Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-06-28
2001-08-14
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S520000, C424S545000, C530S395000, C530S397000
Reexamination Certificate
active
06274550
ABSTRACT:
This invention pertains to the detection of a propensity for cachexia and to the control of obesity.
Cachexia is defined as significant weight loss. It occurs commonly in cancer patients and HIV-infected individuals, but can also be caused by hypercatabolism due to cardiac failure (especially, right-sided or biventricular failure), hepatic failure, renal failure, burns, inflammation (including sepsis), infection or tuberculosis. See R. B. Verdery, “Reversible and irreversible weight loss (cachexia) in the elderly,” in Textbook of Internal Medicine, 2d Edition (V. T. DeVita et at. eds.), Ch. 523, pp. 2424-2425 (1992); K. I. Marton, “Approach to patient with unintentional weight loss,” in Textbook of Internal Medicine, 2d Edition (V. T. DeVita et al. eds.), Ch. 444, pp. 2113-2115 (1992); R. M. Jordan et al., “Weight loss,” in Internal Medicine, 4th Edition (J. H. Stein ed.), Ch. 152, pp. 1260-1262 (1994); C. P. Artz et al., “Burns: Including cold, chemical, and electrical injuries,” in Textbook of Surgery, 11th Edition (D. C. Sabiston, Jr. ed.), Ch. 15, pp. 295-322 (1977); E. Braunwald, “Heart Failure,” in Harrison's Principles of Internal Medicine, 13th Edition (K. J. Isselbacher ed.), Ch. 195, pp. 998-1009 (1994); and D. W. Foster, “Gain and loss in weight,” in Harrison's Principles of Internal Medicine, 13th Edition (K. J. Isselbacher ed.), Ch. 40, pp. 221-223 (1994). Over 50% of cancer and HIV-infected patients experience an unintended weight loss of greater than 10% of their baseline weight. Moreover, this weight loss is associated with an increase in morbidity and mortality. Many cachectic patients manifest multiple physiological problems involving the immune system, muscular system, and hepatic function that can be directly related to loss of body weight or wasting. Therefore, understanding the mechanisms of cachexia in patients can lead to better treatment and consequently can have a substantial impact on the quality of life and survival of many cancer and HIV/AIDS patients. See G. O. Coodley et al., “The HIV Wasting Syndrome: a Review,” Journal of Acquired Immune Deficiency Syndromes, vol. 7, pp. 681-694 (1994); L. M. Hecker et al., “Malnutrition in patients with AIDS,” Nutrition Reviews, vol. 48, pp. 393-401 (1990); N. M. Graham et al., “Clinical factors associated with weight loss related to infection with Human Immunodeficiency Virus Type 1 in the multicenter AIDS cohort study,” American Journal of Epidemiology, vol. 137, pp. 439-46 (1993); and K. A. Nelson et al., “The cancer anorexia-cachexia syndrome,” Journal of Clinical Oncology, vol. 12, pp. 213-25 (1994).
Despite the prevalence of weight loss in cancer patients, the mechanisms underlying the weight loss are unknown. Current explanations for cancer or AIDS-associated weight loss are divided into two general categories—(1) mechanisms that decrease food intake (anorexia); and (2) mechanisms that increase energy expenditure through altered or increased metabolism. Hecker et al., 1990. Any mismatch between energy intake and expenditure will result in a change in weight.
Many cancer or AIDS patients have decreased oral intake and, therefore, decreased energy consumption. Accordingly, despite normal or even decreased energy expenditures in these patients, they may lose weight. Other patients experience anorexia due to the cancerous tumor itself (either by a mechanical obstruction or a change in tissue function) or due to the therapy used to treat the tumor, e.g., chemotherapy. Graham et al., 1993; Nelson et al., 1994. Similarly, many HIV/AIDS patients experience significant weight loss that correlates with decreased caloric intake. See C. Grunfeld et al., “Metabolic disturbance and wasting in the acquired immunodeficiency syndrome,” The New England Journal of Medicine, vol. 327, pp. 329-337 (1992). Thus, anorexia plays a major role in weight loss for the majority of both cancer and HIV/AIDS patients.
Factors that have been identified as causing anorexia in patients include opportunistic gastrointestinal infections or tumors, side effects of treatment, enteropathy, central nervous system disease, and psychiatric disorders. In addition, numerous physiological mediators of anorexia have been reported in the literature, including tumor necrosis factor, interleukin-1, interleukin-6, &ggr;-interferon, and &agr;-interferon. Coodley et al., 1994; Nelson et al., 1994; and Grunfeld et al., 1990. Yet the mechanisms by which these or other mediators induce anorexia remain unknown.
Another proposed mechanism contributing to the weight loss seen in cancer or AIDS patients is an increased or ineffective metabolism. It has been reported, and disputed, that resting energy expenditures in some patients rise throughout the course of the disease and increase even more at the end stage. See Coodley et al., 1994; Nelson et al., 1994; and Grunfeld et al., 1990. However, alterations in resting or total energy expenditures do not correlate with weight loss. Therefore, it is unlikely that increased energy demands alone account for wasting.
Even with decreased energy use, patients may lose weight due to ineffective metabolism. It is hypothesized that during episodes of weight loss, patients fail to switch from carbohydrate and protein oxidation to the fatty acid oxidation that would normally occur under conditions of starvation. This failure explains the observation that patients lose predominantly muscle mass rather than fat tissue. It has also been suggested that futile cycling of lipid metabolism can waste energy, thus accelerating the necessity of carbohydrate and protein breakdown, despite a decrease in total energy expenditure. See Coodley et al., 1994; Nelson et al., 1994; and Grunfeld et al., 1990.
Recently, alterations in hormone metabolism have been proposed as possible etiologies of HIV/AIDS or cancer-related weight loss, particularly due to muscle wasting. During severe or chronic infections, patients, particularly HIV/AIDS patients, demonstrate resistance to the actions of growth hormone. Because growth hormone acts to maintain muscle mass, it has been hypothesized that this resistance leads to muscle wasting and weight loss in HIV/AIDS patients. Recently, researchers demonstrated that HIV/AIDS patients with the wasting syndrome have a decreased response to exogenous growth hormone compared with a control group. In particular, the effects of growth hormone on insulin-like growth factor-I (IGF-I, a major mediator of growth hormone action) secretion was studied. When IGF-I was exogenously administered to patients with the wasting syndrome, the patients experienced a transient increase in nitrogen retention, but returned to baseline after 8-10 days. See S. A. Lieberman et al., “Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immunodeficiency syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 78, pp. 404-410 (1994). Thus, alterations in the growth hormone/IGF-I system may play an important role in HIV/AIDS cachexia.
In cancer patients, growth hormone resistance has been seen, but also other important hormones, including insulin and its antagonist glucagon, appear to be abnormally produced. Since these hormones are essential to normal metabolism, it has been postulated that abnormalities in these pathways explain the wasting syndrome in these patients. See Nelson et al., 1994. Unfortunately, the mechanisms by which cancer or HIV infection causes these alterations in hormone metabolism are poorly understood at best.
The control of caloric intake and body weight maintenance is very complex. The search for endogenous mediators over several decades has led to the identification of a variety of substances ranging from simple amino acids to large proteins and glycoproteins. However, it has been difficult to establish an unequivocal association between the amount of any one of these factors and human disease states such as anorexia/cachexia and anorexia nervosa.
Three glycoproteins or proteoglycans that modulate appetite or body weight have been identified: satieti
Figueroa, II Julio E.
Prasad Chandan
Vijayagopal Parakat
Board of Supervisors of Louisiana State University and Agricultu
Davis Bonnie J.
Runnels John H.
Stucker Jeffrey
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