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WO 2012/144892 Al 26 October 2012 (26.10.2012) P O P C T

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WO 2012/144892 Al 26 October 2012 (26.10.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/144892 Al 26 October 2012 (26.10.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/192 (2006.01) A61P 9/10 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/352 (2006.01) A61P 31/04 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61P 3/10 (2006.01) A61K 133/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) Number: International Application HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/NL20 12/050241 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 12 April 2012 (12.04.2012) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 2006621 18 April 201 1 (18.04.201 1) NL GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (71) Applicant (for all designated States except US): TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, FYTAGORAS B.V. [NL/NL]; Sylviusweg 72, NL-2333 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, BE Leiden (NL). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor; and GW, ML, MR, NE, SN, TD, TG). (75) Inventor/Applicant (for US only): KORTHOUT, Henri- cus Adriaan Anne Jacobus [NL/NL]; Domineestuin 2, Published: NL-1544 PT Zaandijk (NL). — with international search report (Art. 21(3)) (74) Agent: JANSEN, CM.; Johan de Wittlaan 7, NL-251 7 JR Den Haag (NL). (54) Title: MEDICAL USE FOR ACIDIC CANNABINOIDS (57) Abstract: The invention relates to acidic cannabinoids as defined in the specification for use in increasing the natural resistance of an animal, for use in enhancing cellular resistance, for use in therapy of diabetes, for use in therapy of atherosclerosis, reduce the decline in stress response found in age ing or for use in decreasing the necessity for antibiotic treatment. Preferably said acidic cannabinoid is selected from the group consisting of A -tetrahy- drocannabinolic acid or THC acid (THCA), cannabidiolic acid (CBD-A), cannabidiol (CBD), cannabigerolic acid (CBGA), cannabigerol (CBG), can- nabinolic acid (CBN-A) and cannabinol (CBN), cannabichromenic acid (CBC-A) and cannabichromene (CBC). MEDICAL USE FOR ACIDIC CANNAB I OIDS The invention relates to the field of medicine, more particularly the field of immunology, stress and infection. In particular, the invention relates to increasing the natural resistance of animals by administering medicinal acidic cannabinoids. BACKGROUND 9-Tetrahydrocannabinol (THC) is naturally found in cannabis. THC has been reported to have use as an analgesic, for instance for patients suffering from rheumatoid arthritis. A side effect of THC is its psychoactive activity. Further, conventionally THC is administered by smoking, which may be detrimental to general health, in particular to the lungs and the coronary system. WO 89/01332 describes an acidic metabolite of THC, wherein the methyl group at the 9-position, a major metabolite formed in humans and other mammals, is substituted by a carboxyl group. This metabolite is reported to be non-psychoactive. Its use as a therapeutic agent for such purposes as the treatment of chronic pain and tissue inflammation often associated with illnesses such as rheumatoid arthritis is suggested. The Examples show a mouse hot plate test for analgesia, which indicates that, in mice, the metabolite shows about the same analgesic activity as THC and a somewhat lower activity than naproxen. The Examples further indicate that the metabolite does not induce the formation of gastric lesions in an animal test under conditions wherein aspirin does. In a review by Bhargava (Gen. Pharmac. Vol 9 (1978), No 4, pages 195-213), potential uses of cannabinoids are mentioned in rather general terms. Bhargava mentions that several cannabinoids have been pharmacologically tested, without disclosing in any detail, a specific medical activity for carboxylated cannabinoids (THC acids), such as ∆9- tetrahydrocannabinol^ acid or the like. In addition, reference is made to the analgesic activity of THC and several other cannabinoids compared to morphine. THC is reported to perform equi-analgesic with morphine, but other tested cannabinoids are reported to be much less potent or even inactive. Williamson and Evans (Drugs 2000, Dec. 60(6): 1303-1314 discuss in general terms a potential clinical use of cannabis. The specific use of THC acids, such as 9-tetrahydrocannabinolic acid or the like, as the active pharmaceutical ingredient, is not disclosed. GB-A 2 384 707 relates to the use of a cannobinoid acid, in particular cannabidiol (CBD) and cannabidiol acid (CBDA) for use as an active pharmaceutical substance in the treatment of nausea, vomiting, emesis and motion sickness. The compounds may be obtained by extraction from cannabis. As a result of the extraction, relatively small amounts of THC-acids may be present in the extract, but the use of a THC-acid as an active pharmaceutical substance is not mentioned. WO 2005/072719 describes medical uses of novel acidic cannabinoids obtained from plants for relieving pain, for suppression of an inflammatory response, preferably for suppressing release of a pro-inflammatory cytokine (such as TNF-a), and/or stimulating the release of an anti-inflammatory cytokine (such as IL- 10). Appendino et al. (J. Nat. prod. 2008, 71: 1427-1430) describe the antibacterial effect of cannabinoids, amongst which also acidic cannabinoids such as THC-acid, cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), which proved effective in particular against Staphylococcus aureus (MRSA). There remains a continuing desire for alternative therapeutics. It is therefore an object of the invention to provide such a therapeutic. SUMMARY OF THE INVENTION The present inventors now have discovered that acidic cannabinoids are able to induce the expression of heat shock proteins, in particular Hsp70. The invention thus comprises the acidic cannabinoids of Formula la, lb or Ic, as defined in claim 1 for use in increasing the natural resistance of an animal, for use in enhancing cellular resistance, for use in therapy of diabetes, for use in therapy of atherosclerosis, reduce the decline in stress response found in ageing or for use in decreasing the necessity for antibiotic treatment. Preferably, said acidic cannabinoid is selected from the group consisting of ∆9- tetrahydrocannabinolic acid or THC acid (THCA), cannabidiolic acid (CBD-A), cannabidiol (CBD), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabinolic acid (CBN-A) and cannabinol (CBN), cannabichromenic acid (CBC-A) and cannabichromene (CBC), more preferably said acidic cannabinoid is THCA. Also comprised in the invention is a plant extract, comprising at least one acidic cannabinoid as defined claim 1, wherein the amount of ∆9- tetrahydrocannabinol as a weight percentage of the total dry weight of the extract is 0-5 wt%, for use in increasing the natural resistance of an animal subject, for use in enhancing cellular resistance, for use in therapy of diabetes, for use in therapy of atherosclerosis, and to reduce the decline in stress response found in ageing. Preferably said plant extract comprises at least one compound selected from the group consisting of 9-tetrahydrocannabinolic acid or THC acid (THCA), cannabidiolic acid (CBD-A), cannabidiol (CBD), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabinolic acid (CBN-A) and cannabinol (CBN), cannabichromenic acid (CBC-A) and cannabichromene (CBC), more preferably said compound is 9-tetrahydrocannabinolic acid (THCA). Further comprised in the invention is a method of treating an animal subject with an acidic cannabinoid as defined above or a plant extract as defined above, which treatment comprises administering the acid cannabinoid in acidic form, wherein the treatment comprises increasing the natural resistance of a mammalian subject, enhancing cellular resistance, therapy of diabetes, therapy of atherosclerosis, or reducing the decline in stress response found in ageing. Preferably, in such a method the animal subject is chosen from the group consisting of a human, a cow, a sheep, a pig, a horse, a fish and a culture of other animals (shrimps, lobster, bivalves). Further comprised in the invention is a pharmaceutical composition comprising an acidic cannabinoid as defined above or a plant extract as defined above and an immunosuppressant. Preferably said pharmaceutical composition comprises an acidic cannabinoid or a plant extract and (5R )-5- hydroxytriptolyde. The invention also relates to the use of an acidic cannabinoid as defined above or a plant extract as defined above in additional therapy of EAE. The invention also relates to a method to induce expression of Hsp70 in a cell by contacting the cell with an acidic cannabinoid as defined above or with a plant extract as defined above. LEGENDS TO THE FIGURES Figure 1 . Effect of different concentrations of THC-acid on the activation of the human DNAJB1 (Hsp40) promoter in a 023 reporter cell line in the presence of different concentrations of arsenite. The DNAJB1 promotor was coupled to a luciferase reporter gene to measure promoter activation.
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