U.S. patent application number 13/977766 was filed with the patent office on 2014-06-05 for use of the phytocannabinoid cannabidiol (cbd) in combination with a standard anti-epileptic drug (saed) in the treatment of epilepsy.
This patent application is currently assigned to Otsuka Pharmaceutical Co., Limited. The applicant listed for this patent is Gary Stephens, Ben Whalley, Claire Williams. Invention is credited to Gary Stephens, Ben Whalley, Claire Williams.
Application Number | 20140155456 13/977766 |
Document ID | / |
Family ID | 43639013 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140155456 |
Kind Code |
A9 |
Whalley; Ben ; et
al. |
June 5, 2014 |
USE OF THE PHYTOCANNABINOID CANNABIDIOL (CBD) IN COMBINATION WITH A
STANDARD ANTI-EPILEPTIC DRUG (SAED) IN THE TREATMENT OF
EPILEPSY
Abstract
The invention relates to the use of cannabidiol (CBD), at a dose
of greater than 300 mg/day, in combination with a standard
anti-epileptic drug (SAED) which acts via sodium or calcium
channels, for use in the treatment of epilepsy. The SAED is
preferably one which.cndot.modifies low-threshold or transient
neuronal calcium currents,or.cndot.reduces high-frequency neuronal
firing and sodium-dependent action potentials and enhances GABA
effects. Preferred SAEDs are ethosuximide and valproate.
Inventors: |
Whalley; Ben; (Reading,
GB) ; Williams; Claire; (Reading, GB) ;
Stephens; Gary; (Reading, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Whalley; Ben
Williams; Claire
Stephens; Gary |
Reading
Reading
Reading |
|
GB
GB
GB |
|
|
Assignee: |
Otsuka Pharmaceutical Co.,
Limited
Tokyo
JP
GW Pharma Limited
Salisbury
GB
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130296398 A1 |
November 7, 2013 |
|
|
Family ID: |
43639013 |
Appl. No.: |
13/977766 |
Filed: |
January 3, 2012 |
PCT Filed: |
January 3, 2012 |
PCT NO: |
PCT/GB2012/050002 PCKC 00 |
371 Date: |
July 1, 2013 |
Current U.S.
Class: |
514/425; 514/557;
514/736 |
Current CPC
Class: |
A61K 31/05 20130101;
A61K 31/515 20130101; A61K 45/06 20130101; A61P 25/08 20180101;
A61K 31/4015 20130101; A61K 31/352 20130101; A61K 36/00 20130101;
A61K 31/19 20130101; A61K 31/05 20130101; A61K 2300/00 20130101;
A61K 31/19 20130101; A61K 2300/00 20130101; A61K 31/4015 20130101;
A61K 2300/00 20130101; A61K 31/515 20130101; A61K 2300/00 20130101;
A61K 31/352 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/425; 514/736;
514/557 |
International
Class: |
A61K 31/05 20060101
A61K031/05; A61K 31/4015 20060101 A61K031/4015; A61K 31/19 20060101
A61K031/19; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 4, 2011 |
GB |
1100043.7 |
Claims
1. A method for treating epilepsy comprising administering to a
subject in need thereof cannabidiol (CBD), at a dose of greater
than 300 mg/day, in combination with a standard anti-epileptic drug
(SAED) which acts via sodium or calcium channels.
2. (canceled)
3. The method of claim 1, wherein the SAED is a drug which:
modifies low-threshold or transient neuronal calcium currents, or
reduces high-frequency neuronal firing and sodium-dependent action
potentials and enhances GABA effects.
4. The method of claim 1, wherein the SAED is selected from the
group consisting of: ethosuximide and valproate.
5. The method of claim 1, wherein the type of epilepsy to be
treated is generalised seizure or temporal lobe seizure.
6. The method of claim 1, wherein the type of epilepsy to be
treated is refractory to existing medication.
7. The method of claim 1, wherein the CBD is used with one or more
other therapeutically effective phytocannabinoids.
8. The method of claim 7, wherein the one or more other
therapeutically effective phytocannabinoid is THCV and/or CBDV.
9. The method of claim 1, wherein the CBD is an isolated
phytocannabinoid.
10. The method of claim 1, wherein the CBD is in the form of a
botanical drug substance.
11. (canceled)
12. A combination product comprising cannabidiol (CBD), at a dose
of greater than 300 mg/day, and a standard anti-epileptic drug
(SAED) which acts via sodium or calcium channels.
Description
[0001] This invention relates to the use of the phytocannabinoid
cannabidiol (CBD) in combination with a standard anti-epileptic
drug (SAED). Preferably the CBD is used in combination with a SAED
with a mechanism of action which acts via sodium or calcium
channels, more preferably one which: [0002] modifies low-threshold
or transient neuronal calcium currents, as exemplified by
ethosuximide; or [0003] reduces high-frequency neuronal firing and
sodium-dependent action potentials and may additionally enhance
GABA effects, as exemplified by valproate.
BACKGROUND
[0004] Epilepsy is a chronic neurological disorder presenting a
wide spectrum of diseases that affect 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).
[0005] 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).
[0006] In 1975 Consroe et al. described the case of young man whose
standard treatment (phenobarbitol 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`.
[0007] 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.
[0008] Three controlled trials have investigated the anti-epilepsy
potential of cannabidiol. In each, cannabidiol was given in oral
form to sufferers of generalised grand mal or focal seizures.
[0009] 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 200-300 mg 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.
[0010] Ames (1986) reported a less successful study in which 12
epileptic patients were given 200-300 mg of cannabidiol per day, in
addition to standard antiepileptic drugs. There seemed to be no
significant improvement in seizure frequency.
[0011] Trembly et al (1990) performed an open trial with a single
patient who was given 900-1200 mg of cannabidiol a day for 10
months. Seizure frequency was markedly reduced in this single
patient.
[0012] 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.
[0013] In WO 2006/054057 it is suggested that the cannabinoid
Tetrahydrocannabivarin (THCV) may behave as anti epileptic,
something confirmed by Thomas et al 2005.
[0014] 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.
[0015] 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.
[0016] 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:
[0017] a. Partial, and [0018] b. 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).
[0019] 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).
[0020] The league also categorized generalised seizures into
numerous clinical seizure types, some examples of which are
outlined below:
[0021] 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).
[0022] 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.
[0023] 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).
[0024] 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: [0025] mental health
problems (e.g. prevention of normal glutamatergic synapse
development in childhood); [0026] cognitive deficits (e.g.
diminishing ability of neuronal circuits in the hippocampus to
learn and store memories); and [0027] morphological changes (e.g.
selective loss of neurons in the CA1 and CA3 regions of the
hippocampus in patients presenting mesial temporal lobe epilepsy as
a result of excitotoxicity) (Swann, 2004, Avoli et al., 2005)
[0028] 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 mal
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).
[0029] 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, valproate,
vigabatrin, and zonisamide.
[0030] The mode of action of some of these is understood and for
others is unknown. Some modes of action are set out in Table 1
below: (Adapted from: Schachter S C. Treatment of seizures. In:
Schachter S C, Schomer D L, eds. The comprehensive evaluation and
treatment of epilepsy. San Diego, Calif.: Academic Press; 1997. p.
61-74)
TABLE-US-00001 TABLE 1 Sodium or calcium Antiepileptic drug
Mechanism of action channel involvement Barbiturates: primidone
Enhances GABAergic inhibition (Mysoline), phenobarbital
Carbamazepine (Tegretol, Inhibits voltage-dependent sodium Sodium
Tegretol-XR, Carbatrol) channels Ethosuximide (Zarontin) Modifies
low-threshold or transient Calcium neuronal calcium currents
Felbamate (Felbatol) Unknown Gabapentin (Neurontin) Unknown
Lamotrigine (Lamictal) Inhibits voltage-dependent sodium Sodium
channels, resulting in decreased release of the excitatory
neurotransmitters glutamate and aspartate Phenytoin (Dilantin,
Phenytek) Blocks sodium-dependent action Sodium/Calcium potentials;
reduces neuronal calcium uptake Valproate (Depakote, Depakote
Reduces high-frequency neuronal Sodium ER, Depakene, valproic acid)
firing and sodium-dependent action potentials; enhances GABA
effects
[0031] Three well-established and extensively used in vivo models
of epilepsy are: [0032] pentylenetetrazole-induced (PTZ) model of
generalised seizures (Obay et al., 2007, Rauca et al., 2004);
[0033] pilocarpine-induced model of temporal lobe (i.e.
hippocampus) seizures (Pereira et al., 2007); and [0034]
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.
[0035] 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.
[0036] The application GB0911580.9 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.
[0037] It is an object of the present invention to identify novel
drug combinations which will enhance or otherwise offer benefits in
the use of SAED's. The use of a combination may allow for lower
doses of SAED's to be used then is conventional.
BRIEF SUMMARY OF THE DISCLOSURE
[0038] In accordance with a first aspect of the present invention
there is provided cannabidiol, (CBD), at a dose of greater than 300
mg/day, in combination with a standard anti-epileptic drug (SAED)
which acts via sodium or calcium channels, for use in the treatment
of epilepsy.
[0039] The SAED which acts via sodium or calcium channels may be
exemplified by a drug which: [0040] modifies low-threshold or
transient neuronal calcium currents, such as, ethosuximide; or
[0041] reduces high-frequency neuronal firing and sodium-dependent
action potentials (and may additionally enhance GABA effects), such
as, valproate; In contrast, a SAED which (solely) enhances
GABAergic inhibition (as opposed to acting via sodium or calcium
channels), such as, phenobarbital, does not appear to provide
benefits in combination with CBD, when tested in a pilocarpine
model. Thus, the selective benefits of CBD with e.g. ethosuximide
and valporate (SAED's with defined and distinct mechanisms of
actions involving calcium and sodium channels) could not be
anticipated.
[0042] In accordance with a second aspect of the present invention
there is provided the use of cannabidiol (CBD), at a dose of
greater than 300 mg/day, in combination with a standard
anti-epileptic drug (SAED) which acts via sodium or calcium
channels, in the manufacture of a medicament for use in the
treatment of epilepsy.
[0043] 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 cannabidiol
(CBD), at a dose of greater than 300 mg/day, in combination with a
standard anti-epileptic drug (SAED) which acts via sodium or
calcium channels.
[0044] In accordance with a forth aspect of the present invention
there is provided a combination product comprising cannabidiol
(CBD), at a dose of greater than 300 mg/day, and a standard
anti-epileptic drug (SAED) which acts via sodium or calcium
channels.
[0045] The respective drugs may be packaged separately with
instructions to be taken in combination or may be formulated as a
single use product.
[0046] Preferably the standard anti-epileptic drug acting via
sodium or calcium channels is taken from the group consisting of:
ethosuximide and valproate.
[0047] Preferably the type of epilepsy to be treated is a
generalised seizure or a temporal lobe seizure.
[0048] The combination may prove beneficial in one or more of the
following: [0049] a. reducing the incidence of tonic-clonic
seizures; [0050] b. increasing the amount of time a patient is
seizure free; [0051] c. increasing the latency to onset of seizure;
[0052] d. decreasing the overall duration of the seizure; and
[0053] e. reducing the severity and mortality of the seizures.
Thus, the combinations are particularly well suited in the
treatment of conditions generally considered refractory to existing
medication. The combinations would also appear to allow for the use
of lower doses of the SAED's than would be used were the SAED to be
used alone.
[0054] In one embodiment the CBD is used with one or more
therapeutically effective other phytocannabinoid(s).
[0055] Preferably the one or more therapeutically effective other
phytocannabinoid is THCV and/or CBDV.
[0056] In one embodiment the CBD is in an isolated form.
[0057] In a further embodiment the CBD is in the form of a
botanical drug substance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] By way of example only, a number of embodiments of the
invention are described hereinafter with reference to the
accompanying drawings, in which
[0059] FIG. 1A-C shows the effect of CBD at 100 mg/kg in
combination with valproate on PTZ-induced seizures;
[0060] FIG. 2A-C shows the effect of CBD and valproate on latency,
duration and severity of PTZ-induced seizures;
[0061] FIG. 3A-C shows the effect of CBD at 100 mg/kg and
ethosuximide on PTZ-induced seizures;
[0062] FIG. 4A-C shows the anti-convulsant effects of 100 mg/kg CBD
in combination with valproate on the development of
pilocarpine-induced seizures; and
[0063] FIG. 5A-C shows the effect of 100 mg/kg CBD in combination
with valproate on the development of pilocarpine-induced seizure
and mortality incidence.
[0064] Legend to FIG. 1: A: % mortality with (black bars) and
without 100 mg/kg CBD (white bars). B: % seizure free with (black
bars) and without 100 mg/kg CBD (white bars). C: % of animals that
developed the most severe (tonic-clonic) seizures with (black bars)
and without 100 mg/kg CBD (white bars).
[0065] Legend to FIG. 2: A: latency to seizure onset; B: duration
of seizure activity of those animals that survived; C: median
seizure severity.
[0066] Legend to FIG. 3: A: latency to onset of seizures at
different doses of ethosuximide without (black) or with (grey
unfilled) 100 mg/kg CBD. B: Seizure severity. C: Percentage
mortalities, key as in A.
[0067] Legend to FIG. 4: Mean latency to onset (A), development of
bilateral seizures (B) and tonic-clonic seizures (C).
[0068] Legend to FIG. 5: A: Proportion (%) of animals in each dose
group that exhibited fully developed tonic-clonic seizures. B:
Proportion (%) of animals in each dose group that died. C:
Proportion (%) of animals in each dose group that were seizure
free.
DETAILED DESCRIPTION
[0069] The examples below describe the use of isolated CBD in
combination with standard anti-epileptic drugs (SAEDs) in two
different models of epilepsy, namely the PTZ-induced seizure model
and the pilocarpine-induced seizure model. The SAEDs used in these
examples are ethosuximide, valproate and Phenobarbital (Pilocarpine
model only). It is important to note that there are many different
SAEDs available and the drugs chosen for these experiments provide
a general overview of how the phytocannabinoid CBD is able to work
in combination with different classes of drugs used in the
treatment of epilepsy.
EXAMPLE 1
[0070] The Use of the Phytocannabinoid CBD in Combination with a
Standard Anti-Epileptic Drug (SAED) in the PTZ-Model of
Epilepsy
Methodology:
Animals:
[0071] Male Wistar rats (P24-29; 75-110 g) were used to assess the
effects of the phytocannabinoid CBD in combination with SAEDs 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.degree. C.
on a 12 hour light: dark cycle (lights on 0900) in 50% humidity,
with free access to food and water.
[0072] The human dose equivalent (HED) can be estimated using the
following formula:
HED = Animal dose ( mg / kg ) multiplied by Animal K m Human K m
##EQU00001## [0073] The K.sub.m for a rat is 6 and the K.sub.m for
a human is 37. Thus, for a human of approx 60 Kg a 100 mg/Kg dose
in rat would equate to a human dose of about 1000 mg. Human doses
of greater than 300 mg/day, through 400 mg/day in 100 mg intervals
(namely through 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300 and
1400 mg) to as much as 2000 mg/day are envisaged based on dose
escalating studies with CBD (Example 2).
Experimental Setup:
[0074] Five 6 L 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:
[0075] A range of doses of PTZ (50-100 mg/kg body weight) were used
to determine the best dose for induction of seizures (data not
shown). As a result, a dose of 80 mg/kg injected intra-peritoneally
(IP; stock solution 50mg/ml in 0.9% saline) were used to screen the
CBD/SAEDs combinations.
Experimental Protocols:
[0076] On the day of testing, isolated CBD was administered via
intra-peritoneal (i.p.) injection at a dose of 100 mg/kg alongside
animals that were injected with a matched volume of the cannabinoid
vehicle (2:1:17 ethanol:Cremophor:0.9% w/v NaCl solution), which
served as the negative control group. Animals were then observed
for 1 hour, after which time they received an IP injection of 80
mg/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:
[0077] 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 (Pohl & Mares, 1987). All signs
of seizure were detailed for all animals.
TABLE-US-00002 TABLE 1.1 Seizure severity scoring scale, adapted
from Pohl & Mares, 1987. Seizure Righting score Behavioural
expression 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 Preserved twist 4
Tonic-clonic seizure with suppressed tonic phase Lost 5 Fully
developed tonic-clonic seizure Lost 6 Death
Latency from Injection of PTZ to Specific Indicators of Seizure
Development:
[0078] 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:
[0079] This is given as the median value for each experimental
group based on the scoring scale below.
Percentage Mortality:
[0080] 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:
[0081] 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:
[0082] For measures of latency and severity, one way analysis of
variance (ANOVA) was performed on the test groups to detect overall
combinational effects of CBD and SAEDs (p.ltoreq.0.05 considered
significant).
[0083] Significant ANOVA results were followed by post hoc tests to
test differences between vehicle and drug groups (Tukey's test,
p.ltoreq.0.05 considered significant).
Results:
[0084] From FIG. 1 it can be seen that the addition of CBD to the
SAED valproate has an effect on reducing the percentage mortality
and the incidence of tonic-clonic seizures. It is also shown that
the combination of CBD and the higher dose of valproate is more
effective at increasing the amount of time that the animal was
seizure free.
[0085] FIG. 2 demonstrates that the combination of CBD and
valproate was able to increase the latency to onset of seizure at
all dose ranges, in addition it decreased the overall duration of
the seizure.
[0086] The data shown in FIG. 3 demonstrates that the combination
of CBD with the SAED ethosuximide was also effective at reducing
the severity and mortality of the seizures. It also at the higher
dose of ethosuximide was able to increase the latency to onset of
the seizures.
Conclusion:
[0087] The data demonstrated in this Example clearly shows that the
combination of CBD with a SAED which has a mechanism of action
involving sodium or calcium channels is of value when treating
generalised seizures.
EXAMPLE 2
[0088] The Use of the Phytocannabinoid CBD in Combination with a
Standard Anti-Epileptic Drug (SAED) in the Pilocarpine Model of
(Temporal Lobe) Epilepsy
Methodology:
[0089] Isolated CBD was injected intra-peritoneally (IP) in the
standard vehicle (1:1:18 ethanol:Cremophor:0.9% .sup.w/.sub.v NaCl)
at doses of 50, 100 and 200 mg/kg alongside animals that received
vehicle alone at a matched volume. 15 minutes later
methylscopolamine (1 mg/kg; to reduce peripheral muscarinic effects
of pilocarpine) was administered followed, 45 minutes later by
pilocarpine (380 mg/kg, IP) administration.
Results:
[0090] FIG. 4 demonstrates the anti-convulsant effects of a
combination of CBD and valproate in the pilocarpine model of
epilepsy. These data show that the combination of the CBD and
valproate was able to increase the latency of onset of the
seizure.
[0091] It can be seen from the data illustrated in FIG. 5 that in
addition to increasing the latency of onset of the seizure the
combination of CBD and valproate was able to decrease mortality and
the percentage of tonic-clonic seizures.
[0092] Table 2.1 below describes the data in more detail.
TABLE-US-00003 TABLE 2.1 Anti-convulsant effects of CBD and
valproate in the pilocarpine model of epilepsy CBD in Combination
Val- with CBD proate Valproate Seizure Measure Effects Effects
Effects ALL Mean number of ** # EPISODES episodes Mean time spent
in * episodes Mean duration of * episodes Mean severity of * **
episodes Percentage .gtoreq.3 episodes # Percentage episode free **
EPISODE 1 Latency ** Duration Severity * EPISODE 2 Latency #
Duration # Severity * Key: # = p < 0.01; * = p < 0.05; ** = p
< 0.01
[0093] The table above clearly shows some of the advantages of
using a combination of the two compounds.
[0094] Table 2.2 below describes the effect of using the
phytocannabinoid CBD in combination with yet a further SAED,
phenobarbital, in the pilocarpine model of epilepsy.
TABLE-US-00004 TABLE 2.2 Effects of CBD and phenobarbital on the
pilocarpine model of epilepsy CBD Phenobarbitol (mg/kg) (mg/kg)
Seizure free (%) Onset latency (s) 0 0 0 750 100 0 0 500 0 10 25
800 100 10 25 750 0 20 55 900 100 20 55 930 0 40 75 1800 100 40 85
900
[0095] In contrast to the valproate combination data, this result
demonstrate the selective nature of the combinations which is
likely attributed to the different mechanisms of actions of these
SAED's.
Overall Conclusion:
[0096] The data demonstrated in the above Examples shows that the
combination of CBD with standard anti-epileptic drugs acting via
sodium or calcium channels may be beneficial in the treatment of
different types of epilepsy. This finding is of great significance
to the many epilepsy sufferers whose condition is refractory to
existing medication.
* * * * *
References