GB2479153A - Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy - Google Patents
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Abstract
The invention relates to the use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy, in particular epilepsy characterised by generalised seizures. CBDV may be used in an isolated form or as a botanical drug substance. Preferably, CBDV is used with one or more therapeutically effective phytocannabinoids such as tetrahydrocannabivarin (THCV) and cannabidiol (CBD), and in combination with a standard anti-epileptic drug, Also claimed is a cannabis plant extract for use in the treatment of epilepsy, the extract containing at least 50 wt% of a phytocannabinoid fraction including CBDV as principal phytocannabinoid and CBD as secondary phytocannabinoid, and a non-phytocannabinoid fraction including monoterpenes and sesquitelpenes. Preferably the cannabis plant extract further comprises THCV. Some of the examples relate only to the use of THCV or CBD in models of epilepsy.
Description
USE OF THE PHYTOCANNABINOID CAN NABIDIVARIN (CBDV) IN THE TREATMENT OF
EPILEPSY
[0001] This invention relates to the use of the phytocannabinoid cannabidivarin (CBDV) and combinations of the phytocannabinoid CBDV with tetrahydrocannabivarin (THCV) and cannabidiol (CBD) in the treatment of epilepsy.
BACKGROUND
[0002] Epilepsy is a chronic neurological disorder presenting a wide spectrum of diseases that affects approximately 50 million people worldwide (Sander, 2003). Advances in the understanding of the body's internal endocannabinoid' system has lead to the suggestion that cannabis-based medicines may have the potential to treat this disorder of hyperexcitability in the central nervous system (Mackie, 2006, Wingerchuk, 2004, Alger, 2006).
[0003] Cannabis has been ascribed both pro-convulsant (Brust et al., 1992) and anti-convulsant effects. Therefore, it remains to determine whether cannabinoids represent a yet to be unmasked therapeutic anticonvulsant or, conversely, a potential risk factor to recreational and medicinal users of cannabis (Ferdinand et al., 2005).
[0004] In 1975 Consroe et al. described the case of young man whose standard treatment (phenobarbital and phenytoin), didn't control his seizures. When he began to smoke cannabis socially he had no seizures. However when he took only cannabis the seizures returned. They concluded that marihuana may possess an anti-convulsant effect in human epilepsy'.
[0005] A study by Ng (1990) involved a larger population of 308 epileptic patients who had been admitted to hospital after their first seizure. They were compared to a control population of 294 patients who had not had seizures, and it was found that using cannabis seemed to reduce the likelihood of having a seizure. However this study was criticized in an Institute of Medicine report (1999) which claimed it was weak', as the study did not include measures of health status prior to hospital admissions and differences in their health status might have influenced their drug use' rather than the other way round.
[0006] Three controlled trials have investigated the anti-epilepsy potential of cannabidiol. In each, can nabidiol was given in oral form to sufferers of generalised grand mal or focal seizures.
[0007] Cunha et al (1980) reported a study on 16 grand mal patients who were not doing well on conventional medication. They received their regular medication and either 200-300mg of cannabidiol or a placebo. Of the patients who received CBD, 3 showed complete improvement, 2 partial, 2 minor, while 1 remained unchanged. The only unwanted effect was mild sedation.
Of the patients who received the placebo, 1 improved and 7 remained unchanged.
[0008] Ames (1986) reported a less successful study in which 12 epileptic patients were given 200-300mg of cannabidiol per day, in addition to standard antiepileptic drugs. There seemed to be no significant improvement in seizure frequency. This is a finding that was replicated in a report by Trembly et al (1990). However, Trembly performed an open trial with a single patient who was given 900-1200mg of cannabidiol a day for 10 months. This trial showed a more positive result -seizure frequency was markedly reduced in the patient.
[0009] In addition to the disclosures suggesting CBD may be beneficial there is a report (Davis & Ramsey) of tetrahydrocannabinol (THC) being administered to 5 institutionalized children who were not responding to their standard treatment (phenobarbital and phenoytin).
One became entirely free of seizures, one became almost completely free of seizures, and the other three did no worse than before.
[0010] In WO 2006/0540571 it is suggested that the cannabinoid Tetrahydrocannabivarin (THCV) may behave as anti epileptic, something confirmed by Thomas et al 2005.
[0011] In addition WO 2009/007697 describes a THCV and CBD pharmaceutical formulation.
Such a formulation is suggested to be of use in many different types of diseases including epilepsy.
[0012] However, there are more than forty recognisable types of epileptic syndrome partly due to seizure susceptibility varying from patient to patient (McCormick and Contreras, 2001, Lutz, 2004) and a challenge is finding drugs effective against these differing types.
[0013] Neuronal activity is a prerequisite for proper brain function. However, disturbing the excitatory -inhibitory equilibrium of neuronal activity may induce epileptic seizures. These epileptic seizures can be grouped into two basic categories: partial and generalised seizures.
Partial seizures originate in specific brain regions and remain localised -most commonly the temporal lobes (containing the hippocampus), whereas generalised seizures appear in the entire forebrain as a secondary generalisation of a partial seizure (McCormick and Contreras, 2001, Lutz, 2004). This concept of partial and generalised seizure classification did not become common practice until the International League Against Epilepsy published a classification scheme of epileptic seizures in 1969 (Merlis, 1970, Gastaut, 1970, Dreifuss et al., 1981).
[0014] The International League Against Epilepsy further classified partial seizures, separating them into simple and complex, depending on the presence or the impairment of a consciousness state (Dreifuss et al., 1981).
[0015] The league also categorized generalised seizures into numerous clinical seizure types, some examples of which are outlined below: [0016] Absence seizures occur frequently, having a sudden onset and interruption of ongoing activities. Additionally, speech is slowed or impeded with seizures lasting only a few seconds (Dreifuss et al., 1981).
[0017] Tonic-clonic seizures, often known as "grand mal", are the most frequently encountered of the generalised seizures (Dreifuss et al., 1981). This generalised seizure type has two stages: tonic muscle contractions which then give way to a clonic stage of convulsive movements. The patient remains unconscious throughout the seizure and for a variable period of time afterwards.
[0018] Atonic seizures, known as "drop attacks", are the result of sudden loss of muscle tone to either a specific muscle, muscle group or all muscles in the body (Dreifuss et al., 1981).
[0019] The onset of epileptic seizures can be life threatening with sufferers also experiencing long-term health implications (Lutz, 2004). These implications may take many forms: * mental health problems (e.g. prevention of normal glutamatergic synapse development in childhood); * cognitive deficits (e.g. diminishing ability of neuronal circuits in the hippocampus to learn and store memories); * morphological changes (e.g. selective loss of neurons in CAl and CA3 regions of hippocampus in patients presenting mesial temporal lobe epilepsy as a result of excitotoxicity) (Swann, 2004, Avoli et al., 2005) [0020] It is noteworthy that epilepsy also greatly affects the lifestyle of the sufferer -potentially living in fear of consequential injury (e.g. head injury) resulting from a grand ma! seizure or the inability to perform daily tasks or the inability to drive a car unless having had a lengthy seizure-free period (Fisher et al., 2000).
[0021] There are many different standard anti-epileptic drugs available at the present time including: acetozolamide, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, gabapentin, lacosamide, lamotriquine, levetiracetam, oxcarbazepine, Phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide.
[0022] Three well-established and extensively used in vivo models of epilepsy are: * pentylenetetrazole-induced model of generalised seizures (Obay et al., 2007, Rauca et al., 2004); * pilocarpine-induced model of temporal lobe (i.e. hippocampus) seizures (Pereira et al., 2007); and * penicillin-induced model of partial seizures (Bostanci and Bagirici, 2006).
These provide a range of seizure and epilepsy models, essential for therapeutic research in humans.
[0023] The application WO 02/064109 describes a pharmaceutical formulation where the cannabinoids THC and CBD are used. The application goes on to state that the propyl analogs of these cannabinoids may also be used in the formulation. Since this application was written it has been shown that THCV behaves in a very different manner to THC and therefore the assumption that the propyl analogs of cannabinoids behave in a similar manner to their pentyl counterparts is now not valid.
[0024] The application GBO91 1580.9 describes the use of THCV for the treatment of generalised seizures, also described is the use of the cannabinoid CBD in combination with the THCV.
[0025] It is an object of the present invention to identify novel cannabinoids or combinations of cannabinoids for use in the treatment of epilepsy.
DEFINITIONS
[0026] "Phytocannabinoids" are cannabinoids that originate from nature and can be found in the cannabis plant. The phytocannabinoids can be isolated cannabinoids or present as a botanical drug substance.
[0027] An "isolated cannabinoid" is defined as a phytocannabinoid that has been extracted from the cannabis plant and purified to such an extent that all the additional components such as secondary and minor cannabinoids and the non-cannabinoid fraction have been removed.
[0028] A "botanical drug substance" or "BDS" is defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research as: "A drug derived from one or more plants, algae, or microscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverisation, decoction, expression, aqueous extraction, ethanolic extraction or other similar processes." A botanical drug substance does not include a highly purified or chemically modified substance derived from natural sources. Thus, in the case of cannabis, BDS derived from cannabis plants do not include highly purified Pharmacopoeial grade cannabinoids.
[0029] In the present invention a BDS is considered to have two components: the phytocannabinoid-containing component and the non-phytocannabinoid containing component. Preferably the phytocannabinoid-containing component is the larger component comprising greater than 50% (wlw) of the total BDS and the non-phytocannabinoid containing component is the smaller component comprising less than 50% (wlw) of the total BDS.
[0030] The amount of phytocannabinoid-containing component in the BDS may be greater than 55%, through 60%, 65%, 70%, 75%, 80% to 85% or more of the total extract. The actual amount is likely to depend on the starting material used and the method of extraction used.
[0031] The "principle phytocannabinoid" in a BDS is the phytocannabinoid that is present in an amount that is higher than that of the other phytocannabinoids. Preferably the principle phytocannabinoid is present in an amount greater than 40% (wlw) of the total extract. More preferably the principle phytocannabinoid is present in an amount greater than 50% (wlw) of the total extract. More preferably still the principle phytocannabinoid is present in an amount greater than 60% (wlw) of the total extract.
[0032] The amount of the principle phytocannabinoid in the BDS is preferably greater than 75% of the phytocannabinoid-containing fraction, more preferably still greater than 85% of the phytocannabinoid-containing fraction, and more preferably still greater than 95% of the phytocannabinoid-containing fraction.
[0033] In some cases, such as where the principle cannabinoid is either CBDV or THCVA the amount of the principle phytocannabinoid in the BDS is lower. Here the amount of phytocannabinoid is preferably greater than 55% of the phytocannabinoid-containing fraction.
[0034] The "secondary phytocannabinoid/s" in a BDS is the phytocannabinoid/s that is I are present in significant proportions. Preferably the secondary phytocannabinoid is present in an amount greater than 5% (w/w) of the total extract, more preferably greater than 10% (w/w) of the total extract, more preferably still greater than 15% (w/w) of the total extract. Some BDS's will have two or more secondary phytocannabinoids that are present in significant amounts.
However not all BDS's will have a secondary phytocannabinoid. For example CBG BDS does not have a secondary phytocannabinoid in its extract.
[0035] The "minor phytocannabinoidls" in a BDS can be described as the remainder of all the phytocannabinoid components once the principle and secondary phytocannabinoids are accounted for. Preferably the minor phytocannabinoids are present in total in an amount of less than 10% (w/w) of the total extract, more preferably still less than 5% (w/w) of the total extract, and most preferably the minor phytocannabinoid is present in an amount less than 2% (w/w) of the total extract.
[0036] Typically the non-phytocannabinoid containing component of the BDS comprises terpenes, sterols, triglycerides, alkanes, squalenes, tocopherols and carotenoids.
[0037] These compounds may play an important role in the pharmacology of the BDS either alone or in combination with the phytocannabinoid.
[0038] The "terpene fraction" may be of significance and can be broken down by the type of terpene: monoterpene or sesquiterpene. These terpene components can be further defined in a similar manner to the cannabinoids.
[0039] The amount of non-phytocannabinoid containing component in the BDS may be less than 45%, through 40%, 35%, 30%, 25%, 20% to 15% or less of the total extract. The actual amount is likely to depend on the starting material used and the method of extraction used.
[0040] The "principle monoterpene/s" in a BDS is the monoterpene that is present in an amount that is higher than that of the other monoterpenes. Preferably the principle monoterpene/s is present in an amount greater than 20% (wlw) of the total terpene content.
More preferably the principle monoterpene is present in an amount greater than 30% (wlw) of the total terpene content, more preferably still greater than 40% (wlw) of the total terpene content, and more preferably still greater than 50% (wlw) of the total terpene content. The principle monoterpene is preferably a myrcene or pinene. In some cases there may be two principle monoterpenes. Where this is the case the principle monoterpenes are preferably a pinene and I or a myrcene.
[0041] The "principle sesquiterpene" in a BDS is the sesquiterpene that is present in an amount that is higher than all the other terpenes. Preferably the principle sesquiterpene is present in an amount greater than 20% (w/w) of the total terpene content, more preferably still t greater than 30% (w/w) of the total terpene content. The principle sesquiterpene is preferably a caryophyllene and I or a humulene.
[0042] The sesquiterpene components may have a "secondary sesquiterpene". The secondary monoterpene is preferably a pinene, which is preferably present at an amount greater than 5% (w/w) of the total terpene content, more preferably the secondary terpene is present at an amount greater than 10% (w/w) of the total terpene content.
[0043] The secondary sesquiterpene is preferably a humulene which is preferably present at an amount greater than 5% (w/w) of the total terpene content, more preferably the secondary terpene is present at an amount greater than 10% (w/w) of the total terpene content.
[0044] Alternatively botanical extracts may be prepared by introducing isolated phytocannabinoids into a non-cannabinoid plant fraction as can be obtained from a zero cannabinoid plant or a CBG-free BDS.
[0045] The structure of CBDV is as shown below: CBDV Cannabidivarin [0046] Phytocannabinoids can be found as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
[0047] Phytocannabinoids can also occur as either the pentyl (5 carbon atoms) or propyl (3 carbon atoms) variant. Initially it was thought that the propyl and pentyl variants would have similar properties, however recent research suggests this is not true. For example the phytocannabinoid THC is known to be a CB1 receptor agonist whereas the propyl variant THCV has been discovered to be a CB1 receptor antagonist meaning that it has almost opposite effects.
[0048] This is confirmed by Pertwee (2000) in Cannabinoid receptor ligands: clinical and neuropharmacological considerations relevant to future drug discovery and development, which describes potential therapeutic targets for CB1 receptor antagonists which include appetite suppression, the reduction of L-dopa dyskinesia in patient's with Parkinson's disease, management of acute schizophrenia and the amelioration of cognitive memory dysfunctions associated with Alzheimer's disease. All of these therapeutic targets are very different from those suggested for CB1 receptor agonists such as appetite stimulation and reduction of pain.
[0049] It is envisaged that a CBDV formulation for clinical development would be delivered orally containing either CBDV BDS or isolated CBDV.
[0050] Unit dosage amounts may vary depending on the type and severity of the epilepsy to be treated. Each dosage unit may comprise less than or equal to 1000mg of CBDV and the number of doses to be taken may also be varied to suit a patient's requirements.
BRIEF SUMMARY OF THE DISCLOSURE
[0051] In accordance with a first aspect of the present invention there is provided a phytocannabinoid CBDV for use in the treatment of epilepsy.
[0052] In accordance with a second aspect of the present invention there is provided the use of the phytocannabinoid CBDV in the manufacture of a medicament for use in the treatment of epilepsy.
[0053] In accordance with a third aspect of the present invention there is provided a method for the treatment of epilepsy, which comprises administering to a subject in need thereof a therapeutically effective amount of the phytocannabinoid CBDV.
[0054] Preferably the type of epilepsy to be treated is generalised seizure.
[0055] In one embodiment the CBDV is used with one or more therapeutically effective phytocannabinoids.
[0056] Preferably the one or more therapeutically effective phytocannabinoid is THCV and I or CBD.
[0057] In one embodiment the CBDV is in an isolated form.
[0058] In a further embodiment the CBDV is in the form of a botanical drug substance.
[0059] In a further embodiment still, the CBDV is used in combination with a standard anti-epileptic drug.
[0060] In accordance with a third aspect of the present invention there is provided a cannabis plant extract comprising a phytocannabinoid containing component and a non-phytocannabinoid containing component, wherein the phytocannabinoid containing component comprises at least 50% (wlw) of the cannabis plant extract and contains as a principle phytocannabinoid, CBDV and as a secondary phytocannabinoid, CBD, and wherein the non-phytocannabinoid containing component comprises a monoterpene fraction and a sesquiterpene fraction, for use in the treatment of epilepsy.
[0061] In accordance with a fourth aspect of the present invention there is provided the use of a cannabis plant extract comprising a phytocannabinoid containing component and a non-phytocannabinoid containing component, wherein the phytocannabinoid containing component comprises at least 50% (w/w) of the cannabis plant extract and contains as a principle phytocannabinoid, CBDV and as a secondary phytocannabinoid, CBD, and wherein the non-phytocannabinoid containing component comprises a monoterpene fraction and a sesquiterpene fraction, in the manufacture of a medicament for use in the treatment of epilepsy.
[0062] Preferably the cannabis plant extract further comprises THCV.
[0063] Preferably the phytocannabinoid containing component comprises 64-78% (wlw) of the cannabis plant extract.
[0064] Preferably the phytocannabinoid containing component comprises 52-64% (w/w) CBDV of the total phytocannabinoid fraction, 22-27% (w/w) CBD of the total phytocannabinoid fraction and 3.9-4.7% (w/w) THCV of the total phytocannabinoid fraction.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which [0066] Figure 1 shows the effect of CBDV on onset and development of PTZ-induced seizures; [0067] Figure 2 shows the effects of CBDV on seizure severity and mortality; [0068] Figure 3 shows the effect of CBDV versus the anti-epileptic drug vaiproate on mortality and severity; [0069] Figure 4shows the effects of THCV BDS and 70mg/kg PTZ on latencies to initial and later seizure seventies; [0070] Figure 5 shows the effects of THCV BDS and 70mg/kg PTZ on seizure duration and time to death; [0071] Figure 6 shows the effects of THCV BDS and 70mg/kg PTZ on median severity scores; [0072] Figure 7 shows the effects of THCV BDS and 70mg/kg PTZ on mortality rates; [0073] Figure 8 shows the effects of THCV BDS and 80mg/kg PTZ on latencies to initial and later seizure seventies; [0074] Figure 9 shows the effects of THCV BDS and 80mg/kg PTZ on seizure duration and time to death; [0075] Figure 10 shows the effects of THCV BDS and 80mg/kg PTZ on median severity scores; [0076] Figure 11 shows the effects of THCV BDS and 80mg/kg PTZ on mortality rates; [0077] Figure 12A-D show PTZ-induced seizure development and duration with isolated THCV; and [0078] Figure 13A-B show the effect of CBD on PTZ-induced seizures.
[0079] Legend to Figure 1: A-C: mean latency to seizure onset (A), clonic (B) and tonic-clonic (C) seizures in s. Statistical significance was assessed by ANOVA and post hoc Tukey test, p«=0.05 was considered to be significant in both cases. Data is presented ± S.E.M., * indicates p<0.05.
[0080] Legend to Figure 2: A: Median severity of seizures (grey line), also shown is the 25th and 75th percentiles (black horizontal lines) and the maximum and minimum values (upward and downward error bars respectively). B: Proportion of animals in each group that developed tonic-clonic seizures. C: Proportion of animals in each group that died. D: Proportion of animals in each group that remained seizure free after PTZ administration. ** and indicate p«=0.05, 0.01 and 0.001 respectively. A: median data tested by ANOVA and post hoc Tukey's test. B-D: Percentages tested by binomial statistics test.
[0081] Legend to Figure 4: The mean latencies to first myoclonic jerk (FMJ) and scores of 3.5 are shown ± S.E.M. n = 8-10.
[0082] Legend to Figure 5: The mean durations of seizures in animals that survived, and the time from first seizure sign to death in those that died, are shown ± S.E.M. for vehicle or for low, medium or high doses n = 3-10 dependent on proportions of animals that died within experimental groups. I = vehicle group had no deaths and so no value is shown here.
[0083] Legend to Figure 6: Median severity scores for groups of animals treated with vehicle or with low, medium or high doses n = 10 for all groups.
[0084] Legend Figure 7: Mortality rates expressed as percentages for animals treated with vehicle or with low, medium or high doses. n 10 for all groups. I = vehicle group had no deaths, therefore no value is shown.
[0085] Legend to Figure 8: The mean latencies to first myoclonic jerk (FMJ) and scores of 3.5 are shown ± S.E.M. for vehicle or for low, medium or high doses. n = 7 -10.
[0086] Legend to Figure 9: The mean durations of seizures in animals that survived, and the time from first seizure sign to death in those that died, are shown ± S.E.M. for vehicle or for low, medium or high doses. n = 3 -7 dependent on proportions of animals that died within experimental groups.
[0087] Legend to Figure 10: Median severity scores for groups of animals treated with vehicle or with low, medium or high doses. n 10 for all groups.
[0088] Legend to Figure 11: Mortality rates expressed as percentages for animals treated with vehicle or with low, medium or high doses. n = 10 for all groups.
[0089] Legend to Figure 12: A, B and C show the mean latency (s) from injection of 80 mg/kg PTZ to: first sign of seizure (A); development of myoclonic seizures (B) and full tonic-clonic seizures (C) for vehicle and THCV-dosed groups. n=5-1 6 depending on incidence of each marker within a specific group). D shows the mean duration of seizures (s) in animals that survived post-seizure. All values ±S.E.M., * indicates significant difference from vehicle group (P<0.05; Mann-Whitney U test).
[0090] Legend to Figure 13: A: % mortality experienced as a result of IP injection of 80mg/kg PTZ in vehicle and CBD-dosed (1, 10,100mg/kg CBD) animals (n=15 for all groups). B: % of vehicle-and CBD-dosed (1, 10,100mg/kg CBD) animals that experienced tonic-clonic seizures as a result of IP injection of 80mg/kg PTZ. * indicates significant result (p<0.O1).
DETAILED DESCRIPTION
[0091] Examples 1 & 2 below describe the use of isolated CBDV in different models of epilepsy. Further examples will describe phytocannabinoid BDS which comprise along with the principle cannabinoid other secondary and minor cannabinoids along with a non-phytocannabinoid containing fraction.
Example 1
Use of isolated CBDV in two in vitro epileptiform models in hippocampal brain slices [0092] Hippocampal slices were produced acutely from P>21 Wistar rats and activity recorded by multi-electrode arrays (MEA).
[0093] To induce epileptiform activity, either Mg2 was removed (Mg2-free model) or 100pM 4-aminopyridine was added (4-AP model). 30 mm after epileptiform burst activity was established, CBDV was added cumulatively (1, 10, 100pM; 30 mm each).
[0094] The effects of CBDV on epileptiform burst amplitude and duration were measured
(Table 1.1).
[0095] Overall, CBDV at »=lOpM or 100pM significantly decreased burst duration and amplitude in both models with CAl and DG regions most sensitive and CA3 least sensitive to the anti-epileptiform effects of CBDV.
Table 1.1 Effects of CBDV on epileptiform activity induced in the Mg2 free and 4-AP models CBDV Burst amplitude (% of control) Burst duration (% of control) ____ (pM) DG CA3 CAl DG CA3 CAl Mg20 1 89.8±8.6 112.7±13.7 82.23±10.4 90.6±4.5 101.7±2.3 99.3±4.5 -free 10 86.4±3.6* 104.8±10.3 79.9±6.9** 92.0±3.2* 93.9±4.1 91.2±3.8* mode 100 ______ ______ 79.5±5.6** 102.9±13.0 80.4±8.0* 75.6±5.4** 78.5±6.6* 74.0±5.8** 4-AP 1 94.2±3.0 103.0±5.8 89.3±5.6 95.7±5.9 91.0±6.0 104.3±8.0 mode 10 91.2±4.9 121.9±17.0 88.3±5.2 83.8±4.4** 82.5±4.8* 85.9±6.2* _____ 100 95.9±4.3 110.3±7.0 89.5±5.3* 83.4±4.1** 79.7±5.4* 85.9±5.8* Data is mean ± S.E.M; * = p«=0.05 and ** = p«= 0.01 respectively, Wilcoxon paired test.
Data from 5 rats/model, n9-13 electrodes.
Example 2
Use of isolated CBDV in the PTZ model of generalised seizures Methodology: Animals: [0096] Male Wistar rats (P24-29; 75-1 1 Og) were used to assess the effects of the phytocannabinoid CBDV in the PTZ model of generalised seizures. Animals were habituated to the test environment, cages, injection protocol and handling prior to experimentation. Animals were housed in a room at 21°C on a 12 hour light: dark cycle (lights on 0900) in 50% humidity, with free access to food and water.
[0097] The human dose equivalent (HED) can be estimated using the following formula: HED = Animal dose (mg/kg) multiplied by Animal Km Human Km The Km for a rat is 6 and the Km for a human is 37.
Experimental setup: [0098] Five 6L Perspex tanks with lids were placed on a single bench with dividers between them. Closed-circuit television (CCTV) cameras were mounted onto the dividers to observe rat behaviour. Sony Topica CCD cameras (Bluecherry, USA) were linked via BNC cables to a low-noise PC via Brooktree digital capture cards (Bluecherry, USA). Zoneminder (http://www.zoneminder.com) software was used to monitor rats, start and end recordings and manage video files. In-house Linux scripts were used to encode video files into a suitable format for further offline analysis using The Observer (Noldus Technologies).
PTZ model: [0099] A range of doses of PTZ (50-1 00mg/kg body weight) were used to determine the best dose for induction of seizures (see below). As a result, a dose of 80mg/kg injected intra-peritoneally (IP; stock solution 50mg/mi in 0.9% saline) were used to screen the CBDV.
Experimental Protocols: [00100] On the day of testing, pure CBDV was administered via intra-peritoneal (i.p.) injection at doses of 50, 100 and 200 mg/kg alongside animals that were injected with a matched volume of the cannabinoid vehicle (2:1:17 ethanol:Cremophor: 0.9%w/v NaCI solution), which served as the negative control group. Animals were then observed for 1 hour, after which time they received an IP injection of 80mg/kg PTZ. Negative vehicle controls were performed in parallel with cannabinoid-dosed subjects. After receiving a dose of PTZ, animals were observed and videoed to determine the severity of seizure and latency to several seizure behaviour types (see in vivo analysis, below). Animals were filmed for half an hour after last sign of seizure, and then returned to their cage.
In vivo analysis: [00101] Animals were observed during experimental procedures, but all analysis was performed offline on recorded video files using The Observer behavioural analysis software (Noldus, Netherlands). A seizure severity scoring system was used to determine the levels of seizure experienced by subjects (PohI & Mares, 1987). All signs of seizure were detailed for all animals.
Table 2.1 Seizure severity scoring scale, adapted from PohI & Mares, 1987.
Seizure score Behavioural expression Righting reflex 0 No changes to behaviour Preserved 0.5 Abnormal behaviour (sniffing, excessive washing, Preserved orientation) 1 Isolated myoclonic jerks Preserved 2 Atypical clonic seizure Preserved 3 Fully developed bilateral forelimb clonus Preserved 3.5 Forelimb clonus with tonic component and body twist Preserved 4 Tonic-clonic seizure with suppressed tonic phase Lost Fully developed tonic-clonic seizure Lost 6 Death Latency from injection of PTZ to specific indicators of seizure development: [00102] The latency (in seconds) from injection of PTZ to first myoclonic jerk (FMJ; score of 1), and to the animal attaining "forelimb clonus with tonic component and body twist" (score of 3.5) were recorded. FMJ is an indicator of the onset of seizure activity, whilst >90% of animals developed scores of 3.5, and so is a good marker of the development of more severe seizures. Data are presented as the mean ± S.E.M. within an experimental group.
Maximum seizure severity: [00103] This is given as the median value for each experimental group based on the scoring scale below.
% mortality: [00104] The percentage of animals within an experimental group that died as a result of PTZ-induced seizures. Note that the majority of animals that developed tonic-clonic seizures (scores of 4 and 5) died as a result, and that a score of 6 (death) automatically denotes that the animal also experienced tonic-clonic seizures.
Seizure duration: [00105] The time (in seconds) from the first sign of seizure (typically FMJ) to either the last sign of seizure or, in the case of subjects that died, the time of death -separated into animals that survived and those that did not. This is given as the mean ± S.E.M. for each experimental group.
Statistics: [00106] For measures of latency and severity, one way analysis of variance (ANOVA) was performed on the four groups together (vehicle and 50, 100 and 200mg/kg CBDV) to detect overall effects of CBDV (p«=0.05 considered significant).
[00107] Significant ANOVA results were followed by post hoc tests to test differences between vehicle and drug groups (Tukey's test, p«=0.05 considered significant).
Results: [00108] Figure 1 illustrates the onset and development of seizures by showing the latency from administration of 80mg/kg PTZ to: the onset of seizure (Figure 1A); the development of clonic seizures (Figure 1 B) and the development of tonic-clonic seizures (Figure 10).
[00109] A significant effect of CBDV on the latency to seizure onset was observed (p=0.041; Figure 1A); this measure was significantly higher in animals that received 200mg/kg CBDV than those that received vehicle alone (p=0.03).
[00110] A near-significant (p=0.055) effect of CBDV on latency to clonic seizures was observed (Figure 1 B), highlighting a significant increase in animals administered 200mg/kg CBDV compared to vehicle-treated animals (pO.O32).
[00111] No significant effect of CBDV on latency to tonic-clonic seizures overall or at any specific dose was observed (Figure 10) in spite of a large difference in mean value between vehicle and 200mg/kg CBDV groups; this is likely to be due to the low number of animals treated with 200mg/kg CBDV that developed these seizures [00112] The severity of seizures experienced by animals in the different groups was also assessed using four measures: median severity (Figure 2A); proportion of animals that had tonic-clonic seizures (the most severe seizure type; Figure 2B); the percentage mortality (Figure 20) and finally the proportion of animals that remained seizure free after PTZ administration (Figure 2D).
[00113] There was an overall significant effect of CBDV on seizure severity (p=0.007; Figure 2A); animals treated with 200mg/kg CBDV had a significantly lower median severity than those treated with vehicle alone (p=0014).
[00114] This was reflected in a lower proportion of animals treated with 200mg/kg CBDV reaching the most severe (tonic-clonic) seizures (3 of 15) compared to vehicle-treated animals (8 of 15; Figure 2B; p=0.01).
[00115] This significant effect was maintained in animals treated with 100mg/kg CBDV (4 of tonic-clonic seizures; p0.036), but not 50mg/kg.
[00116] A significantly lower proportion of animals treated with 100 and 200mg/kg CBDV (1 and 2 out of 15 respectively) died compared to the vehicle-treated group (8 of 15; p=0.002 and <0.001 respectively; Figure 20).
[00117] Finally, a significantly higher percentage of animals treated with 200mg/kg CBDV experienced no seizure at all (5 of 15) compared to the vehicle group (1 of 15; p=0.003; Figure 2D).
[00118] In a further experiment the CBDV was tested against a standard anti-epileptic drug valproate. Figure 3 details the data obtained. The CBDV gave a similar results to valproate for mortality, however significantly CBDV was able to lessen the severity of the epilepsy to a greater degree than the existing epileptic drug valproate.
Conclusion:
[00119] From the above data it would appear that CBDV shows promise as an anti-epileptic agent. Indeed, the fact that CBDV was more effective than valproate is very interesting and means that CBDV shows great potential as an anti-epileptic drug.
Example 3
[00120] As described in the following example, CBDV BDS comprises, as well as CBDV, the cannabinoids CBD and THCV. Given the finding disclosed in GB0911580.9 make it potentially more interesting than isolated CBDV as the BDS comprises three anti-epileptic compounds and unlike THCV BDS has very low amounts of THC.
Cannabidivarin (CBDV) botanical drug substance analysis [00121] A CBDV BDS can be obtained from extraction of CBDV-rich plants. Such chemovars are bred specifically to produce a significant proportion of their cannabinoids as CBDV.
[00122] CBDV BDS can also be prepared by adding isolated CBDV to a cannabinoid free BDS. Such a cannabinoid free BDS can be prepared from either a CBG BDS or a zero cannabinoid plant such as USO-31. Because CBG is the major cannabinoid present in CBG BDS it is possible to remove the CBG present relatively easily using standard techniques known in the art such as column chromatography. It is possible to fractionate the BDS completely so that individual compounds can be removed for purification and the remainder recombined to produce, following solvent removal, a BDS free of the selected compound(s).
[00123] The CBDV chemotype results from the breeding of plants which carry both postulated BD and ApR genes.
[00124] The BD gene instruct the plants to synthesize the cyclic part of the CBD molecule and the APR gene instructs the plant to synthesize this molecule with a propyl side chain, as opposed to the usual pentyl chain found in CBD.
[00125] A CBDV chemovar has been bred and the BDS analysed as described in Table 3.1 below: Table 3.1 Cannabidivarin BDS amount in total and range Range Range Range CBDVBDS Amount (% wiw) (± 10%) (± 25%) (± 50%) CBDVA 0.14 0.13-0.15 0.11 -0.18 0.07-0.21 CBDV 41.19 37.07 -45.31 30.89 -51.49 20.60 -61.79 CBDA 0.07 0.06 -0.08 0.05 -0.09 0.04 -0.11 CBG 0.59 0.53 -0.65 0.44 -0.74 0.30 -0.89 CBD 17.70 15.93-19.47 13.28-22.13 8.85-26.55 THCV 3.06 2.75-6.12 2.30-3.83 1.53-4.59 CBCV 4.35 3.92-4.79 3.26-5.44 2.18-6.53 THC 0.88 0.79-0.97 0.66-1.10 0.44-1.32 CBDV (related 1.98-2.42 1.65-2.75 1.10-3.30 substances) 2.20 CBC 0.93 0.84-1.02 0.70-1.16 0.47-1.40 Total Cannabinoids 71.11 Total Non-cannabinoids 28.89 [00126] The total phytocannabinoid containing fraction of CBDV BDS comprises approximately 41% of the total BDS. According to variation this fraction may vary by ± 10% up to ± 50%.
Table 3.2 Cannabidivarin BDS by percentage cannabinoid Amount
CBDV BDS
(% of total cannabinoid) CBDVA 0.20 CBDV 57.92 CBDA 0.10 CBG 0.83 CBD 24.89 THCV 4.30 CBCV 6.12 THC 1.24 CBDV (related substances) 3.09 CBC 1.31 [00127] The amount of the principle phytocannabinoid in the CBDV BDS as a percentage of the phytocannabinoid containing fraction is approximately 58%. According to variation this fraction may vary by ± 10% up to ± 50%.
[00128] In this Example it is intended that references be made to the principle or secondary components independently of the other' cannabinoids.
[00129] The finding that the CBDV BDS comprises the known anti-epileptic phytocannabinoids CBD and THCV in relatively large amounts and relatively little THC, as compared to THCV extract below infers that the use of CBDV in the form of a BDS will be a promising new treatment for epilepsy.
Tetrahydrocannabivari n (THCV) botanical drug substance analysis [00130] Table 3.3 below details the cannabinoid components of THCV BDS, as can be seen the secondary cannabinoid is THC and is present at a significant amount in comparison to the other cannabinoids.
Table 3.3 Tetrahydrocannabivarin BDS amount in total and range Range Range Range THCVBDS Amount (% wiw) (± 10%) (± 25%) (± 50%) CBGV 0.15 0.14-0.17 0.11 -0.19 0.07-0.23 CBNV 1.30 1.20 -1.40 1.00 -1.60 0.65 -1.95 THCV 64.49 58.04 -70.94 48.37 -80.61 32.25 -96.74 CBCV 0.65 0.59 -0.72 0.49 -0.81 0.33 -0.98 THC-C4 0.82 0.74 -0.90 0.62 -1.03 0.41 -1.23 CBN 0.15 0.14-0.17 0.11 -0.19 0.07-0.23 THCVA 0.36 0.32-0.40 0.27-0.45 0.18-0.54 THC 13.43 12.09-14.77 10.07-16.79 7.72-20.15 Unknowns 0.58 0.52 -0.64 0.44 -0.73 0.29 -0.87 Total Cannabinoids 81.93 Total Non-cannabinoids 18.07 [00131] The total phytocannabinoid containing fraction of THCV BDS comprises approximately 74-90% (wlw) of the total BDS.
Table 3.4 Tetrahydrocannabivarin BDS by percentage cannabinoid THCVBDS Amount (% of total cannabinoid) CBGV 0.18 CBNV 1.59 THCV 78.71 CBCV 0.79 THC-C4 1.00 CBN 0.18 THCVA 0.44 THC 16.39 Unknowns 0.71 [00132] The amount of the principle phytocannabinoid in the THCV BDS as a percentage of the phytocannabinoid containing fraction is approximately 71-87% (wlw). The THCV BDS also has a secondary cannabinoid THC which is present at approximately 14.8-18% (wlw) of the phytocannabinoid containing fraction.
Non-cannabinoid containing components [00133] The non-cannabinoid components of a phytocannabinoid BDS may play an important role in the BDS's pharmacology. As such the terpene profile is classified below. The following tables illustrate the terpene profile of a CBD chemovar which is representative of a high phytocannabinoid containing plant. Five plants were freshly harvested and extracted using steam distillation. The principle monoterpene and sesquiterpene are highlighted in bold.
Table 3.5 Monoterpene amount by percentage of total terpene fraction and ranges Amount Range Range Range Monoterpenes (% of (± 10%) (± 25%) (± 50%) terpene fraction) Pinene (alpha & beta) 10.56 9.50 -11.62 7.92 -13.20 5.28 -15.84 Myrcene 39.46 35.51 -43.41 29.60-49.33 19.73-59.19 Limonene 4.14 3.73-4.55 3.11 -5.18 2.07-6.21 Beta-ocimene 4.04 3.64 -4.44 3.03 -5.05 2.02 -6.06 Total 58.20 [00134] The monoterpene containing fraction comprises approximately 52-64% (wlw) of the total terpene fraction.
Table 3.6 Monoterpene amount by percentage of monoterpenes Amount Monoterpenes (% of monoterpene fraction) Pinene (alpha & beta) 18.14 Myrcene 67.80 Limonene 7.12 Beta-ocimene 6.94 [00135] The amount of the principle monoterpene myrcene in the monoterpene fraction as a percentage of the monoterpene fraction is approximately 61-75% (wlw). The monoterpene fraction also has a secondary monoterpene pinene which is present at approximately 16.3- 20% (wlw) of the monoterpene fraction.
Table 3.7 Sesquiterpene amount by percentage of total terpene fraction and ranges Amount Range Range Range Sesquiterpenes (% of (± 10%) (± 25%) (± 50%) terpene fraction) Caryophyllenes (t & oxide) 29.27 26.34-32.20 21.95-36.59 14.64-43.91 Bergotamene 0.18 0.16-0.20 0.14-0.23 0.09-0.27 Humulene 7.97 7.17-8.77 5.98-9.96 3.99-11.96 Aromadendrene 0.33 0.30-0.36 0.25-0.41 0.17-0.50 Selinene 0.59 0.53 -0.65 0.44 -0.74 0.30 -0.89 Anon 0.44 0.40 -0.48 0.33 -0.55 0.22 -0.66 Farnesene (Z,E & alpha) 1.55 1.40-1.71 1.16-1.94 0.78-2.33 alpha Gurjunene 0.12 0.11 -0.13 0.09-0.15 0.06-0.18 Bisabolene 0.39 0.35 -0.43 0.29 -0.49 0.20 -0.59 Nerolidol 0.43 0.39 -0.47 0.32 -0.54 0.22 -0.65 Diepicedrene-1-oxide 0.38 0.34-0.42 0.29-0.48 0.19-0.57 Alpha-Bisabolol 0.16 0.14-0.18 0.12-0.20 0.08-0.24 Total 41.80 [001 36] The sesquiterpene containing fraction comprises approximately 27-32% (wlw) of the total terpene fraction.
Table 3.8 Sesquiterpene amount by percentage of sesquiterpenes Amount Sesquiterpenes (°Io of sesquiterpene fraction) Caryophyllenes (t & oxide) 70.02 Bergotamene 0.43 Humulene 19.07 Aromadendrene 0.79 Selinene 1.41 Anon 1.05 Farnesene (Z,E & alpha) 3.71 alpha Gurjunene 0.29 Bisabolene 0.93 Nerolidol 1.03 Diepicedrene-1-oxide 0.91 Alpha-Bisabolol 0.38 [00137] Patent application number PCT1GB20081001837 describes the production of a zero cannabinoid' plant. These plants were produced by selective breeding to produce a Cannabis sativa L plant that contained a generally qualitatively similar terpene profile as a Cannabis sativa L plant that produced cannabinoids yet it was devoid of any cannabinoids. These plants can be used to produce cannabinoid-free plant extracts which are useful control plants in experiments and clinical trials. A breakdown of the terpene profile produced in the plants can be found in the table below. The primary monoterpenes and sesquiterpene are highlighted in bold.
Table 3.9 Monoterpene amount by percentage of total terpene fraction and ranges Amount Range Range Range Monoterpenes (% of (± 10%) (± 25%) (± 50%) terpene fraction) Pinene (alpha & beta) 29.34 26.41 -32.27 22.01 -36.68 14.67 -44.01 Myrcene 29.26 26.33-32.19 21.95-36.58 14.63-43.89 Limonene 5.32 4.79 -5.85 3.99 -6.65 2.66 -7.98 Linalol 4.50 4.05 -4.95 3.38 -5.63 2.25 -6.75 Verbenol(cis&trans) 3.45 3.11 -3.80 2.59-4.31 1.73-5.18 Total 71.87 [00138] The monoterpene containing fraction comprises approximately 65-79% (wlw) of the total terpene fraction.
Table 3.10 Monoterpene amount by percentage of monoterpenes Amount Monoterpenes (% of monoterpene fraction) Pinene (alpha & beta) 40.82 Myrcene 40.71 Limonene 7.41 Linalol 6.26 [00139] The zero cannabinoid plant was found to comprise two principle monoterpenes; pinene and myrcene. The amount of the principle monoterpene myrcene in the monoterpene fraction as a percentage of the monoterpene fraction is approximately 37-45% (wlw). The amount of the principle monoterpene pinene in the monoterpene fraction as a percentage of the monoterpene fraction is approximately 37-45% (wlw).
Example 4
Use of THCV (BDS), isolated THCV and isolated CBD in models of epilepsy [00140] The data demonstrating the activity of THCV BDS and isolated THCV and CBD are given below in support of the likely benefit of a CBDV extract containing CBD and THCV as well as a non-cannabinoid fraction.
[00141] General methodology is as described in Example 2 Results: [00142] The THCV BDS comprised a whole extract of a chemovar in which THCV was the predominant cannabinoid. (i.e. it was the major cannabinoid present in the extract, 80% by weight of the total cannabinoid content). THC was the second most prevalent cannabinoid, and was present in significant amounts. (i.e. it comprised greater than 10% by weight of the total cannabinoid content, being present at about 16%), and there were a number of minor cannabinoids identified, each comprising less than 2% by weight of the total cannabinoid content as measured by HPLC analysis. The ratio of THCV to THC in this extract is about 5:1.
[00143] In fact the THCV content was 67.5% by weight of the extract and the THC content was 13.6% by weight of the extract, with the other identified cannabinoids in total comprising about 3% by weight of the extract, the remaining 16% comprising non-cannabinoids.
PTZpilotstudy [00144] Seizures induced by a range of PTZ concentrations (50-100mg/kg; the range present in the literature) in rats were investigated to determine an optimal dose prior to the investigation of the cannabinoid effect. PTZ doses of: * 50mg/kg and 60mg/kg induced very little seizure-like activity (n=4); * 70mg/kg typically induced clonic seizures (score of 3.5; 8 of 13 subjects); * 80mg/kg regularly induced tonic-clonic seizures (scores of 4 and 5; 6 of 10 subjects).
[00145] Additionally, it was found that repeated dosing with PTZ resulted in increased sensitivity over time; therefore no experiments were performed on animals that had already received a dose of PTZ.
[00146] The effect of THCV BDS on PTZ-induced seizures was first assessed against a PTZ dose of 70 mg/kg. As described below, this yielded a vehicle control group that did not typically experience severe seizure scores. Therefore THCV BDS was also screened against an 80mg/kg dose of PTZ. It was felt that the increased seizure severity experienced by vehicle control animals exposed to 80mg/kg PTZ was a more appropriate test of potential anti-convulsant activity.
Effect of THCV BDS on moderately severe (70mg/kg) PTZinduced seizures [00147] Three doses of THCV BDS were assessed against a concentration of PTZ known to induce moderate seizures in rats (70mg/kg; see pilot, above). The low, medium and high doses of THCV BDS used were 0.37, 3.70 and 37.04mg/kg, and yielded actual THCV doses of 0.25, 2.5 and 25mg/kg respectively. These doses were matched by THCV content to those being used for screening pure THCV against PTZ-induced seizures.
[00148] THCV BDS did not have any significant effects on latency to first myoclonic jerk or on latency to attaining a severity score of 3.5 on the seizure severity scale (Figure 4). It should be noted that although values for both these variables were higher for animals treated with medium and high dose THCV BDS compared to control, this failed to reach significance (P>0.05). Similarly, no significant impact on duration of seizure was seen (Figure 5).
[00149] The effects of THCV BDS on seizure severity (Figure 6) and mortality (Figure 7) in animals that received doses of 70mg/kg PTZ did not conform to a simple pattern. No animal injected with vehicle-alone exceeded the median severity score of 3.5 for that group, and no animals died (n = 10).
[00150] In contrast, 70mg/kg PTZ induced severe tonic-clonic seizures and death in 50% of animals injected with a low dose of THCV BDS, demonstrating a median severity score of 4.75. This increase in severity was not significant. However, animals injected with medium and high doses of THCV BDS exhibited a lower median severity score and lower mortality rates than those exposed to low doses (Figures 6 & 7). Medium and high dose mortality rates were higher than that of the vehicle group, but not significantly so (P>0.05; Figure 7). However, median severity scores were the same between medium & high doses (Figure 6). This pattern of results suggested that a further set of experiments, in which THCV BDS was screened against a dose of PTZ which would induce severe seizures in control (vehicle-treated) animals, was required.
Effect of THCV BDS on severe (80mg/kg) PTZ-induced seizures [00151] The effects of the same three doses of THCV BDS on seizures induced by 80mg/kg PTZ were assessed. It is worth noting that 80mg/kg induced significantly more severe seizures than 70 mg/kg in vehicle control groups (P = 0.009), with median seizure severity scores of 6 and 3.5 respectively. THCV BDS did not have a significant effect on latencies to FMJ or a severity score of 3.5 (Figure 8). Similarly, no effect was observed on seizure durations (Figure 9).
[00152] Low dose THCV BDS decreased both seizure severity (Figure 10) and mortality (Figure 11) in animals that received doses of 80mg/kg PTZ. Animals that received low THCV BDS had a lower median severity score (3.5 compared to 6) than vehicle controls. However, this difference was not significant (P>0.5). The low THCV BDS dose group also had a mortality rate half that of the vehicle control group (30% vs 60%).
[00153] Groups treated with medium and high doses of THCV BDS had a lower seizure severity score of 4.75 (P>0.5 vs control), and a lower mortality rate of 50%, compared to 6 and 60% respectively.
In vivo summary and conclusion
[00154] Screening of THCV BDS in the PTZ model did not appear to have any significant anti-or pro-convulsant effects on either moderate or severe PTZ-induced seizures. However, a trend towards lower severity and mortality was seen in animals that received a low dose of THCV BDS prior to induction of severe (80mg/kg PTZ) seizures, compared to vehicle controls.
[00155] It is possible that this effect is masked at higher doses of THCV BDS by higher levels of other cannabinoid constituents (such as THC) present in the non-THCV content of the THCV 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.
Isolated THCV: Effect of isolated THCV against PTZ-induced seizures [00156] Low (0.025 mg/kg), medium (0.25 mg/kg) and high (2.5 mg/kg) doses of pure THCV were assessed for their effects on PTZ-induced seizures. It is worth noting at this point, for comparisons to THCV BDS, that differing doses of pure THCV were used compared to THCV BDS. See Table 4.1 below.
Table 4.1. Comparison of THCV BDS and pure THCV doses used in PTZ model Test CB "low" dose (mg/kg) "medium" dose (mg/kg) "high" dose (mg/kg) THCV 025 2.5 25
BDS
Pure 0025 0.25 2.5
TH CV
Values given are for effective THCV content of doses (therefore actual doses of THCV BDS are approx 1.5 times larger).
[00157] 80 mg/kg PTZ successfully induced seizures of varying seventies in animals from all 4 experimental groups (n=1 6 per group). PTZ-induced seizures led to the death of 44% of animals that received vehicle alone. Groups that received low, medium and high THCV all exhibited lower mortality rates of 41%, 33% and 38% respectively; however these values were not significantly different from that of the vehicle group (p>0.05, binomial test).
[00158] The mean values for latency to first seizure sign, and to scores of [3] and [5] on the seizure scoring scale used, as well as the duration of seizure for surviving animals, are described in Figures 12A-D.
[00159] It can be seen that seizures started later, as shown by increased latency to first manifestation of seizure-like behaviour (Figure 12A) in animals that received THCV compared to vehicle controls.
[00160] The delay of onset was significant at the highest dose of THCV (p=O.O2). A similar pattern was seen for latencies to scores of [3] and [5] (Figures 12B and 120) with all THCV doses exhibiting increased latencies, reaching a significant level at the highest dose of THCV (p=0.017 and 0.013 for [3] and [5] respectively).
[00161] It was also observed that duration of PTZ-induced seizures in animals that survived the experimental period were significantly shorter after administration of the medium dose of THCV compared to vehicle controls (Figure 12D; p0.03).
Table 4.2 below displays the values for median seizure severity in each experimental group.
Table 4.2: Seizure severity and incidence Vehicle 0.025 mg/kg 0.25 mg/kg 2.5 mg/kg THCV
THCV THCV
Median severity 4.25 3.5 3.5 3.5 % no seizure 12.5 5.9 333* 18.8 [00162] The median maximum seventies and % of animals that did not experience any signs of seizure for each experimental group are given (n=16 for each value). * indicates significant difference from vehicle group (binomial significance test, P<0.05).
[00163] Vehicle control animals exhibited a median seizure severity of 4.25, whereas all groups which received THCV had a median severity score of 3.5. This decrease was not significantly different.
[00164] 12.5% vehicle control animals displayed no indicators of seizure, suggesting these animals did not develop seizures after PTZ administration. A significantly higher number of animals (33.3%) displayed no signs of seizure in the group that received 0.25 mg/kg (Table 4.2; p = 0.031). This data suggests that the medium dose of 0.25 mg/kg THCV protected against the development of seizures.
In vivo summary and conclusion
[00165] The effects of the high dose of THCV on latency values suggest that THCV can delay both onset and seizure development, whilst the significant effects of the medium dose on the incidence of seizure at medium (0.25 mg/kg) THCV doses suggest a significant anticonvulsive action on PTZ-induced seizures.
Isolated CBD [00166] In addition to THCV, CBD was also screened in the PTZ model. The results strongly indicate that CBD (at levels of 100mg/kg) in this model is anti-convulsant as it significantly decreased the mortality rate and incidence of the most severe seizures compared to vehicle control animals.
Effect of isolated CBD against PTZ-induced seizures [00167] Isolated CBDwas injected intra-peritoneally (IP) in the standard vehicle (1:1:18 ethanol: Cremophor: 0.9%w/v NaCI) at doses of 1, 10 and 100mg/kg alongside animals that received vehicle alone at a matched volume (n=15 for each group). 60 minutes later PTZ (80mg/kg, IP) was administered.
[00168] 46.7% of control animals that received vehicle alone died within 30 minutes of PTZ administration (Figure 13). In contrast only 6.7% (only 1 of 15) of animals that received 100mg/kg CBD died, a marked reduction that proved to be significant (p<0.001).
[00169] Additionally only 6.7% of animals that received 100mg/kg CBD experienced the most severe seizures (score of 5) in comparison to 53.3% of vehicle control animals, a decrease that was also significant (p<0.001; Figure 13 in vivo).
[00170] In contrast to isolated THCV, no significant increases in latency of seizure development were observed. However, the marked and significant reductions indicate a striking anti-convulsant effect on PTZ-induced seizures.
In vivo summary and conclusion
[00171] Screening and analysis of isolated CBD in the PTZ model at high dose (100mg/kg) of CBD on mortality levels and incidence of the most severe seizures suggests that CBD can attenuate the severity of PTZ-induced seizures.
Overall conclusion
[00172] From the three studies it would appear that both isolated THCV and CBD show promise as an anti-epileptic for generalized seizure, particularly clonic/ tonic seizure. The data generated for a THCV rich extract, containing other cannabinoids including significant amounts of THC, suggest that the THC may be countering the effect of the THCV and that a cannabinoid extract which contains THCV as a major or predominant cannabinoid, but which also contains minimal, or substantially no, THC would be desirable for treating epilepsy.
Furthermore the results with pure CBD suggest that an extract containing significant amounts of both THCV and CBD, but again, minimal or substantially no THC may provide an optimum combination. Accordingly it may prove desirable to prepare a THCV predominant extract in which THC is selectively, and substantially, removed (to levels of less than a few percent). This could be mixed with a CBD rich extract in which CBD is the major and predominant cannabinoid (also with low levels of THC) to produce an extract with clearly defined, and significant levels of both THCV and CBD, but with insignificant levels of THC. Such an extract may contain other cannabinoids and the non-cannabinoid components which result from extraction, by for example, carbon dioxide as disclosed in W004/016277, which components may support an "entourage" effect in the endocannabinoid system.
[00173] On dosage, a rat! human conversion factor (x6) suggests a CBD daily dose of at least 600mg (and optionally between 400mg and 800mg) and for THCV at least 1.5mg (medium) and preferably at least 15mg (high).
[00174] Where a phytocannabinoid extract is to be used, an extract with low or negligible levels of THC and therapeutically effective levels of THCV and! or CBD is desired.
Claims (17)
- CLAIMS1. The phytocannabinoid CBDV for use in the treatment of epilepsy.
- 2. The use of the phytocannabinoid CBDV in the manufacture of a medicament for use in the treatment of epilepsy.
- 3. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in claim 1 or claim 2, wherein the type of epilepsy to be treated is generalised seizure.
- 4. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in any of the preceding claims, wherein the CBDV is used with one or more therapeutically effective phytocannabinoids.
- 5. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in claim 4, wherein the one or more therapeutically effective phytocannabinoids is THCV.
- 6. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed claim 4, wherein the one or more therapeutically effective phytocannabinoids is CBD.
- 7. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in claims 4 to 6, wherein the one or more therapeutically effective phytocannabinoids are THCV and CBD.
- 8. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in any of the preceding claims, wherein the CBDV is in an isolated form.
- 9. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in any of the preceding claims, wherein the CBDV is in the form of a botanical drug substance.
- 10. The phytocannabinoid or the use of the phytocannabinoid CBDV as claimed in any of the preceding claims, wherein the CBDV is used in combination with a standard anti-epileptic drug.
- 11. A cannabis plant extract comprising a phytocannabinoid containing component and a non-phytocannabinoid containing component, wherein the phytocannabinoid containing component comprises at least 50% (wlw) of the cannabis plant extract and contains as a principle phytocannabinoid, CBDV and as a secondary phytocannabinoid, CBD, and wherein the non-phytocannabinoid containing component comprises a monoterpene fraction and a sesquiterpene fraction, for use in the treatment of epilepsy.
- 12. The use of a cannabis plant extract comprising a phytocannabinoid containing component and a non-phytocannabinoid containing component, wherein the phytocannabinoid containing component comprises at least 50% (wlw) of the cannabis plant extract and contains as a principle phytocannabinoid, CBDV and as a secondary phytocannabinoid, CBD, and wherein the non-phytocannabinoid containing component comprises a monoterpene fraction and a sesquiterpene fraction, in the manufacture of a medicament for use in the treatment of epilepsy.
- 13. A cannabis plant extract or the use of a cannabis plant extract as claimed in claim 11 or 12, which further comprises THCV.
- 14. A cannabis plant extract or the use of a cannabis plant extract as claimed in any of claims 11 to 13, wherein the phytocannabinoid containing component comprises 64-78% (wlw) of the cannabis plant extract.
- 15. A cannabis plant extract or the use of a cannabis plant extract as claimed in claim 14, comprising 52-64% (wlw) CBDV of the total phytocannabinoid fraction.
- 16. A cannabis plant extract or the use of a cannabis plant extract as claimed in claim 15, comprising 22-27% (wlw) CBD of the total phytocannabinoid fraction.
- 17. A cannabis plant extract or the use of a cannabis plant extract as claimed in claim 15, comprising 3.9-4.7% (wlw) THCV of the total phytocannabinoid fraction.
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GB1005364.3A GB2479153B (en) | 2010-03-30 | 2010-03-30 | The phytocannabinoid cannabidivarin (CBDV) for use in the treatment of epilepsy |
TW100108735A TWI583374B (en) | 2010-03-30 | 2011-03-15 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
ARP110101014 AR080730A1 (en) | 2010-03-30 | 2011-03-28 | USE OF CANABIDIVARINE PHYTOCHANABINOID (CBDV) IN THE TREATMENT OF EPILEPSY |
EP20194696.9A EP3763361B1 (en) | 2010-03-30 | 2011-03-30 | Cannabidivarin (cbdv) for use in the treatment of epilepsy |
JP2013501945A JP5918748B2 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivine (CBDV) in the treatment of epilepsy |
SG2012070793A SG184236A1 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
EP11712658A EP2552430A1 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
MYPI2012004222A MY162129A (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
PCT/GB2011/050649 WO2011121351A1 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
CA2794620A CA2794620C (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
NZ60292511A NZ602925A (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
SG10201502480XA SG10201502480XA (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
CN201180026947.4A CN103025325B (en) | 2010-03-30 | 2011-03-30 | The purposes of plant cannabinoids cannabidivarin CBDV Cannabidivarol (CBDV) in treatment epilepsy |
BR112012024480A BR112012024480A8 (en) | 2010-03-30 | 2011-03-30 | USE OF THE PHYTOCANABINOID CANNABIDIVARIN (CBDV) IN THE TREATMENT OF EPILEPSY |
AU2011234225A AU2011234225B2 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
US13/075,873 US9125859B2 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
MX2012011033A MX2012011033A (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy. |
KR1020127028091A KR101849703B1 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
EA201290975A EA036044B1 (en) | 2010-03-30 | 2011-03-30 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
IL222132A IL222132B (en) | 2010-03-30 | 2012-09-24 | Use of cannabidivarin for the preparation of medicaments for treating epilepsy or epileptic seizures |
ZA2012/08141A ZA201208141B (en) | 2010-03-30 | 2012-10-29 | Use of the phytocannabinoid cannabidivarin (cbdv) in the treatment of epilepsy |
US14/685,753 US10799467B2 (en) | 2010-03-30 | 2015-04-14 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
AU2016244223A AU2016244223A1 (en) | 2010-03-30 | 2016-10-11 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
AU2018217303A AU2018217303A1 (en) | 2010-03-30 | 2018-08-17 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
US17/012,448 US12023305B2 (en) | 2010-03-30 | 2020-09-04 | Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy |
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GB1005364.3A GB2479153B (en) | 2010-03-30 | 2010-03-30 | The phytocannabinoid cannabidivarin (CBDV) for use in the treatment of epilepsy |
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