ANTI-OBESITY AGENT

Abstract: A composition for inducing weight loss, comprising as an active ingredient an effective amount of the Bacillus cereus toxin cerulide.

Description: ANTI-OBESITY AGENT Field of the Invention The present invention relates to the field of health care. More particularly the invention relates to preparations and to a method for the suppression of appetite and the reduction of weight which utilizes pharmaceutical preparations comprising a toxin derived from Bacillus cereus. The invention further relates to the use of the toxin of B. cereus as a drug inducing loss of appetite which is free of harmful side effects. Background of the Invention Obesity and. in general, overweight, are common problems in modern world, which are now recognized as major health hazards. These problems are treated with appetite suppressants and, in some extreme cases, by surgery. The most common drugs which have been used to induce weight loss are amphetamines and their derivatives [Theodore. B.V.I. , Health implications of overweight and obesity in the United States, Annal. Inter. Med. 103: 983-8. 1985]. Other approaches include the use of CNS drugs, such as Prozac, which have shown success in disorders associated with compulsive behavior. However, in general, modern medicine has failed to provide efficient treatment for overweight patients, particularly for those who on the one hand are hazardously overweight, which increases the danger of circulatory and other diseases but, on the other hand, are not considered clinically ill and, therefore, are not cured by using relatively extreme means, such as surgery. Toxins and their use as drugs are well known in the art. For instance, Botulinum toxin is known to cause blockage at the neuro-muscular junction, and has been used as a drug to alleviate muscular spasm as seen in strabismus and myokimia [Botulinum toxin, The Lancet 340: 1508-9, 1992]. Curare toxin has also been used as an intravenously injectable drug to relax muscles, usually during abdominal and thoracic surgery. The toxin of B. cereus (cerulide), known to cause emesis, has been identified as a dodecapeptide consisting of the following amino acid: LEV-ALA-VAL-VAL (Norio, A. et al., FEMS Microbiol Lett. 121:31-34, 1994). As ondansetron-hydrochloride (5-HT3 receptor antagonist) inhibits the emesis induced by Cereulide, it is suggested that serotonin receptor is associated in this effect [N. Agata et al., FEMS Microbiol. Lett. 1995, Jun 1, 129(1): 17-20. A novel dodecadepsipeptide, cereulide, is an emetic toxin of Bacillus cereus]. According to the literature, the emetic dose was calculated to 2U/g per os in the monkey, while the lethal dose is 45.4 U/g, IV in the mouse [Shinagawa et al., J. Vet. Med. Sci. 1996 Oct.58(10):1027-1029, Mouse lethal activity of a Hep-2 vacuolation factor, cereulide. produced by Bacillus cereus isolated from vomiting-tj e food poisoning; P. C. Turnbull, J. Clin. Pathol. 1976 Oct. 29(10):941-948, Studies on the production of enterotoxins by Bacillus cereus]. The ratio of emetic/lethal is about 1:22, which is very safe. In our experiments, the animals were examined by veterinarian and no adverse reactions were noted (black squares referring to dog weight, dotted squares to food consumption 1:10). Summary of the Invention It has now been found, and this is an object of the invention, that the toxin cerulide, which can be derived from B. cereus, is active in reducing the appetite with only mild side effects, if any. This is unexpected also because, as stated above, cerulide is known to be emetic and, therefore, the ability to administer it without inducing vomit is surprising. It has further been found, and this is another object of the invention, that the toxin cerulide from B. cereus can be used effectively in small amounts as an appetite-suppressing drug to induce weight reduction. It is object of the invention to provide a composition comprising the toxin cerulide as an active ingredient for controlling appetite. It is another object of the invention to provide a composition comprising the toxin cerulide as an active ingredient for inducing weight loss. It is still another object of the invention to provide a method for reducing the appetite comprising administering to a subject in need thereof an appetite reducing effective amount of the B. cereus toxin cerulideas an active ingredient. It is also an object of the invention to provide a method of inducing weight reduction, comprising administering to a subject in need thereof a weight reducing effective amount of the B. cereus toxin cerulide as the active material. Other objects and advantages of the invention will become apparent as the description proceeds. In one aspect, therefore, the invention is directed to a composition for inducing weight loss, comprising as an active ingredient an effective amount of the Bacillus cereus toxin cerulide. In another aspect, the invention is directed to a composition for inducing loss of appetite, comprising as an active ingredient an effective amount of the Bacillus cereus toxin cerulide. The composition of the invention may further comprise pharmaceutically acceptable carriers, as well as other additives which are conventional in the pharmaceutical art. According to a preferred embodiment of the invention the toxin is a natural extract, e.g.. a B. cereus extract. However, since cerulide is a short peptide it ca be easily synthesized by techniques well known in the art. Therefore, according to another preferred embodiment of the invention the toxin is a synthetic product. The toxin can be administered in different ways. According to one embodiment of the invention, the toxin is provided in an orally administrable formulation. The various forms of the composition of the invention include tablet form, capsule form and liquid form. The invention is further directed to a method of treating an overweight patient, which method comprises administering to said patient a weight-loss inducing effective amount of the B. cereus toxin cerulide. The invention is also directed to a method of treating overweight, comprising administering to a subject in need thereof an appetite-reducing effective amount of the B. cereus toxin cerulide. Further encompassed by the present invention is a method of inducing appetite loss and weight reduction comprising an effective amount of the B. cereus toxin cerulide. As said, the toxin can be either of natural or of synthetic origin, and can be administered in any suitable way. Detailed Description of Preferred Embodiments The invention will now be further described through the following illustrative and non-limitative examples. Toxin Sources Toxin was obtained from Bacillus cereus, which is an aerobic, spore-forming gram positive that is widely distributed in nature. The CN 7401 species was procured from Nagoya City Public Health Research Institute. Example 1 Two groups of 5 mice each (ICR, male, 20+ 0.2g) were injected daily intraperitoneal (IP) with 0.5ml of saline (PBS) or supernatant of CN7401 bacterial culture (0.6 O.D540). All mice gained weight during the four days of the experiment, however, the control mice gained an average of 3.25 +0.1, gr/mouse, while the CN-treated mice gained an average of 1.98+ gr/mouse, a difference of 39% (pc 0.05 t-tert, Figure 1) Example 2 Three groups of five mice each (ICR 1.8 ±O.lgr, male) were injected twice a day intraperitoneal with 0.5 ml -of saline (PBS), bacterial culture media (LB) and supernatant of the CN7401 bacterial (CN) culture 0.6 O.D54Q. The mice were injected for 10 days and weighed once a day. The mice treated with PBS and LB gained 8.5 + 0.9 gr/mouse and 9.45 + 0.8 gr/mouse, respectively, while the CN-treated mice gained 6.6+ 0.5 gr, a difference of 22-30% (P <0.05 t - test Fig. 2). Example 3 An isolated young dog (2 kg) was treated with increased doses of supernatant of the CN7401 (CN) bacterial culture (0.6 O.D540). The dog and the food consumed were weighed daily. The first treatment was started on day 20 and included 2 ml of CN for three days per os. The second course of treatment was on day 28, consisting of 4 ml of CN for three days. The third treatment was on day 38, consisting of 8 ml of CN for three days. The last treatment was given on day 48 and lasted three days. No adverse effects, such as vomiting, were noted during treatment. As can be seen in Fig. 3, each treatment moderated weight gain (the first and the second) or even reduction of weight when higher doses were used (the third and the fourth). In addition, food consumption was reduced parallel to the second, third and fourth treatment courses. All the above description and examples have been provided for the purpose of illustration, and are not intended to limit the invention in any way. Many modifications can be made in the invention: for instance, different pharmaceutical compositions can be prepared, containing different additives and/or drugs which act in combination with cerulide; or different administration methods can be employed, all without exceeding the scope of the invention.

Claims: CLAIMS: 1. A composition for inducing weight loss, comprising as an active ingredient an effective amount of the Bacillus cereus toxin cerulide. 2. A composition for inducing loss of appetite, comprising as an active ingredient an effective amount of the Bacillus cereus toxin cerulide. 3. A composition according to claim 1 or 2, further comprising pharmaceutically acceptable carriers. 4. A composition according to claim 1 or 2, wherein the toxin is a natural extract. 5. A composition according to claim 4, wherein the toxin is a B. cereus extract. 6. A composition according to claim 1 or 2, wherein the toxin is a synthetic product. 7. A composition according to any one of claims 1 to 6, wherein the toxin is provided in an orally administrable formulation. 8. A composition according to claim 7, in tablet form. 9. A composition according to claim 7, in capsule form. 10. A composition according to claim 7, in liquid form. 11. A composition according to claim 7, in injectable form. 12. A method of treating an overweight patient, comprising administering to said patient a weight-loss inducing effective amount of the B. cereus toxin cerulide. 13. A method of treating overweight, comprising administering to a subject in need thereof an appetite-reducing effective amount of the B. cereus toxin cerulide. 14. A method of inducing appetite loss and weight reduction comprising an effective amount of the B. cereus toxin cerulide. 15. A method according to claim 14 wherein the toxin is a natural extract. 16. A method according to claim 15 wherein the extract is a B. cereus extract. 17. A method according to claim 14 wherein the toxin is a synthetic product. 18. A method according to any of claims 12 to 17 wherein B. cereus is administered orally. 19. A method according to any of claims 12 to 17 wherein B. cereus is administered by injection. 20. A pharmaceutical preparation for inducing weight loss and/or for inducing loss of appetite, essentially as described and with particular reference to the examples.

Inventors: NADEL YAACOV, NADEL, YAACOV
Applicants: NADEL YAACOV, NADEL, YAACOV
Application year: 1998
Main classification: A61K31
IPC codes: A61K35, A61K38