WO1999052524A1 - Use of cannabinoids as anti-inflammatory agents - Google Patents

Use of cannabinoids as anti-inflammatory agents Download PDF

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Publication number
WO1999052524A1
WO1999052524A1 PCT/GB1999/001140 GB9901140W WO9952524A1 WO 1999052524 A1 WO1999052524 A1 WO 1999052524A1 GB 9901140 W GB9901140 W GB 9901140W WO 9952524 A1 WO9952524 A1 WO 9952524A1
Authority
WO
WIPO (PCT)
Prior art keywords
cbd
cannabinoid
formula
mice
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1999/001140
Other languages
English (en)
French (fr)
Inventor
Marc Feldmann
Anne-Marie Malfait
Ruth Gallily
Raphael Mechoulam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kennedy Trust for Rheumatology Research
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Mathilda and Terence Kennedy Institute of Rheumatology
Yissum Research Development Co of Hebrew University of Jerusalem
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mathilda and Terence Kennedy Institute of Rheumatology, Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Mathilda and Terence Kennedy Institute of Rheumatology
Priority to JP2000543134A priority Critical patent/JP2002511411A/ja
Priority to DE69923671T priority patent/DE69923671T2/de
Priority to DK99915942T priority patent/DK1071417T3/da
Priority to US09/673,207 priority patent/US6410588B1/en
Priority to CA002328368A priority patent/CA2328368C/en
Priority to IL13897999A priority patent/IL138979A0/xx
Priority to AU34361/99A priority patent/AU757945B2/en
Priority to EP99915942A priority patent/EP1071417B1/en
Priority to AT99915942T priority patent/ATE288749T1/de
Publication of WO1999052524A1 publication Critical patent/WO1999052524A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This application relates to anti-inflammatory agents, and in particular to the use of
  • cannabinoids for the treatment of inflammatory diseases such as rheumatoid arthritis,
  • Cannabis sativa commonly known as marijuana, has been used for several years for its
  • cannabis constituents termed cannabinoids, naturally occur as 21 carbon atom compounds
  • THC Delta-9-tetrahydrocannabinoid
  • THC may suppress or enhance (depending on dosage) the production of various
  • CBD cannabidiol
  • Cannabidiol was first isolated in 1940 by Todd and Todd.
  • Cannabidiol has no psychotropic (cannabimimetic activity) and does not bind either the
  • Cannabidiol has also
  • mice injected with cannabidiol did not show significant change in the level of mRNA of IL-1, IL-6 and TNF ⁇ . At an 8 mg/kg dose of cannabidiol, the mortality of mice
  • cannabidiol inhibited PBQ-induced writhing in mice when given orally at doses up to 10
  • Cannabidiol was also shown to reduce TPA-induced erythema, which is dependent
  • cannabinoids may be used to treat
  • IL-1, IL-6 and IL-8 TNF- ⁇
  • various mediators such as nitric oxide, ROI and PGE ⁇ .
  • Cannabinoids have been found by the inventors to act as anti-inflammatory agents in vivo.
  • a first aspect of the invention provides use of one or more cannabinoids as
  • the cannabinoid is an isolated cannabinoid such as cannflavone-2 (formula I)
  • Rl is a straight or branched chain saturated or unsaturated alkyl having preferably
  • R2 is H or a saturated or unsaturated straight, branched or cyclic hydrocarbon group, or forms a substituted or unsubstituted cyclic ether with the O atom at the
  • Especially preferred cannabinoids are: olivetol Formula UJ
  • isolated is intended to include a naturally occurring cannabinoid which has been purified from a natural source or one which has been chemically synthesised.
  • the cannabinoid is used as an anti-inflammatory agent against inflammatory diseases, especially rheumatoid arthritis or Crohn's Disease, sarcoidosis, asthma,
  • Alzheimer s disease multiple sclerosis, Psoriasis, ulcerative colitis, osteoarthritis or
  • spondyloarthropathy e.g. ankylosing spondylitis
  • the invention also provides a method of treating a patient suffering from an inflammatory
  • the cannabinoid is preferably as defined above.
  • the patient is preferably a mammal such as a human.
  • Cannabinoids may be used separately or as mixtures of two or more cannabinoids. They
  • the invention also provides the use of one or more cannabinoids as previously defined in the manufacture of a medicament to treat inflammatory diseases.
  • a further aspect of the invention provides a method of treating an inflammatory disease
  • the cannabinoids may for example be applied orally, intramuscularly, subcutaneously, intradermally, intravenously, by nasal spray or topically.
  • administered will be in the range of 1 ⁇ g/kg/day to 50 mg/kg/day of patient body weight, preferably 2.5 to 10 mg/kg/day especially 5 mg/kg/day.
  • the invention also relates to medicinal preparations, including topical
  • formulations capsules, tablets and/or injectable formulations, containing one or more
  • cannabinoids as previously defined for use as anti-inflammatory agents.
  • cannabinoids according to any previous aspect of the invention, are used or
  • rheumatoid arthritis compounds such as methotrexate. This allows advantageous properties
  • Figure 1 shows the clinical scores for mice treated with CBD (cannabidiol).
  • the hind paws were assessed as normal, mildly affected or severely destroyed.
  • Figure 4 shows dose-dependent effects of CBD in a chronic CIA model. From the first
  • mice 5 mg/kg or 10 mg/kg i.p. Control mice were treated with vehicle alone, as described in
  • Results are expressed as a mean of 6 mice.
  • control group is 38.4, and for the 5 mg/kg group 28.9.
  • Figure 5 shows the effect of oral feeding of CBD. From the first signs of arthritis mice were treated daily over a 10 day period with CBD at the concentrations mentioned. The
  • Results are expressed as a mean +/- SEM.
  • Figure 6 shows the effect of oral feeding of CBD on chronic CIA. Mice were fed 25
  • Figure 7 shows the effects of CBD on experimental autoimmune encephalomylitis.
  • Two groups of 6 SJL/J female mice were injected with mouse spinal cord homogentate to
  • CBD was injected i.p. at a dose of 10 mg/kg.
  • the control group
  • FIG. 8 shows that CBD reduces serum TNF ⁇ levels after LPS stimulation.
  • C57BL/6 mice were injected ip (intraperitonally) with 100 ⁇ g LPS along with CBD ip or
  • mice subcutaneously (s.c.) 200 ⁇ g/mouse (10 mg/kg). After 90 min. the mice were bled and
  • Figure 9 shows the effect of CBD on response of lymphocytes to Mitogens.
  • Figure 10 shows the effect of CBD on mixed leukocyte reaction.
  • Figure 11 shows the effect of CBD on cell mediated cytotoxicity.
  • Spleen cells (1.25 x 10 6 /ml) from B6 (H-2 b ) mice were incubated for 5 days with an equal
  • CBD mixed leukocyes cultures, MLC. Cells harvested from MLC were
  • Cytotoxic activity is given in LU/10 6 cells (see Materials and Methods).
  • IFN- ⁇ and IFN- ⁇ were purchased from Boehringer Mannheim, Germany. The
  • Table 1 shows that CBD inhibits TNF ⁇ production. Low concentrations of CBD appear
  • CBD was dissolved in ethanol/DMSO. The ethanol was subsequently evaporated by means of a SpeedVac, and the CBD was resuspended in warm medium at a stock concentration
  • PBMC Peripheral blood mononuclear cells
  • the stimulus for TNF and IL-1 production was LPS, the stimulus
  • Bovine type II collagen (CII) was purified from hyaline cartilage, as described [Williams,
  • mice Female DBA/1 mice (8-12 weeks old) were immunized with lOO ⁇ g of CII emulsified in complete Freund's adjuvant CFA (Difco, Detroit, MI) by intradermal
  • mice were immunized with mouse CII (100 ⁇ g).
  • mice From day 30 after immunization onwards, the mice developed a
  • Cannabidiol (CBD) treatment commenced at the onset of disease and was administered i.p.
  • CBD was dissolved in ethanol/cremophor (Sigma Chemical Co., Poole, UK) (1/1, v/v) and further diluted in saline. Mice injected with vehicle alone (ethanol/cremophor in saline)
  • mice were treated from the first symptoms of
  • CBD was injected at doses of 10
  • CBD was dissolved in olive oil and
  • CBD has a dose-dependent therapeutic effect on CIA CBD at the doses of both 20 mg/kg and 10 mg/kg had a slight therapeutic effect on CIA
  • AUC area under the curve
  • FIG. 6 shows that oral feeding of 25 mg/kg CBD resulted in suppression of the
  • mice were moderately or severely affected. In mice treated with 5
  • CBD at 5 mg/kg/day, has a marked therapeutic effect on CIA.
  • EAE resembles the disease state of human
  • MS multiple sclerosis
  • acute disseminating encephalomyelitis MS and acute disseminating encephalomyelitis.
  • Mouse spinal cord homogenate was obtained as follows. Spinal cords from 3-10
  • MSCH was prepared by
  • Tuberculin purified protein derivative (PPD) was obtained from Statens Serum Institute,
  • MI MI
  • mice were treated with cannabidiol at a dose of 10 mg/kg. The results are shown in Figure
  • FIG. 8 indicates that CBD at 10 mg/kg decreases serum TNF ⁇ production in LPS
  • mice Female mice (aged 8-12 weeks) of strains C57BL/6 (B6, H-2 b ) and BALB/c (H-2 d ) were
  • Spleen cells at a final concentration of 5 x 10 6 cells/ml, were cultured in triplicate wells
  • MLR Mixed Leukocyte Reaction
  • Spleen cells 1 x 10 6 /well were co-cultured in triplicate wells of flat-bottom microtiter
  • splenocytes in a final volume of 200 ⁇ l/well. After 3-days incubation, the cells were
  • MLC Mixed Leukocyte culture
  • MHC-restricted CTL were activated in MLC by co-culturing 2.5 x 10 6 responding spleen
  • effector cells were serially diluted (threefold) in triplicate wells of conical-bottom
  • Microplates were centrifuged (70 x g, 2
  • Percent of specific cytotoxic activity was calculated according to the formula: [(experimental cpm - background cpm)/(maximal cpm - background cpm) x 100]. Lytic units (LU), were drawn from the cytotoxicity measured at 4-6 E:T cell ratios. One 1 LU
  • Concanavalin A ConA
  • LPS Concanavalin A
  • Figure 1 1 shows that low concentrations of CBD increase cytotoxicity, above approximately
  • ROI Reactive oxygen intermediation
  • Thioglycollate-elicited granulocytes were harvested from C57BL/6 mice by sterile lavage
  • luminol 10 ⁇ l and zymosan 30 ⁇ l was added for 0, 1 or 2 hours.
  • the tube was inserted into luminometer (Biolumate LB 95 oot Berhold Wildbad Germany)
  • the granulocyte luminol-enhanced chemiluminescence response to zymosan was considered as the positive control.
  • the granulocyte cells were pretreated with CBD 6 ⁇ g/ml for 0-2 hours before performing
  • the ROI test After 1-2 hours of CBD treatment, the cells were about 100% available.
  • Synovial membrane tissue was obtained from a patient fulfilling the revised American
  • synovial cell cultures were prepared as described. Briefly, synovial membrane
  • tissue was digested with collagenase type A (1 mg/ml) and DNAase I (0.15 mg/ml) in
  • synovial cell cultures were performed as previously described. Briefly, synovial
  • CBD suppresses spontaneous TNF release by synovium taken from arthritic animals
  • rheumatoid synovial cells spontaneously produce cytokines when cultured in
  • Table 7 shows the effects of CBD on the release of several cytokines, as measured
  • CBD 5 u ⁇ mi 0.422 0.251 100

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pyrane Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/GB1999/001140 1998-04-14 1999-04-14 Use of cannabinoids as anti-inflammatory agents Ceased WO1999052524A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2000543134A JP2002511411A (ja) 1998-04-14 1999-04-14 抗炎症剤
DE69923671T DE69923671T2 (de) 1998-04-14 1999-04-14 Verwendung von cannabidiol als entzündunghemmende mittel
DK99915942T DK1071417T3 (da) 1998-04-14 1999-04-14 Anvendelse af cannabidiol som anti-inflammatorisk middel
US09/673,207 US6410588B1 (en) 1998-04-14 1999-04-14 Use of cannabinoids as anti-inflammatory agents
CA002328368A CA2328368C (en) 1998-04-14 1999-04-14 Anti-inflammatory agents
IL13897999A IL138979A0 (en) 1998-04-14 1999-04-14 Use of cannabinoids as anti-inflammatory agents
AU34361/99A AU757945B2 (en) 1998-04-14 1999-04-14 Use of cannabinoids as anti-inflammatory agents
EP99915942A EP1071417B1 (en) 1998-04-14 1999-04-14 Use of cannabidiol as anti-inflammatory agent
AT99915942T ATE288749T1 (de) 1998-04-14 1999-04-14 Verwendung von kannabidiol als entzündunghemmende mittel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9807639.1 1998-04-14
GBGB9807639.1A GB9807639D0 (en) 1998-04-14 1998-04-14 Anti-inflammatory agents

Publications (1)

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WO1999052524A1 true WO1999052524A1 (en) 1999-10-21

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US (1) US6410588B1 (https=)
EP (1) EP1071417B1 (https=)
JP (1) JP2002511411A (https=)
AT (1) ATE288749T1 (https=)
AU (1) AU757945B2 (https=)
CA (1) CA2328368C (https=)
DE (1) DE69923671T2 (https=)
DK (1) DK1071417T3 (https=)
ES (1) ES2241277T3 (https=)
GB (1) GB9807639D0 (https=)
IL (1) IL138979A0 (https=)
WO (1) WO1999052524A1 (https=)

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US8119697B2 (en) 2002-02-19 2012-02-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Anti-nausea and anti-vomiting activity of cannabidiol compounds
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WO2021195691A1 (en) * 2020-04-02 2021-10-07 Incannex Healthcare Limited Methods and compositions for treating or preventing an inflammatory condition
WO2021228366A1 (en) * 2020-05-11 2021-11-18 Add Advanced Drug Delivery Technologies Ltd. Uses and formulations of cannabinoids
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