS sac · approximately 1.5 times greater).
    / mg / kg induced. successfully seizures of different severities in animals from all 4 experimental groups (n-15 per group). PT2-induced crises led to the death of 44% of the animals that received only. © vehicle .. Gs groups that received low, medium and high THCV all exhibited lower mortality rates of 4x1, 331 s 381, respectively / however these values were not significantly different than those in the group : vehicle (p> 0.05, binomial test),
    The median values for latWcia for p first sign of crisis, and for scores of [3] and [S] on the scale of IS crisis d score used, as well as the duration of crisis for surviving animals, are described in Figs AA -D.
    I could see that the crises started later, as shown by the increased latency for the first bad ones, resulting in a shortening similar to the crisis (Fig.
    SA) in animals that received THCV compared to vehicle uontrdl.es, delay of onset was significant at the highest dose of thcv (pw, 02). A similar pattern was observed - for latentia for [3J and [5) 2S (Figs. W and 4C) with all doses of THCV that exhibit increased latencies, reaching a significant level at the highest dose of THCV (p ~ 0, Q17 and 0.013 for [3] and [§], respectively ),
    It was also observed that the duration dé. crises induced by PTZ in animals that survived the experimental period were significantly shorter after the administration of the average dose of THCV compared to vehicle controls (Figure 3D, p ~ Q # 83),.
    Table 3 below shows the median crisis intensity values in each experimental group
    animals that did not show any signs of crisis for anything experimental group are provided (n «.lé for each value) * indicates significant difference of the vehicle group (binomial significance test, P <0, Ç5),
    The vehicle control animals had a median seizure severity of 4.25, while all groups receiving aTHCV had a median severity score of 35. This decrease was not significantly different.
    12.5% of the animals in the vehicle control group did not show signs of crisis, suggesting that these animals do not develop crises after the administration of 2T2 a significantly larger number of animals (33.3%) did not show signs of crisis in the group that received 0 ', .- 2-5 mg / kg (Table 3, p ~ 9.031). These data suggest that a. average dose of 0.25 mg / kg of THÇV protected them against the development of crises «
    SeswiO in vivo and conclusion
    W of the high dose of THCV in. latency valdrés suggest that THCV can delay both the onset and the development of the crisis, while the significant effects of the medium dose on the incidence of crises in medium doses (0.25 mg / kg) of THCV suggest an action on ticonvuls significant effect on seizures induced by 10 PTZ ,.
    Example 3 - CSD (pure)
    In addition to THCV, the CDB was also verified in the
    PT2L The results strongly indicate that the CBD (in levels of itomg / kg)
    1.5 in this model is anti-convulsive since it has significantly reduced the mortality rate and the incidence of as main serious crises compared to vehicle control animals.
    Effect of pure CBD against PTf-induced iris
    The pure CBD was injected intra-intraperitoneally (IPj in the standard vehicle (ethanol aifOXiis; Cremator; 5 f |% W / v of WC1) nm. Of the sest * s X, 10 and 1 < 0 mg / kg, g unt amen tn with animals that received only the vehicle in a combined volume (n ^ XB for each, group) 60 minutes later, BT2
    [SOmg / kg, IP) was administered <
    45 ·, 7t of the control animals that received only the vehicle died within 30 minutes of. administration of PTÉ (Fig. 10). Hell, only S f 7ã (only 1 of 15) of the animals they received. lõOmq / kg of CBD died, a marked reduction that was significant (ρ <0 ; θθό1).
    In addition, only 5.7% of the animals that received 100mg / kg of CBD went through more severe attacks (score of 5), compared to 53.3% of the control animals, a decrease that was also significant (p < 0.001, / Fig. 10 in vivo) *.
    The tenant of pure wcv, netáiw significant increase in the latency of the development of the crisis was observed. However, the marked and significant reductions indicate a notable anti-convulsive effect in FTB-induced crises,
    Screening and analysis of pure CBD in the FT2 model in. high dose (100mg / kg) of CBB on levels of mortality and incidence of the most severe crises suggests that CBD can mitigate the severity of crises induced by PTB
    FiladarpiBa Model Bxumplos 4 and §
    Example 4 - Pure THCV
    Pure TMCV benefit against pilocarpine-induced crises
    THCV pulls injected intraintraperitoneally Í.LP; nc run ethanol standard Cremo fort 0 <2% rf / v of MaCl) in dances of 0.025, 0.25 and 2.5 mg / kg in animals that received vehicle alone at an impressive volume (n> 14 for each group). 15 minutes later methylsaapolamine (1 mg / kg; to reduce peripheral muscaxinic effects of prcarcine) was administered followed by, 45 minutes later, administration of piloaarpin (380 mg / kg, XF).
    Results
    No significant effect of WCV at any dose was observed on the 1 reached the baseline d · iniçib of crisis (P> 0, S for all doses vs cbntróle, analysis of simple variance (l-way AMOVA) with post Ίϋν test Tukey), Menhwa. significant change in the percentage of mortality vs control was observed for any dose of THFV (Figure 11),
    In addition, THCV had no effect on median severity. maximum urise reached by group of animals (Figure 12).
    The percentage of animals in each group that reached a state of particular crisis (clusus of the front forelimb, clonus of the bilateral forelimb, clonus of the bilateral forelimb with tonic and chronic tonic fall) was also assessed (Figure 13Α-Ϊ2).
    The IH <V did not cause significant changes in the percentage of animals that had unilateral forelimb olonus, bilateral forelimb clonus or tonic-clonic seizures at any dose. Interestingly, 2.25 mg / kg of THCV caused an increase: significant in the percentage of animals that have bilateral forelimb clonus: with raising and falling. although this effect has not been seen in any of the other.
    Example S - Pure CBD
    Effect of pure CBD against crises induced by pilocarpine
    Pure CEP was injected intra-intraperitoneally (XP) in the standard vehicle (ethanol lilt 12: NaCl Cramofort 9F7v) in doses 1, 10 and 100 mg / kg in animals that received a vehicle with a corresponding volume (n> l 30 for each group) .. 15 minutes later matilscopola.mina (1 mg / kg; for xeduxir perl muscarinic effects, fax lets of pilobaxpine) was administered. followed by 45 minutes later, pilocarpine administration (380 mg / kg, IF) ·,
    Mewltados kenhum «significant achievement of CBD at any dose was observed on the latandia for the onset of the crisis (P> G, 5 for all doses vs control, analysis of the simple variant ia (l-wap AKOVA) with post test ·· hoc of Tufcny)> W significant increase in the percentage of
    10. Control mortality was observed for the 1G W./W dose of CBD, as shown in Figure: 14 · »·
    Figure 15 details that the CSD had no effect on the. maximum median severity of the crisis reached by group of animals.
    Figures 5 AD detail, c percentage of animals in each group that reaches one. particular crisis state (olômus unilatera the foreleg, the foreleg of bilateral olônus, clõhus bilateral forepaw is the creation tônicoulônica fall) The
    G CBD caused significant reductions in the percentage of animals with unilateral forelimb burden at doses of CBD> 1 mg / kg. Interestingly, although no significant differences were found in the percentage of animals that exhibit bilateral clonus of the forepaw 25, the perceptual of animals that manifest with bilateral front paw clone with breeding and the drop was significantly reduced in all doses of CBD> 1 mg / kg The percentage of animals exhibiting tonic ·· clonic seizures was significantly reduced by a dose of CDB of
    1 mg / kg and 100 mg / kg, but not 1Q mg / .kg (see Figure 14).
    The effects; of the CSDs on the tonic-colon çriúe events, examining the median frequency of tonic-clonic seizure events are as shown in Figure 17, D CBD caused a significant reduction in the tonic frequency ·· S average clonic of all tested doses. The effects of the CDB on the average frequency of all crisis scores were also assessed in the same way, but no significant difference in the control was found (F> 0.5 for, all).
    The percentage of time spent in the tonic-clonic state compared to the total duration of the orisha period was examined (Figure 15). The CBD significantly reduced the percentage duration, at doses of 1 mg / kg and 1 SD mg / kg, but not 10 mg / kg <
    Example S
    Model d »Phenicillin - Bxample <(only}
    Bxample 6 «CBD Hole
    Effects of pure cbd on penicillin-induced seizures
    The CBD (1, 10 and 100 mg / kg) or CBD vehicle (lcl; 18 of the ethalol: cremator; d, $% w / v of DãCl) was administered i.p. to adult Wistar rats (> 2SUg). A week before that, the animals had been surgically implanted with a cannula in the right lateral ventricle only under anesthesia. At the time after the administration of the CBD, ISO XU of penicillin was infused in the right lateral ventricle in 1, S pl of saline solution one minute is of video behavior of criseregistado during two hours.
    After: the detailed analysis of the animals' responses to penicillin alone (using data obtained from groups of tentrole vehicles, a completed crisis score scale for partial, penicillin-induced seizures was derived, the pentaaçác a system below, which was derived from several existing and published 5 scoring systems for this model, will therefore be used to analyze the effects of drugs on these crises,
    Crisis paxxtuátion system for partial seizures induced by penicillin »
    0 Latency period h 1 Wild running / jumping 2 Myoclonic Phase 3 unilateral forelimb clonus 4 bilateral forelimb clonus 5 Postural crisiswithheld 5 Created tônloo-clanioa without postural control
    Seven of the dara. animals treated by vehicle developed the most severe crises (toniao-clanioas crises without postux'a control): Figure 19 Al, while the administration of 100mg / kg of CDS completely prevented the development of these crises in a significant way (pto, 001}. Almost significant reductions in the development of these attacks were observed in animals treated with 1 and 10mg / kg of CBD (Figure 15A, p ~ 0.075 for both). The frequency with which the animals experienced the most severe attacks was also significantly affected ( AWVA,
    0 p-0.003; Figure 19 B), with a significant decrease in vehicle group coverage, at 100 mg / kg CDB (ρ ^ Ο, βΟδ) and an almost significant effect of: temq / kg ipo ~ 0.0 ’1>.
    The effect: of the treatment of CBD on: the severity of the crisis and the mortality of the animal is described in Figure 11 AÇ. A dose of 10O mg / kg of C ”S significantly reduced the wdian severity of penicillin-induced seizures compared to animals treated with the vehicle (ANOVA p« S, 014; difference between b vehicle and IGOmg / kg CDB p ^ G , 011; Figure 10 A), curipsamenta, all doses of CBD (1, 10 and 10tmg / kg) significantly increased the proportion of animals that remained free of cries © (ρνο, οοι to 10 all doses; Figure S 20 ), Finally, IGGmg / kg had one. almost significant effect on mortality compared to the vehicle (p * G f 057).
    Overall conclusion
    From these studies, it appears that both THCV (pure) and CBD (pure) show promise as an antiepileptic for the generalized, particularly clonic / tonic crisis. The data generated for a rich THCV extract, containing other cannabindides including significant amounts of THC, suggests that THC may counteract the THCV elect and that a cannabinoid extract that contains THCV as a main predominant cannabinoid .. but which also contains minimal, or substantially none, THC would be desirable for treatment of epilepsy.
    In addition, the results with pure CBD suggest that an extract that contains significant amounts of both THCV and CBD, but, neverthe- less, minimal or substantial ThC does not ask to provide an ideal combination. In this way, it can be desirable to prepare a predominant extract and THCV extract in which TüC is selectively.
    it is substantially removed (to levels of less than a few percent). This could be mixed with. an extract rich in CBD (which contains very low levels of THC) in which. CBD is the main and predominant oanabinoid ( also with low levels of THC) for the production of an extract with clearly defined significant levels of both THCV and CBD, but with insignificant levels of TBC, such an extract may contain other cannabinoids and the non-oanahinoid components that result from the l example, of carbon didxide as described in ^ 004/915277, whose components that can supertax · an entourage effect in the endoc & nabinoid system,
    At dosage, a human / rat conversion factor (χβ) suggests a daily dose of CBD, at least 600 mg (and, optionally, between ãOOmg and BOOmg) and for a. THCV, at least 1.5 mg (average) preferably at least 15 mg (high).
    whenever a phytocannabindid® extract has to be used, an extract with low or negligible levels 10 gives TSC and therapeutically effective levels of THCV to, / or CBD is desired,
    The examples described in the Examples above clearly show that, although the CBD shows some anti-convulsive properties in all three models, it would be better to treat generalized or partial creations. Unlike THCV, it was only effective in the PTB model. This finding suggests that the two çanabincide® may have different mechanisms of action and that a. combination can provide more general treatments ;, in this regard, 30 THCV seems selective for generalized seizures, more particularly tonic-clonus is CBD appears to be more effective in generalized and partial seizures.
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    权利要求:
    Claims (11)
    [1]
    1. Use of cannabidiol (CBD) characterized by the fact that it is in the preparation of a drug to treat a partial seizure, in which CBD is present in an amount that provides a daily dose of at least 400 mg.
    [2]
    2. Use, according to claim 1, characterized by the fact that CBD is present in a
    quantity that provides one dose daily of hair any less 400 to 800 mg.3. Use, in wake up with any an of claims 1 to 2, featured by the fact that that partial crisis developed in a more crisis serious.
    [3]
    4. Use, according to claim 3, characterized by the fact that the most severe crisis is a tonic-clonic crisis.
    [4]
    Use according to any one of claims 1 to 4, characterized by the fact that CBD is used in combination with THCV.
    [5]
    6. Use, according to claim 5, characterized by the fact that THCV is present in an amount that provides a daily dose of at least 1.5 mg.
    [6]
    7. Use according to claim 6, characterized by the fact that THCV is present in an amount that provides a daily dose of at least 15 mg.
    [7]
    8. Use according to any of claims 1 to 7, characterized by the fact that CBD alone or in combination with THCV is present as a plant extract.
    2/2
    [8]
    9. Use, according to the fact that it comprises less than 5% in (THC) as a percentage with claim 8, that the plant extract tetrahydrocannabinol weight of any cannabinoids present in the plant extract.
    [9]
    10. Use according to claim 9 characterized by the fact that plant extract comprises less than
    1% by weight of tetrahydrocannabinol (THC) as a percentage of any cannabinoids
    10 present in the plant extract.
    [10]
    11. Use according to any one of claims 1 to 7, characterized by the fact that CBD alone or in combination with THCV is present as a pure or isolated cannabinoid.
    [11]
    12. Composition for use in the treatment of partial seizures characterized by the fact that it comprises cannabidiol (CBD).
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    同族专利:
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    DK2448637T3|2014-05-26|
    EP3718603A1|2020-10-07|
    CA3040410A1|2011-01-06|
    HRP20140398T1|2014-06-20|
    MX2012000257A|2012-01-27|
    IL217280D0|2012-02-29|
    UA108852C2|2015-06-25|
    US20170273913A1|2017-09-28|
    US20120165402A1|2012-06-28|
    JP2016166205A|2016-09-15|
    JP2012532093A|2012-12-13|
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    GB2471523A|2011-01-05|
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    CN102596322A|2012-07-18|
    RU2012103603A|2013-08-10|
    TWI461191B|2014-11-21|
    US20190247324A1|2019-08-15|
    CA2766082A1|2011-01-06|
    SI2448637T1|2014-07-31|
    EP2448637A1|2012-05-09|
    GB2471565B|2012-07-04|
    MY156759A|2016-03-31|
    CA2766082C|2019-06-11|
    AU2010267775B2|2016-10-06|
    IN2012DN00804A|2015-06-26|
    NZ620838A|2015-08-28|
    EP2448637B1|2014-03-12|
    ZA201200373B|2012-09-26|
    GB201121919D0|2012-02-01|
    EP2727626A1|2014-05-07|
    JP5904938B2|2016-04-20|
    TW201105318A|2011-02-16|
    GB2485291A|2012-05-09|
    GB2471565A|2011-01-05|
    HK1164766A1|2012-09-28|
    NZ597704A|2014-05-30|
    PL2448637T3|2014-08-29|
    IL217280A|2018-05-31|
    US20150335590A1|2015-11-26|
    PT2448637E|2014-05-27|
    CN106236744A|2016-12-21|
    US9522123B2|2016-12-20|
    WO2011001169A1|2011-01-06|
    KR101727000B1|2017-05-02|
    RU2563143C2|2015-09-20|
    CY1115338T1|2017-01-04|
    GB2485291B|2013-03-27|
    US9066920B2|2015-06-30|
    AU2010267775A1|2012-02-23|
    KR20120088648A|2012-08-08|
    GB0911580D0|2009-08-12|
    SG176914A1|2012-01-30|
    GB201010897D0|2010-08-11|
    AR077448A1|2011-08-31|
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    法律状态:
    2020-06-23| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-06-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-08-18| B25A| Requested transfer of rights approved|Owner name: GW PHARMA LIMITED (GB) |
    2020-09-08| B25G| Requested change of headquarter approved|Owner name: GW PHARMA LIMITED (GB) |
    2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-09-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2021-12-28| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    优先权:
    申请号 | 申请日 | 专利标题
    GB0911580A|GB2471523A|2009-07-03|2009-07-03|Use of tetrahydrocannibivarinand optionally cannabidiolin the treatment of epilepsy|
    GB0911580.9|2009-07-03|
    PCT/GB2010/051066|WO2011001169A1|2009-07-03|2010-06-29|Use of one or a combination of phyto-cannabinoids in the treatment of epilepsy|
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