WO2003070232A1 - Anti-nausea and anti-vomiting activity of cannabidiol compounds - Google Patents

Anti-nausea and anti-vomiting activity of cannabidiol compounds Download PDF

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Publication number
WO2003070232A1
WO2003070232A1 PCT/IL2003/000120 IL0300120W WO03070232A1 WO 2003070232 A1 WO2003070232 A1 WO 2003070232A1 IL 0300120 W IL0300120 W IL 0300120W WO 03070232 A1 WO03070232 A1 WO 03070232A1
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cannabidiol
compound
use according
cbd
nausea
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PCT/IL2003/000120
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French (fr)
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Raphael Mechoulam
Linda Parker
Aviva Breuer
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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Priority to AU2003206118A priority Critical patent/AU2003206118A1/en
Priority to EP03703002.0A priority patent/EP1476145B1/en
Priority to ES03703002.0T priority patent/ES2461556T3/en
Publication of WO2003070232A1 publication Critical patent/WO2003070232A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • 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
  • R' stands for CH 3 , COOH or CH 2 OH
  • R" stands for a straight or branched alkyl of 5 to 12 carbon atoms
  • b a group -O-R'", where R'" is 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
  • c a group - (CH 2 ) n -O-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms
  • antiinflammatory agents and have analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity
  • marihuana which have anti-nausea and anti-vomiting activity
  • many of them are psychoactive which is undesired for this purpose
  • cannabidiol compounds of general formula I are not psychoactive but are very useful in the treatment of nausea and of anti-vomiting activity
  • 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 chemotherepy-induced nausea
  • 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
  • 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 pharmaceutical effective compound etc
  • 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
  • the carrier may consist essentially of a solution of ethanol, a surfactant or water, or essentially of an emulsion comprising t ⁇ glyce ⁇ des, lecitin, glycerol, an emulsifier, an antioxidant, water, etc
  • Figure 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 mm after an injection of vehicle or cannabidiol (CBD) The groups varied on the basis of the pretreatment drug (CBD or Vehicle) administered 30 mm prior to an mtraoral infusion of saccharin solution during the conditioning trial and the conditioning drug (Lithium or Saline) administered following saccharin exposure Figure 2.
  • Figure 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.
  • Figure 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.
  • 1 Materials and Methods a. Experiment 1 uses cannabidiol of formula II
  • Experiment 1 29 male rate 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° C on a 12:12 hr ligh 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 Whyr University Animal Care Committee according to the guidelines of the Canadian Council on Animal Care. b.
  • the rats were surgically implanted with intra-oral cannulae as described by Parker, LA 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.
  • the cannulae were flushed with a chlorhexidine rinse (Novlosan; 0.1 % chlorhexidine) to prevent infection.
  • a chlorhexidine rinse Novlosan; 0.1 % chlorhexidine
  • the rats were randomly assigned to independent groups on the basis of the pretreatment drug and the conditioning drug.
  • mice 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. 6 Tr?e order of the test trials was counterbalanced among the rats in each group.
  • CBD and CBD-DMH were prepared in a mixture (2 5 mg/ml Vehicle) of 1 ml alcohol/1 ml emuls ⁇ f ⁇ er/18 ml saline and were administered at a volume of 2 ml/kg Lithium chloride was prepared in a 15 M (wt/vol) solution with sterile water and was administered at a volume of 20 ml/kg All injections were intrape ⁇ toneally (ip) administered 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 x 25 cm x 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,
  • the conditioning trial occurred on the following day, it was identical to the adaptation trial, except that the rats were infused with 1 % saccharin solution rather than water
  • 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
  • the rats were injected ip with 20 ml/kg of lithium chloride or saline
  • the orofacial and somatic responses displayed by the rats were videotaped from a mirror mounted at a 45o angle beneath the test chamber
  • the rat was returned to its home cage
  • 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
  • the rats were injected with either 5 mg/kg of the test drug (CBD Experiment 1
  • Figures 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 cannabmoid drug interfered with both the establishment of conditioned rejection and with the expression of previously established conditioned rejection reactions
  • 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 ⁇ .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 ⁇ .05) indicating that the CBD pretreatment during conditioning attenuated the establishment of conditioned rejection reactions, presumably by interfering with lithium-induced nausea.
  • Figures 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.
  • 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.
  • CBD and CBD-DMH have relatively weak affinity for the CB1 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. 4) Conclusions:

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.

Description

Anti-nausea and Anti-vomiting Activity of Cannabidiol Compounds
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
There is known that cannabidiol compounds of general formula I
R'
Figure imgf000003_0001
in which R' stands for CH3, COOH or CH2OH, and
R" stands for a straight or branched alkyl of 5 to 12 carbon atoms, b a group -O-R'", where R'" is 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, c a group - (CH2)n-O-alkyl, where n is an integer from 1 to 7 and the alkyl group contains 1 to 5 carbon atoms, are antiinflammatory agents and have analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity 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
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
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 chemotherepy-induced nausea
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
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 pharmaceutical effective compound etc
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
The carrier may consist essentially of a solution of ethanol, a surfactant or water, or essentially of an emulsion comprising tπglyceπdes, lecitin, glycerol, an emulsifier, an antioxidant, water, etc
The present invention will hereinafter be described in detail without being limited by said description
The Figures illustrate the following reactions
Figure 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 mm after an injection of vehicle or cannabidiol (CBD) The groups varied on the basis of the pretreatment drug (CBD or Vehicle) administered 30 mm prior to an mtraoral infusion of saccharin solution during the conditioning trial and the conditioning drug (Lithium or Saline) administered following saccharin exposure Figure 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 dimethylheptyl (CBD-DMH).
Figure 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.
Figure 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. 1 ) Materials and Methods a. Experiment 1 uses cannabidiol of formula II
Figure imgf000005_0001
Experiment 2 uses cannabidiol-dimethyl heptyl of formula III
Figure imgf000005_0002
In Experiment 1 were used 29 male rate 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° C on a 12:12 hr ligh 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. b. The rats were surgically implanted with intra-oral cannulae as described by Parker, LA 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. 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. 6Tr?e order of the test trials was counterbalanced among the rats in each group. CBD and CBD-DMH were prepared in a mixture (2 5 mg/ml Vehicle) of 1 ml alcohol/1 ml emulsιfιer/18 ml saline and were administered at a volume of 2 ml/kg Lithium chloride was prepared in a 15 M (wt/vol) solution with sterile water and was administered at a volume of 20 ml/kg All injections were intrapeπtoneally (ip) administered 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 x 25 cm x 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, MA) After 60 s, the pump delivered water through the tube into the rat's mouth at the rate of 1 ml/mm for 2 mm The rat was then returned to its home cage
The conditioning trial occurred on the following day, it was identical to the adaptation trial, except that the rats were infused with 1 % saccharin solution rather than water Thirty mm 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 mtraoral infusion, the orofacial and somatic responses displayed by the rats were videotaped from a mirror mounted at a 45o angle beneath the test chamber Immediately following the TR test, the rat was returned to its home cage 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 mm prior to receiving an infusion of saccharin solution for 2 mm at the rate of 1 ml/mm 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 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 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 forehmb 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 Experiment 1 Vehicle test r (29) = 91 , CBD test r (29) = 90, Experiment 2 Vehicle test r(24) = 95, CBD-DMH test r (24) = 97 2) Results a Taste reactivity test
Figures 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 cannabmoid drug interfered with both the establishment of conditioned rejection and with the expression of previously established conditioned rejection reactions
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= 022, conditioning drug, F (1 , 25) = 10.9; p = .003, test drug, F (1 , 25) =7.4; p = .012, test drug by conditioning drug, F(1 , 25) = 6.0; p = .021 and a pretreatment by conditioning drug interaction that approached statistical significance, F(1 , 25) = 3.6; p = .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 < .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 <.05) indicating that the CBD pretreatment during conditioning attenuated the establishment of conditioned rejection reactions, presumably by interfering with lithium-induced nausea.
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 = .044 and a significant pretreatment drug by conditioning drug by test drug interaction, F (1 , 20) = 5.6; p = .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 < .01 ) and that this group displayed more rejection reactions during the vehicle test than during the drug test (p < .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.
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. b. Consumption test:
Figures 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 < .001) and a marginally significant effect of conditioning drug for Experiment 2 (F(1 , 19) =4.36; p = .051). There were no other significant effects. 3) Interpretation
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 CB1 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. 4) Conclusion
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.

Claims

1. Use of a cannabidiol compound of general formula I as herein defined in the treatment of nausea and of vomiting activity.
2. Use according to Claim 1 , wherein the cannabidiol compound is used in particular in the treatment of chemotherepy-induced nausea.
3. Use according to Claim 1 or 2 in which the cannabidiol compound is a compound of formula II as herein defined.
4. Use according to Claim 1 or 2, wherein the cannabidiol homolog is a compound of formula III as herein defined.
5. Use according to any of Claims 1 to 4, wherein the cannabidiol compound and/or its DMH homolog is used as such.
6. Use according to any of Claims 1 to 4, wherein the cannabidiol compound of formula I is part of a pharmaceutical preparation being selected among a tablet, a capsule, a granule, and a suspension in a solution.
7. Use according to Claim 6, wherein said pharmaceutical compound comprises in addition to the active ingredient an excipient selected among a carrier, a disintegrant, a lubericant, a stabilizer, a flavoring agent, a diluent, and another pharmaceutical effective compound.
8. Use according to Claim 7, 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. Use according to Claim 6 or 7, wherein the carrier essentially of a solution of ethanol, a surfactant or water, or essentially of an emulsion comprising triglyceπdes, lecitin, glycerol, an emulsifier, an antioxidant, water
PCT/IL2003/000120 2002-02-19 2003-02-17 Anti-nausea and anti-vomiting activity of cannabidiol compounds WO2003070232A1 (en)

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EP1476145A1 (en) 2004-11-17
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