Source: https://patents.google.com/patent/US8071641
Timestamp: 2018-11-21 14:29:25
Document Index: 241905983

Matched Legal Cases: ['Application No. 160420', 'Application No. 05703237', 'Application No. 05703237', 'Application No. 160420', 'Application No. 160420', 'Application No. 05703237', 'Application No. 05703237']

US8071641B2 - Treating or preventing diabetes with cannabidiol - Google Patents
Treating or preventing diabetes with cannabidiol Download PDF
US8071641B2
US8071641B2 US10589623 US58962305A US8071641B2 US 8071641 B2 US8071641 B2 US 8071641B2 US 10589623 US10589623 US 10589623 US 58962305 A US58962305 A US 58962305A US 8071641 B2 US8071641 B2 US 8071641B2
US10589623
US20070099987A1 (en )
Michael Zeira
Hadsit Hadasit Medical Res Services and Dev Ltd
This application is a National Phase Application of PCT Patent Application No. PCT/IL2005/000196 having International Filing Date of Feb. 16, 2005, which claims the benefit of Israel Application No. 160420 filed on Feb. 16, 2004. The contents of the above Applications are all incorporated herein by reference.
Type II diabetes results from a loss of insulin production combined with body's inability to properly use insulin, and is oftentimes associated with aging. In Type II diabetes, patients typically begin therapy by following a regimen of an optimal diet, weight reduction and exercise. Drug therapy is initiated when these measures no longer provide adequate metabolic control. Initial drug therapy includes sulfonylureas (for example, tolbutamide, chlorpropamide and glibenclamide), biguanides (for example, metformin and buformin) and α.-glucosidase inhibitors (for example, acarbose and voglibose). However, over 50% of all diabetics treated by presently available drugs demonstrate poor glycemic control within six years, and require insulin replacement therapy as the last resort.
There is thus a widely recognized need for, and it would be highly advantageous to have new, safe and effective therapies for diabetes mellitus. Accordingly, the present invention provides a novel method and an article of manufacture for treating or preventing diabetes mellitus and related disorders.
According to further features in preferred embodiments of the invention described below, the cannabidiol comprises a compound having the general formula:
Preliminary studies by Formukong et al. [Inflammation 12: 361-371 (1988)] showed that CBD inhibited PBQ-induced writhing in mice when administered orally at doses of up to 10 mg/kg. Topical administration of CBD to mice was also shown to reduce TPA-induced erythema, which is dependent upon prostaglandin release.
In an in vitro study, Coffey et al [Biochem. Pharmacol, 52: 743-751 (1996)] demonstrated that cannabidiol inhibited nitric oxide (NO) produced by mouse peritoneal macrophages activated by LPS and IFNγ. Watzl et al [Drugs of Abuse, Immunity and Immunodeficiency, Plenum Press, New York, pp. 63-70 (1991)] studied in vitro the effects of CBD on secretions of IL-1, IL-2, IL-6, TNFα and IFNγ by human leukocytes. They found that CBD in low concentrations increased IFNγ production, whereas in high concentrations (5-24 pg/ml) it completely blocked IFNγ synthesis, decreased IL-1 and TNFα, production and did not affect IL-2 secretion.
The term “cannabinoid” refers to any natural or synthetic agonist of a cannabinoid receptor (e.g., CB1 and CB2). Naturally occurring cannabinoids may be divided into two categories, plant-derived and endogenous. Plant-derived cannabinoids are exemplified by the well-known Δ9-tetrahydrocannabinol (THC), the psychotropic principle in marijuana. Endogenous cannabinoids (endocannabinoids) are a class of lipid-like molecules that share receptor binding sites with plant-derived cannabinoids and mimic many of their neurobehavioral effects [Mechoulam et al., Adv. Exp. Bio. Med. 402:95-101 (1996)]. Two endocannabinoids have been characterized in some detail: arachidonyl ethanolamide (anandamide) [Devane et al., Science 258:1946-1949 (1992); Felder et al., Proc. Natl. Acad. Sci. USA. 90:7656-7660 (1993)] and 2-arachidonoyl glycerol (2-AG) [Mechoulam et al., Biochem. Pharmacol 50:83-90 (1995)].
In addition to the above, presently known cannabinoids include, for example, Δ8-THC, Δ9-THC-dimethylheptyl, 11-hydroxy-Δ8-THC-dimethylheptyl (HU-210), 5′-F-Δ8-THC, 11-OH-cannabinol, Δ8-THC-11-oic-dimethylheptyl acid, 1-deoxy-11-OH-Δ8-THC-dimethylheptyl (JWH-051), 11-Hydroxy THCs, desacetyl-L-nantradol, 11-OH-cannabinol-dimethylheptyl, cannabinol-dimethylheptyl-11-oic acid, HU-308, HU 243, L-759633, L-759656, L-768242, JWH-133, JWH-139, JWH-051, JWH-015, CP55940, CP47497, CP55244, R-(+)-WIN55212, ACEA, ACPA, 0-1812, 2-arachidonoylglyceryl ether, and methanandamide, and analogs or derivatives thereof. Additional cannabinoids are described in the references cited in the background section above.
Further additional natural or synthetic cannabinoids are described in U.S. Pat. Nos. 4,371,720, 5,013,387, 5,081,122, 5,292,736, 5,461,034, 5,618,955, 6,166,066 and 6,531,636; International Patent applications WO 01/9773, WO 97/29079, WO 99/02499, WO 98/41519, and WO 94/12466; European Patent Nos. EP 0570920 and EP 0444451; French Patent No. FR 2735774; and Israeli Pat. Nos. IL 01/00551 and IL 99/00187; Gaoni and Mechoulam, J. Amer. Chem. Soc. 93, 217 (1971); Mechoulam et al., Science 169, 611 (1970); Edery et al., Ann. N.Y. Acad. Sci., 191,40 (1971); Mechoulam et al., J. Amer. Chem. Soc., 94,7930 (1972); R. Mechoulam (ed.), “Marijuana: Chemistry, Metabolism, Pharmacology, and Clinical Effects” Academic Press, 1973, New-York; Houry et al., J. Med. Chem., 17, 287 (1974); Houry et al., J. Med. Chem., 18, 951 (1975); Mechoulam et al., Chem. Reviews, 76,75 (1976); Mechoulam et al., J. Med. Chem., 23, 1068 (1980); Srebnik et al., J. Chem. Soc., Perkin Trans. I, 2881 (1984); Mechoulam et al., Tetrahedron: Asymmetry, 1, 315 (1990); Devane et al., Science, 258,1946 (1992); Burstein et al., J. Med. Chem., 35, 3135 (1992); Hanus et al., J. Med. Chem., 36, 3032 (1993); Mechoulam et al., Biochem. Pharmacol., 50, 83 (1995); Sheskin et al., J. Med. Chem., 40, 659 (1997); Rhee et al., J. Med. Chem. 40, 3228 (1997); and Hanus et al., PNAS, 98, 3662 (2001).
For oral administration, the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. As used herein, the term “oral administration” includes administration of the pharmaceutical compound to any oral surface, including the tongue, gums, palate, or other buccal surfaces. Addition methods of oral administration include provision of the pharmaceutical composition in a mist, spray or suspension compatible with tissues of the oral surface.
Dosage amount and interval may be adjusted individually to levels of the active ingredient which are sufficient to, for example, reduce glucosuria or hyperglycemia in diabetic subjects. Methods of monitoring glucosuria are routine and well known in the art such as, for example, Combi Teststrips (Medi-Test, Macherey-Nagel, Duren, Germany). Similarly, methods of monitoring plasma glucose levels are routine and well known in the art such as, for example, using Glucose Analyzer 2 (Beckman Instruments).
Example 1 Preventing Diabetes in NOD Mice by Administering Cannabidiol
Experimental design: Cannabidiol (CBD) was extracted and purified from Cannabis plant as described by Gaoni and Mechoulam (J. Am. Chem. Soc. 93: 217-224, 1971). The purified CBD was dissolved in a solution of alchohol:chremophor-el:saline at a ratio of 1:1:18 and was administered to mice intraperitoneally at a dose of 5 mg a.i/kg (100 μg per mouse), five i.p. injections per week for a total of 10-23 injections. Mice injected with vehicle alone as well as untreated mice served as controls.
Plasma INFγ: INFγ is associated with the progression of diabetes in NOD mice (Schloot, N. C., Diabetes Metab. Res. Rev. 18:64, 2002; Weiss et al., Cytokine 19:85, 2002; Braz, J., Med. Biol. Res. 35: 1347, 2000).
Histopathology: Twenty weeks after onset of treatment mice were sacrificed. Pancreatic tissue samples were fixed in 4% buffered formation, embedded in paraffin, sectioned (5 μm thickness) and stained with hematoxylin and eosin. The stained pancreatic sections were observed under a microscope for infiltration of mononuclear lymphocytes into the islets of Langerhans (insulitis). The sections were scored by two uninformed observers as follows: 0, no cell infiltration; 1, cell infiltration in <20% of islet area; 2, cell infiltration in <50% of islet area; cell infiltration in <75% of islet area; and 4, cell infiltration in 90-100% of islet area.
As can be seen in Table 1 below, 86.4 (19/22) and 69.2% (9/13) of untreated and vehicle treated mice, respectively, developed diabetes. On the other hand, only 21.7% (5/23) of the CBD-treated mice developed diabetes under the experimental conditions, representing a greater than 65% rate of protection. It is important to note, however, that the onset of symptoms in the 5 CBD-treated diabetic mice was substantially delayed compared to untreated and vehicle-treated controls.
As can be seen in Table 2 below, the plasma INFγ level in CBD-treated mice (43 pg/ml) was significantly lower (p<0.05) than in untreated and vehicle control mice (107 and 94 pg/ml, respectively).
As can be seen in Table 3 below, administration of CBD significantly prevented or inhibited the insulitis characteristic of autoimmune diabetes. Analysis of sections of pancreatic tissue from untreated control and vehicle treated mice revealed 85% (62/73) and 96% (50/52), respectively, of totally infiltrated or fully destroyed islets, indicating widespread insulitis. Intact and partially infiltrated islets in the untreated controls and vehicle-treated mice were observed in only 3.8% and 15.1% of the pancreas samples obtained from vehicle treated and untreated mice, respectively. In samples from the CBD-treated mice, on the other hand, 87% (47/54) of the CBD-treated mice were protected, demonstrating intact (48%, 26/54) or only partially infiltrated pancreatic islets (39%, 21/54), while only 11% (6/54) and 1.9% (1/54) of the islets showed total infiltration or destruction, respectively.
Example 2 Cannabidiol Suppressing diabetes in male NOD mice induced with the disease
Experimental design—Male NOD mice were irradiated (650 cGy), 24 hrs prior to intravenous injection of spleen cells (25-28×106) derived from female diabetic mice. The injected mice were divided into three groups including untreated control; vehicle treated mice (20 IP injections, 5 times/week); and CBD treated mice (5 mg/kg CBD, 20 IP injections, 5 times/week).
Intraperitoneal glucose tolerance tests (IPGTT)—see Example 1 above. Blood glucose levels above 140 mg/dl were considered diabetic by testing blood glucose at t-0, 60 min following IP injection of 1 gr/Kg body weight of glucose [Glucometer Elite apparatus (Bayer Diagnostics, ELKART, IN)]. Alternatively, urine samples were taken twice a week from diabetic mice for testing glucose levels. Urine glucose levels above 1000 mg/dl as determined by combi 9 Teststrips (Medi-Test, Macherey-Nagel, Duren, Germany) were considered diabetic;
The effect of CBD was tested on a more progressive stage of diabetes. To this end a large number of diabetic cells were transferred to male NOD mice.
Diabetic developed in all the animals thus injected. As can be seen in Table 4 below, CBD suppressed the appearance of diabetes by about half in male NOD mice which were initially injected with splenocytes from diabetic female NOD mice.
1. A method of treating Type II diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of cannabidiol (CBD), wherein said cannabidiol is comprised in a composition having no psychotropic activity, thereby treating type II diabetes in the subject.
2. The method of claim 1, wherein said administering is via parenteral administration.
3. The method of claim 1, wherein said administering is via oral administration.
4. The method of claim 1, wherein said administering is via transdermal administration.
5. The method of claim 1, wherein said subject has transplanted pancreatic cells.
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