U.S. patent application number 10/368935 was filed with the patent office on 2003-12-04 for anti-nausea and anti-vomiting activity of cannabidiol compounds.
This patent application is currently assigned to Yissum Research Development Company. Invention is credited to Breuer, Aviva, Mechoulam, Raphael, Parker, Linda.
Application Number | 20030225156 10/368935 |
Document ID | / |
Family ID | 11075945 |
Filed Date | 2003-12-04 |
United States Patent
Application |
20030225156 |
Kind Code |
A1 |
Mechoulam, Raphael ; et
al. |
December 4, 2003 |
Anti-nausea and anti-vomiting activity of cannabidiol compounds
Abstract
The present invention relates the use of certain cannabidiol
derivatives and of their dimethyl heptyl homologs (CBD-DMH) in the
treatment of nausea, in particular chemotherapy-induced nausea, and
of anti vomiting activity. The present invention relates also to
the use of said cannabidiol derivatives being part of a
pharmaceutical composition.
Inventors: |
Mechoulam, Raphael;
(Jerusalem, IL) ; Parker, Linda; (Waterloo,
CA) ; Breuer, Aviva; (Jerusalem, IL) |
Correspondence
Address: |
John R. Van Amsterdam, Ph.D., Esq.
600 Atlantic Avenue
Boston
MA
02210
US
|
Assignee: |
Yissum Research Development
Company
Jerusalem
IL
|
Family ID: |
11075945 |
Appl. No.: |
10/368935 |
Filed: |
February 19, 2003 |
Current U.S.
Class: |
514/454 ;
514/627 |
Current CPC
Class: |
A61P 1/08 20180101; A61K
31/05 20130101 |
Class at
Publication: |
514/454 ;
514/627 |
International
Class: |
A61K 031/353; A61K
031/16 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 19, 2002 |
IL |
148,244 |
Claims
1. A method for the treatment of nausea and of vomiting, comprising
administering to a subject an effective amount of a cannabidiol
compound of general formula I.
2. The method of claim 1, wherein the cannabidiol compound is used
in particular in the treatment of chemotherapy-induced nausea.
3. The method of claim 1, wherein the cannabidiol compound is a
compound of formula II.
4. The method of claim 3, wherein the cannabidiol compound is used
in particular in the treatment of chemotherapy-induced nausea.
5. The method of claim 1, wherein the cannabidiol compound is a
cannabidiol homolog of formula III.
6. The method of claim 5, wherein the cannabidiol compound is used
in particular in the treatment of chemotherapy-induced nausea.
7. The method of claim 1, wherein the cannabidiol compound of
formula I is part of a pharmaceutical preparation being selected
from the group consisting of a tablet, a capsule, a granule, and a
suspension in a solution.
8. The method of claim 7, wherein said pharmaceutical compound
comprises in addition to the active ingredient an excipient
selected from the group consisting of a carrier, a disintegrant, a
lubricant, a stabilizer, a flavoring agent, a diluent, and another
pharmaceutically effective compound.
9. The method of claim 8, wherein the diluent is an aqueous
cosolvent solution comprising a pharmaceutically acceptable
cosolvent, a micellar solution prepared with natural or synthetic
ionic or nonionic surfactants, or a combination of such cosolvent
and micellar solutions.
10. The method of claim 3, wherein the cannabidiol compound of
formula II is part of a pharmaceutical preparation being selected
from the group consisting of a tablet, a capsule, a granule, and a
suspension in a solution.
11. The method of claim 10, wherein said pharmaceutical compound
comprises in addition to the active ingredient an excipient
selected from the group consisting of a carrier, a disintegrant, a
lubricant, a stabilizer, a flavoring agent, a diluent, and another
pharmaceutically effective compound.
12. The method of claim 11, wherein the diluent is an aqueous
cosolvent solution comprising a pharmaceutically acceptable
cosolvent, a micellar solution prepared with natural or synthetic
ionic or nonionic surfactants, or a combination of such cosolvent
and micellar solutions.
13. The method of claim 5, wherein the cannabidiol homolog of
formula III is part of a pharmaceutical preparation being selected
from the group consisting of a tablet, a capsule, a granule, and a
suspension in a solution.
14. The method of claim 13, wherein said pharmaceutical compound
comprises in addition to the active ingredient an excipient
selected from the group consisting of a carrier, a disintegrant, a
lubricant, a stabilizer, a flavoring agent, a diluent, and another
pharmaceutically effective compound.
15. The method of claim 14, wherein the diluent is an aqueous
cosolvent solution comprising a pharmaceutically acceptable
cosolvent, a micellar solution prepared with natural or synthetic
ionic or nonionic surfactants, or a combination of such cosolvent
and micellar solutions.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates the use of certain cannabidiol
derivatives and of their dimethyl heptyl homologs (CBD-DMH) in the
treatment of nausea and of anti vomiting activity.
[0002] It is known that cannabidiol compounds of general formula I
1
[0003] in which R' stands for CH.sub.3, COOH or CH.sub.2OH; and
[0004] R" stands for
[0005] a. straight or branched alkyl of 5 to 12 carbon atoms;
[0006] b. a group --O--R'", where R'" . . . . is a straight or
branched alkyl of 5 to 9 carbon atoms, or a straight or branched
alkyl substituted at the terminal carbon atom by a phenyl
group;
[0007] c. a group --(CH.sub.2).sub.n--O-alkyl, where n is an
integer from 1 to 7 and the alkyl group contains 1 to 5 carbon
atoms, are antiiflammatory agents and have analgesic, antianxiety,
anticonvulsive, neuroprotective, antipsychotic and anticancer
activity.
[0008] There are known many compounds being present in marihuana
which have anti-nausea and anti-vomiting activity. However, many of
them are psychoactive which is undesired for this purpose.
SUMMARY OF THE INVENTION
[0009] It has now been found that cannabidiol compounds of general
formula I are not psychoactive but are very useful in the treatment
of nausea and of anti-vomiting activity.
[0010] The present invention thus consists in the use of
cannabidiol compounds of general formula I in the treatment of
nausea and of vomiting activity. The compounds are used in
particular in the treatment of chemotherapy-induced nausea.
[0011] Thus the invention provides methods for treating nausea
and/or vomiting by administering to a subject in need of such
treatment a cannabidiol compound as described herein. As used
herein, a "subject" shall mean a human, a vertebrate mammal
including but not limited to a dog, cat, horse, cow, pig, sheep,
goat, or non-human primate, e.g., monkey, or a fowl, e.g., chicken.
Included within the scope of the present invention are all animals
which are susceptible to nausea and/or vomiting. The term
"effective amount" of a cannabidiol compound (optionally combined
with other non-cannabidiol compounds) refers to the amount
necessary or sufficient to realize a desired biologic effect, e.g.,
a lessening of nausea and/or vomiting activity.
[0012] The cannabidiol compound of formula II and/or its DMH
homolog of formula III may be used as such. It may also be used as
part of a pharmaceutical preparation being selected among a tablet,
a capsule, a granule, a suspension in a solution, etc.
[0013] Said pharmaceutical preparation may comprise in addition to
the active ingredient an excipient selected among a carrier, a
disintegrant, a lubricant, a stabilizer, a flavoring agent, a
diluent, another pharmaceutically effective compound, etc.
[0014] The diluent may be an aqueous cosolvent solution comprising
a pharmaceutically acceptable cosolvent, a micellar solution
prepared with natural or synthetic ionic or nonionic surfactants,
or a combination of such cosolvent and micellar solutions, etc.
[0015] The carrier may consist essentially of a solution of
ethanol, a surfactant or water, or essentially of an emulsion
comprising triglycerides, lecitin, glycerol, an emulsifier, an
antioxidant, water, etc.
[0016] The present invention will hereinafter be described in
detail without being limited by said description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The Figures illustrate the following reactions:
[0018] FIG. 1. Mean (+sem) frequency of conditioned rejection
reactions elicited by a lithium- or saline-paired saccharin
solution in Experiment 1 when rats were tested 30 min after an
injection of vehicle or cannabidiol (CBD). The groups varied on the
basis of the pretreatment drug (CBD or Vehicle) administered 30 min
prior to an intraoral infusion of saccharin solution during the
conditioning trial and the conditioning drug (Lithium or Saline)
administered following saccharin exposure.
[0019] FIG. 2. Mean (+sem) frequency of conditioned rejection
reactions elicited by a lithium- or saline paired saccharin
solution in Experiment 2 when the pretreatment and test drug was
cannabidiol dimethyllheptyl (CBD-DMH).
[0020] FIG. 3. Mean (+sem) ml consumed of lithium-paired or
saline-paired saccharin solution during a 6 hr consumption test on
the day following the final taste reactivity (TR) test trial among
rats pretreated with 5 mg/kg of CBD or Vehicle prior to the
conditioning trial in Experiment 1.
[0021] FIG. 4. Mean (+sem) ml consumed of lithium-paired or
saline-paired saccharin solution during a 6 hr consumption test on
the day following the final TR test trial among rats pretreated
with 5 mg/kg of CBD-DMH or Vehicle prior to the conditioning trial
in Experiment 2.
DETAILED DESCRIPTION OF THE INVENTION
[0022] 1) Materials and Methods
[0023] a. Experiment 1 uses cannabidiol (CBD) of formula II: 2
[0024] Experiment 2 uses cannabidiol-dimethyl heptyl (CBD-DMH) of
formula III: 3
[0025] Experiment 1 were used 29 male rats and in Experiment 2 were
used 24 male Sprague-Dawley rats (Charles River Labs, St. Constant,
Quebec), which weighed 290-350 gm on the conditioning day. They
were individually housed in stainless steel hanging cages in a
colony room kept at 21.degree. C. on a 12:12 hr light:dark schedule
with the lights on at 07.00 h. Throughout the experiment, the rats
were maintained on ad-lib Purina Rat Chow and water. The procedures
were approved by the Wilfrid Laurier University Animal Care
Committee according to the guidelines of the Canadian Council on
Animal Care.
[0026] b. The rats were surgically implanted with intra-oral
cannulae as described by Parker, L.A. Learn Motiv., 13, 281-303
(1982). The surgical anesthesia preparation included administration
of 0.4 mg/kg atropine solution i.p. 15 min prior to ketamine (75
mg/kg, i.p.) combined with xylazine (10 mg/kg, i.p.) which was
dissolved in sterile water and administered at a volume of 1 ml/kg.
On each of three subsequent days during recovery from surgery, the
cannulae were flushed with a chlorhexidine rinse (Novlosan; 0.1%
chlorhexidine) to prevent infection.
[0027] c. The design of the experiments evaluated the effect of CBD
(Experiment 1) and of CBD-DMH (Experiment 2) on the establishment
of conditioned rejection reactions, on the expression of
conditioned rejection reactions during testing and the potential
role of state dependent learning decrements in responding. The rats
were randomly assigned to independent groups on the basis of the
pretreatment drug and the conditioning drug. In Experiment 1, the
groups were as follows: CBD-lithium (n=8), CBD-saline (n=6),
Vehicle-lithium (n=8), Vehicle-saline (n=7). In Experiment 2, the
groups were as follows: CBD-DMH--lithium (n=6), CBD-DMH--saline
(n=6), Vehicle-lithium (n=6), Vehicle-saline (n=6). All rats were
administered two test trials, one following an injection of the
drug (Experiment 1: CBD; Experiment 2: CBD-DMH) and the other
following an injection of the vehicle. C.sub.6H.sub.13 The order of
the test trials was counterbalanced among the rats in each
group.
[0028] d. CBD and CBD-DMH were prepared in a mixture (2.5 mg/ml
Vehicle) of 1 ml alcohol/1 ml emulsifier/18 ml saline and were
administered at a volume of 2 ml/kg. Lithium chloride was prepared
in a 0.15 M (wt/vol) solution with sterile water and was
administered at a volume of 20 ml/kg. All injections were
intraperitoneally (ip) administered.
[0029] e. One week following the surgery, the rats were adapted to
the conditioning procedure. On the adaptation trial, each rat was
transported into the room that contained the Plexiglass test
chamber (25 cm.times.25 cm.times.12 cm ). The room as illuminated
by four 25-W light bulbs located 30 cm from either side of the
chamber. Each rat was placed individually into the test chamber,
and a 30-cm infusion hose was then connected to the cannula through
the ceiling of the chamber. A syringe was connected to the hose and
placed into the holder for the infusion pump (Model 22; Harvard
Apparatus, South Natick, Mass.). After 60 s, the pump delivered
water through the tube into the rat's mouth at the rate of 1 ml/min
for 2 min. The rat was then returned to its home cage.
[0030] f. The conditioning trial occurred on the following day; it
was identical to the adaptation trial, except that the rats were
infused with 0.1% saccharin solution rather than water. Thirty min
prior to the conditioning trial, the rats were injected ip with
either 2 ml/kg of the drug (CBD: Experiment 1; CBD-DMH: Experiment
2) or with the vehicle in which the drug was mixed. Immediately
following the infusion of saccharin solution, the rats were
injected ip with 20 ml/kg of lithium chloride or saline. During the
intraoral infusion, the orofacial and somatic responses displayed
by the rats were videotaped from a mirror mounted at a 45.degree.
angle beneath the test chamber. Immediately following the TR test,
the rat was returned to its home cage.
[0031] g. The Taste Reactivity (TR) test trials were administered 4
and 6 days after the conditioning trial; on the day prior to the
first test trial, the rats received an adaptation trial as
described above. On each of two test trials, the rats were injected
with either 5 mg/kg of the test drug (CBD: Experiment 1; CBD-DMH:
Experiment 2) or with the vehicle, thirty min prior to receiving an
infusion of saccharin solution for 2 min at the rate of 1 ml/min.
The order of the tests was counterbalanced among the rats within
each group. The orofacial and somatic reactions displayed by the
rats were videotaped during the saccharin exposure.
[0032] h. In both experiments, on the day following the final TR
test trial, the rats were administered a consumption test trial in
a non-deprived state. On this trial, the water bottles were
replaced with tubes containing the saccharin solution and the
amounts consumed over a 6 hr period of drinking were recorded.
[0033] i. Taste reactivity scoring: A rater blind to the
experimental conditions scored the videotapes on two occasions in
slow motion (1/5 speed) using the Observer (Noldus, NL)
event-recording program on a PC computer. The frequency of the
rejection reactions of gaping (rapid large amplitude opening of the
mandible with retraction of the corners of the mouth), chin rubbing
(mouth or chin in direct contact with the floor or wall of the
chamber and body projected forward) and paw treads (sequential
extension of one forelimb against the floor or wall of the chamber
while the other forepaw is being retracted) were summated to
provide a rejection reaction score (inter-rater reliability:
[0034] Experiment 1: Vehicle test r (29)=0.91, CBD test r
(29)=0.90; Experiment 2: Vehicle test r(24)=0.95; CBD-DMH test r
(24)=0.97.
[0035] 2) Results
[0036] a. Taste Reactivity Test:
[0037] FIGS. 1 and 2 present as indicated above the mean frequency
of rejection reactions displayed by the rats in the various groups
during the vehicle test trial and during the drug (CBD: Experiment
1, CBD-DMH: Experiment 2) test trial. In both experiments, the
pattern of responding indicates that the cannabinoid drug
interfered with both the establishment of conditioned rejection and
with the expression of previously established conditioned rejection
reactions.
[0038] In Experiment 1 with CBD, the 2 by 2 by 2 mixed factor ANOVA
revealed significant effects of pretreatment drug, F(1, 25)=6.0;
p=0.022, conditioning drug, F (1, 25)=10.9; p=0.003, test drug, F
(1, 25)=7.4; p=0.012, test drug by conditioning drug, F(1, 25)=6.0;
p=0.021 and a pretreatment by conditioning drug interaction that
approached statistical significance F(1, 25)=3.6; p=0.069.
Subsequent Least Significant Difference (LSD) post-hoc pair-wise
comparison tests [20] revealed that the lithium-conditioned rats,
but not the saline-conditioned rats, displayed significantly fewer
conditioned rejection reactions during the CBD test trial than
during the vehicle test trial (p's<0.05). This indicates that
CBD attenuated the expression of previously established conditioned
rejection reactions. Additionally, across both test drug
conditions, the lithium-conditioned rats pretreated with CBD
displayed fewer rejection reactions than those pretreated with
vehicle (p<0.05) indicating that the CBD pretreatment during
conditioning attenuated the establishment of conditioned rejection
reactions, presumably by interfering with lithium-induced
nausea.
[0039] In Experiment 2, with CBD-DMH, the 2 by 2 by 2 mixed factors
ANOVA revealed a significant effect of test drug, F (1, 20)=4.6;
p=0.044 and a significant pretreatment drug by conditioning drug by
test drug interaction, F (1, 20)=5.6; p=0.028. Subsequent LSD
post-hoc pair-wise comparison tests revealed that Group
Vehicle-Lithium displayed significantly more rejection reactions
during the vehicle test than any other group (p's<0.01) and that
this group displayed more rejection reactions during the vehicle
test than during the drug test (p<0.01). CBD-DMH interfered with
the establishment of conditioned rejection reactions when
administered prior to a saccharin-lithium pairing and with the
expression of these conditioning rejection reactions when
administered prior to the subsequent test of conditioning.
[0040] The attenuation of lithium-induced conditioned rejection
reactions during conditioning or testing cannot be interpreted as
state-dependent learning decrement, because when rats were trained
and tested in the same cannabinoid sate, they displayed fewer
rejection reactions than when they were trained and tested in the
same vehicle state.
[0041] b. Consumption Test:
[0042] FIGS. 3 and 4 present the mean ml of saccharin solution
consumed by the various groups in Experiments 1 and 2 respectively.
As is apparent, rats suppressed their consumption of a
lithium-paired saccharin solution, but pretreatment with CBD
(Experiment 1) or CBD-DMH (Experiment 2) prior to conditioning did
not modulate the strength of the avoidance response. A 2 by 2 ANOVA
for each Experiment revealed only a significant effect of
conditioning drug for Experiment 1 (F(1,22)=25.01; p<0.001) and
a marginally significant effect of conditioning drug for Experiment
2 (F(1, 19)=4.36; p=0.051). There were no other significant
effects.
[0043] 3) Interpretation
[0044] The non-psychoactive cannabinoids, CBD and CBD-DMH,
interfered with the establishment of conditioned rejection
reactions (presumably by reducing the lithium-induced nausea) and
with the expression of previously established conditioned rejection
reactions (presumably by reducing conditioned nausea during the
test). These results are the first to describe the anti-nausea
properties of the naturally occurring cannabinoid, found in
marijuana and its dimethylheptyl homolog. It has previously been
reported similar effects produced by the 5HT3 antagonist
anti-emetic agent, ondansetron, and THC; that is, both agents
interfered with the establishment and the expression of conditioned
rejection reactions in rats. As has previously been reported using
the antiemetic agent, ondansetron, as the pretreatment agent, CBD
and CBD-DMH pretreatment did not interfere with the establishment
of conditioned taste avoidance in a consumption test. Since
treatments without emetic properties elicit taste avoidance, but
not conditioned rejection reactions, taste avoidance does not
reflect conditioned sickness. On the other hand, only treatments
with emetic effects produce conditioned rejection reactions in rats
suggesting that this affective change in taste palatability is
mediated by nausea. The anti-emetic effects of cannabinoid
agonists, such as THC and WIN 55-212, appear to be mediated by
specific actions at the CB1 receptor, because these effects are
blocked by administration of the CB1 receptor antagonist,
SR-141716. On the other hand, CBD and CBD-DMH have relatively weak
affinity for the CB 1 receptor and may be act by preventing the
uptake of the endogenous cannabinoid agonist, anandamide. Further
research is necessary to determine the specific mechanism by which
CBD and CBD-DMH prevent nausea in rats.
[0045] 4) Conclusion
[0046] The above results demonstrate that the non-psychoactive
component of marijuana, cannabidiol, and its synthetic analog,
cannabidiol dimethylheptyl, interfere with nausea and with
conditioned nausea in rats.
[0047] Therapeutically effective amounts of cannabidiol compounds
and homologs can be determined from animal models as described
above and as will be well known to and routinely performed by one
of ordinary skill in the art. The applied dose can be adjusted
based on the relative bioavailability and potency of the
administered compound. Adjusting the dose to achieve maximal
efficacy based on the methods described above and other methods as
are well-known in the art is well within the capabilities of the
ordinarily skilled artisan.
[0048] All references that are recited in this application are
incorporated in their entirety herein by reference.
[0049] What is claimed is:
* * * * *