The prevalence of obesity is rapidly increasing globally. Obesity is a serious health problem throughout the world. More than half of U.S. adults are overweight (61%) and more than a quarter (26%) of U.S. adults are obese. The inability of many individuals to keep their weight in check by diet and exercise has created a need for additional therapeutic means to combat obesity. Despite great effort, the pharmaceutical industry has not come up with the solution; because most weight-loss drugs to date have serious adverse effects to health and well-being.
Epidemiological studies have associated obesity with a range of cancer types, although the mechanisms by which obesity induces or promotes tumorigenesis vary by cancer site. These include insulin resistance and resultant chronic hyperinsulinaemia, increased bioavailability of steroid hormones and localized inflammation. Gaining a better understanding of the relationship between obesity and cancer can provide new insight into mechanisms of cancer pathogenesis. Calle E E, Kaaks R, 4(8) Nat Rev Cancer 579-91 (2004).
According to the Centers for Disease Control and Prevention, an astonishing two of every three American adults are overweight. Simply put, being overweight poses grave health risks for aging adults. Excess fat can unleash a cascade of pathological effects in the body, damaging every cell and organ system while increasing the risk of age-related health problems. Western society is increasingly concerned with personal weight and appearance. Diets and weight loss programs are extensively advertised and utilized by a large segment of Western society with varying degrees of effectiveness. There is a continuing search for new and effective means to facilitate weight loss.
Weight loss has become an industry to itself, with a number of well known and successful programs such as Jenny Craig, of Carlsbad, Calif. that offers packaged foods and weekly meetings and counseling; NutriSystem, Inc., of Horsham, Pa. that delivers packaged foods to the home and promotes a “low glycemic index”; South Beach Diet, of Miami, Fla., a book based program of two weeks of protein only followed by the slow inclusion of “good” fats and “good” carbohydrates; and Medifast, Inc., of Owings Mills, Md., an on-line program that instructs its participants to eat every 2 hours and offers shakes, bars, drinks, oatmeal, chili, soups, and puddings.
Attempts to facilitate weight loss and weight control are abundant, and include both pharmaceutical and nutraceutical compositions. U.S. Pat. Nos. 6,576,272 and 6,420,350 disclose methods of promoting fat loss by administering Citrus aurantium extract standardized for about 6% synephrine alkaloids, caffeine and hypericum, and U.S. Application No. 20060210650 discloses a weight loss composition having one of calcium and/or a salt of calcium and garcinia cambogia extract.
U.S. Application No. 20060182825 discloses a composition for reducing body fat having at least one plant-derived substance which inhibits adipogenesis in the body of said mammal; and b. at least one plant-derived substance which promotes lipolysis in the body of said mammal.
U.S. Pat. No. 6,447,818 discloses a weight loss composition of ephedrine pseudo-ephedrine, synephrine tyramine, octopamine, methyl tyramine, or horderine in combination with a Crataegus extract containing flavonoids and Gingko biloba extract. U.S. Pat. No. 5,422,352 discloses a method for reducing weight by administering ephedrine and caffeine in a weight ratio of about 1:12, calculated on the amount of ephedrine in the form of the free base; and U.S. Pat. No. 5,055,460 discloses a weight loss composition of ephedrine, caffeine and aspirin.
U.S. Pat. No. 6,784,206 discloses a method of manufacture of a soft-gel capsule comprising 1% Corosolic acid, wherein the Corosolic acid is absorbed into the intestinal tract of a human in order to sustain weight loss management and maintain blood sugar levels. Moreover, this patent purports to aim to improve high blood sugar levels in subjects suffering from non-insulin dependant diabetes mellitus.
Sequential Formulations
The use of more than one weight loss compounds that work through distinct mechanisms has been disclosed, though none are directed to the combination of a beta-3 adrenergic compound and an adenyl cyclate receptor replenishing compound. U.S. Pat. No. 6,403,641 discloses the use, simultaneously, separately or sequentially of sibutramine hydrochloride monohydrate and orlistat results in benefit on weight loss. Sibutramine is a 5-hyrdroxytryptamine and noradrenaline reuptake inhibitor and reduces body weight by decreasing food intake and enhancing satiety and stimulating thermogenesis. Orlistat inhibits lipase enzymes which are responsible for breaking down ingested fat.
Similarly, U.S. Pat. No. 5,716,976 discloses the sequential use of the genus of anorexic compounds for the treatment of carbohydrate addiction by administering to a human suffering from carbohydrate addiction a first anorexient or combination of anorexients in amounts sufficient to relieve the addiction for a period of time insufficient to develop tolerance to the administration; and then replacing said anorexient or combination of anorexients with an appropriate amount of a different anorexient or combination of anorexients. Most specifically the anorexients may be a serotonin agonist, a serotonin reuptake inhibitor, a norepinephrine agonist, phenylpropanolamine or others.
U.S. Pat. App. Nos. 20070105843 and 20070066601 disclose pharmaceutical composition that combine a serotonin reuptake inhibitor in combination with a 5-HT.sub.2C receptor antagonist, inverse agonist or partial agonist, adapted for sequential use, and methods for treating various psychiatric disorders by the administration of said composition. U.S. Pat. App. No. 20030130355 discloses a composition that combines serotonin reuptake inhibitor and/or a noradrenaline reuptake inhibitor and 5-HT.sub.1A agonist and methods to treat obesity. Different forms of 5-HT receptor agonists and antagonists and the like are combined in U.S. Pat. App. No. 20020068732.
Similar compositions and methods for treating various psychiatric disorders, U.S. Pat. App. No. 20060223857, 20050288355 and 20020103249 that combine a serotonin reuptake inhibitor, and another compound; diabetes, U.S. Pat. App. No. 20060111428 and 20050059706; and digestive disorders, U.S. Pat. App. No. 20040191237.
A need continues to exist for improved weight loss compositions which are safe, effective and exhibit reduced side effects in humans. A new approach to weight loss composition and methods for use in humans is needed.
Excess insulin functions as a death hormone that devastates virtually every cell and organ system in the body. Insulin overload increases the risk of heart disease, cancer, blindness, stroke, Alzheimer's, and other age-related diseases. Heinbronn, L K, 295(13) JAMA 1577-8 (2006). The International Agency for Research on Cancer has determined that, based on results from epidemiological studies, people who are overweight or obese are at increased risk of developing several cancer types, including adenocarcinoma of the oesophagus, colon cancer, breast cancer in postmenopausal women, endometrial cancer, renal cancer and cancers of the liver, gallbladder and pancreas. Insulin resistance develops as a metabolic adaptation to increased levels of circulating free fatty acids released from adipose tissue, especially intra-abdominal adipose. Insulin resistance is generally compensated by increased pancreatic insulin secretion. There is mounting epidemiological and experimental evidence to indicate that chronic hyperinsulinaemia increases risk of cancers of the colon and endometrium, and probably other tumours. Successful intervention strategies for weight loss and maintenance at the individual and community level are needed to reduce cancer risk. Calle E E, Kaaks R, 4(8) Nat Rev Cancer 579-91 (2004).
The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease. Men with the metabolic syndrome were 2.9 times more likely to die of cardiovascular disease. Lakka, H M, et al, 288(21) JAMA. 2709-16 (2002). Similar results were observed by another group of researchers, who found that metabolic syndrome was associated with about a 2-fold increase in age-adjusted risk of fatal cardiovascular disease in men and nonfatal cardiovascular disease in women. Dekker, J M et al 112(5) Circulation. 666-73 (2005).
Adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. 21 Spec Med Sci (Paris) 10-8 (2005). White adipose tissue is now recognized as a major endocrine and secretory organ, releasing a wide range of protein factors and signals termed adipokines—in addition to fatty acids and other lipid moieties. A paradigm shift came with the discovery of leptin, a pleiotropic hormone which is a critical signal to the hypothalamus in the control of appetite and energy balance. A number of adipokines, including adiponectin, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor-1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of mild inflammation, and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands; a notable exception is adiponectin, with its anti-inflammatory action, the levels of which fall. White adipose tissue may be the main site of inflammation in obesity, increased circulating levels of inflammatory markers reflecting spillover from an ‘inflamed’ tissue, leading to the obesity-associated pathologies of type 2 diabetes and the metabolic syndrome. Trayhurn P, 184(4) Acta Physiol Scand. 285-93 2005). Scientists have identified more than 100 proteins, fatty acids, hormones, and inflammatory agents that are secreted by adipose tissue. Hauner H, 64(2) Proc Nutr Soc. 163-9 (2005).
Obesity, originally presumed to result from simple overeating or the combination of overeating with inactivity, has more recently been attributed to a genetic predisposition in combination with poor diet and exercise habits. It has been suggested that predisposition to obesity is associated with a defect in the sympathetic nervous system. This defect is manifested as a high efficiency in food utilization and a reduced thermogenic response to food intake. In normal persons, food intake results in a thermogenic response, that is, an increase in body temperature in which the caloric content of food is expended as heat. Some studies suggest that persons with a genetic predisposition to obesity are metabolically more efficient than lean persons, storing excess caloric energy as body fat. In obese persons, thermogenic defects may make a significant contribution to weight gain in the absence of controlled food intake. Calories not expended as heat are stored as excess weight. See Dulloo, A. G. and Miller, D. S., Wld. Rev. Nutr. Diet., vol. 50, pp. 1-56, 1987.
Pharmaceutical compositions have been developed with the purpose of stimulating thermogenesis and thereby inducing weight loss. The theory that beta agonists, especially beta 3 agonists, can affect body weight and fat mass is well accepted. Ephedrine has proven time and time again that it is an effective weight loss agent through its ability to increase thermogenesis and quench appetite. However, the publicity concerning adverse reactions has led to its gradual withdrawal from use by many despite the perceived consequences of obesity. Many companies are now substituting Citrus aurantium for ephedra in their formulations. Citrus aurantium, an agent containing beta agonists, has been reported to aid in weight loss in two studies and increase thermogenesis Preuss, et al 33(1-4) 1 J Med 247-64 (2002).
The theory that beta agonists, especially beta 3 agonists, can affect body weight and fat mass is well accepted. Preuss, et al 33(1-4) 1 J Med 247-64 (2002). Thermogenesis has been shown to be controlled by the beta-3 receptors of the adrenergic system. Hoeks, et al, 285 μm J Physiol Endocrinol Metab E775-E782 (2003).