Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-11-19
1997-01-28
Schain, Howard E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, A61K 3800, A61K 3724, C07K 1400
Patent
active
055977979
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of restoring ideal population-based body composition in obese mammals or preventing obesity especially in humans.
2. Description of Background and Related Art
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease. Rissanen et al., British Medical Journal, 301: 835-837 (1990).
Obese subjects tend to have low basal levels of growth hormone (GH) and fail to secrete significant amounts of GH in response to a variety of stimuli, including growth hormone releasing hormone (GHRH). Williams, New Engl. J. Med., 311: 1403 (1984) Kopelman, Clin. Endocrinol., 23: 87 (1985); Kopelman, Clin. Endocrinol., 24: 157 (1986) Loche, Clin. Endocrinol., 27: 145 (19871) Ghigo et al., Metabolism, 41: 560-563 (1992). The GH responsiveness to GHRH in obese rats shows sexual dimorphism. Cocchi et al., Pharmacol. Res., 25: Suppl. 2, 336-337 (1992). This failure to secrete GH has been postulated to be the result of a hypothalamic disorder (Kopelman, 1986, supra), leading to a chronic state of somatostatin hypersecretion. Cordido, J. Clin. Endocrinol. Metab., 68: 290 (1989). This defect in GH secretion appears to be a result rather than a cause of obesity, since it is, at least in part, reversible with weight reduction.
While it has been suggested that the refractoriness of obese subjects to release GH is due to the feedback inhibition operated by the elevated plasma levels of insulin-like growth factor (IGF-I) (Loche et al., Clin. Endocrinol., 27: 145-153 [1987]), in fact, no correlation was found between IGF-I and indices of overweight. Cordido et al., Horm. Res., 36: 187-191 (1991). Thus, adiposity is not associated with a decline in IGF-I levels. Hochberg et al., Metabolism, 41: 106-112 (1992); Gama et al., Clin. Chim. Acta, 188: 31-38 (1990); Rosskamp et al., Eur. J. Pediatr., 146: 48-50 (1987). Further, impaired hGH stimulation in obese human subjects is not explained by an altered relationship between hGH and IGF-I levels. Jungmann et al., Med. Klin., 86: 237-240 (1991). Nor does reduction in circulating insulin levels lead to a higher ability to secrete GH. Chalew et al., Inter. J. Obesity, 16:459-463 (1992).
Certain diseases such as diabetes mellitus, especially adult onset or Type II diabetes, show a much higher prevalence of obesity. It has been found that low IGFBP-1 levels in obesity are related to elevated insulin levels, which are, in turn, related to body fat distribution and insulin resistance. The chronically depressed levels of IGFBP-1 may promote IGF bioactivity as well as its feedback regulation of GH secretion, thus contributing to the metabolic and mitogenic consequences of obesity. Conover et al., J. Clin. Endocrinol. Metab., 74: 1355-1360 (1992).
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Jung and Chong, Clinical Endocrinology, 35: 11-20 (1991); Bray, Am. J. Clin. Nutr., 55: 538S-544S (1992). Protein-sparing modified fasting has been reported to be effective in weight reduction in adolescents. Lee et al., Clin. Pediatr., 31: 234-236 (April 1992). Caloric restriction as a treatment for obesity causes catabolism of body protein stores and produces negative nitrogen balance. Protein-supplemented diets, therefore, have gained popularity as a means of lessening n
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Genentech Inc.
Hasak Janet E.
Schain Howard E.
Touzeau P. Lynn
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