Anti-Obesity Drug Discovery and Development

Cancer is the leading cause of morbidity and mortality worldwide, and the number of new cases is expected to rise. Among all the risk factors for cancers, lifestyle, eating habit and obesity are considered the most significant determining factors. In this chapter, we review evidence indicating that diet and obesity play significant roles in both the initiation and promotion of the cancer development. Furthermore, we also critically summarize how cancers can be prevented or its growth be inhibited by dietary modulation and reducing obesity. The evidence reviewed here overwhelmingly suggests that nutritional recommendations for cancer prevention should focus on improving host immunity. Specifically, this means consuming diets high in omega-3 polyunsaturated fatty acids (PUFAs) in a low omega-6 to omega-3 ratio, and rich in fiber and anti-angiogenic compounds such as omega-3 PUFAs, antioxidants and polyphenols. Given the causal link between obesity and cancer, reduced obesity, for instance, by dietary modulation may help to reduce cancer risk. Nevertheless, the conventional studies of the anti-cancer and/ or anti-obesity effects of dietary components or compounds may be complicated by the influences from background diet, life style, gut microbiome, age, environmental factors, genetic factors, drug therapy, and an individual’s physical and pathological conditions. Therefore, in order to have the most effective dietary modulation for an individual for cancer prevention and treatment, “personalized nutrition” may be an alternative approach. Facing the challenge of how to optimize the individual’s nutrition, we believe “omic” technologies and system biology will have great potential for designing “personalized nutrition” that can prevent the onset and slow down, if not reverse, the progression of the cancer.

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy and the most frequent cause of anovulatory infertility in women of reproductive age. PCOS can lead to various clinical consequences including reproductive, metabolic and psychological problems. Obesity has been defined as having excess body fat that is closely related to insulin resistance, and the estimated incidence of obesity in PCOS has been reported to be 40% to 60%. The initial management option includes lifestyle interventions in patients with PCOS complicated by obesity and insulin resistance. For the dietary management, it is important to have reduced body weight and maintain a lower long-term body weight by preventing further weight gain. Although these lifestyle interventions can provide modest weight loss, in some cases it is necessary to use pharmacologic agents to gain optimal weight loss and maintain optimal weight in the long term. Studies including the use of pharmacologic agents for the treatment of obesity and insulin resistance have increased over the last decade. Pharmacologic agents including orlistat, metformin, glucagon-like peptide-1 receptors (exenatide and liraglutide), phentermine, topiramate, lorcaserin are available for the treatment of obesity and studies have also focused on the effectiveness of these anti-obesity medications in patients with PCOS in the recent years. It has been demonstrated that anti-obesity drugs have beneficial effects on metabolic parameters and weight loss in the obese patients with PCOS used in conjunction with diet and lifestyle modification. However, the administration of these drugs for the PCOS treatment should be under constant medical supervision due to the requirement of monitorization of possible side effects and dose adjustment.

Obesity is the most prevalent, costly and harmful epidemic of the 21st century. Considered a disease of excess, it is now known that it doesn’t take just to have increased food intake with reduced expenditure, but a number of other factors have increasingly been reported to have similar influence. At the center of all metabolic pathways lie mitochondria. The powerhouses of the cell is the cornerstone of cuttingedge research on metabolic alterations in obesity and related conditions. Boosting mitochondrial activity, removing damaged units and producing new, energy-consuming mitochondria are some of the strategies currently used in the development to combat obesity. In this chapter, we will focus on the near-future applicability of therapeutic strategies that achieve this goal. Specifically, we will address how sirtuin-activating compounds and bile acids promote mitochondrial homeostasis in spite of constant fat and carbohydrate insult, resulting in the unclogging of metabolic pathways and promoting the restoration of a normal energetic, redox and functional cellular environment. Activation of sirtuins 1 and 3 stimulates mitochondrial oxidative metabolism and prevents the accumulation of reduced substrates, a major factor driving cellular dysfunction in the setting of obesity. By acting on adipose tissue and stimulating energy expenditure, which may be associated with an increase in fatty acid oxidation, bile acids improve metabolic status.

On health front, today’s generation is struggling with increasing rate of obesity which is undisputedly reckoned as a leading cause for a number of pathological conditions e.g. coronary heart disease (CHD), high blood pressure, stroke, abnormal blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, reproductive problems, gallstones, and type 2 diabetes etc. In recent research, calcium silicate based two formulations i.e., floating microspheres and floating granules have been developed for anti-obesity drug i.e., orlistat, to deliver the incorporated therapeutic agent in effective concentrations and extended therapeutic course of time. Floating characteristic over the gastric content of such formulations is capable to provide prolonged retention in gastric region. Formulation of microspheres with incorporation of calcium silicate increases the effectiveness of this granular formulation to matchup the desired release pattern with buoyancy. The developed formulations of orlistat are found to be safer and more effective which is the need of day in pharmaceutical industry as an alternative drug delivery system for a highly prevalent and chronic disease like obesity.

Obesity, a chronic metabolic disorder, is caused by an imbalance between energy intake and expenditure, and has been associated with insulin resistance, Type 2 Diabetes Mellitus (T2DM), hypertension, myocardial infarction, fatty liver disease, stroke, osteoarthritis and certain cancers. Currently, drugs used for the management of obesity like orlistat (lipase inhibitor) and Phentermine (norepinephrine and dopamine releasing agent) have been reported to exhibit adverse side effects.

Recent advancements in the understanding of biological systems have opened up new possibilities towards a multi targeted approach, designed to target more than one biological mechanism that might ultimately be more effective in producing sustained weight loss along with improvement in comorbidities. Multi-targeted drugs have emerged as a new paradigm in the last decade owing to their advantages in the treatment of complex multifactorial diseases such as obesity and T2DM. Most recently, glucagon-like peptide-1 (GLP-1) mimetics and insulin secretagogues have been reported for their anti-obesity activity, due to their property of delaying the rate of gastric emptying and appetite suppression in CNS, thus promoting satiety and weight loss.

Medicinal plants have been established as rich resources for the identification of potential drug candidates. Most of these isolated natural products exhibit multi-targeted action owing to their diverse and complex structure. Numerous natural bioactive molecules including polyphenols, alkaloids, sterols, glycosides, terpenes and saponins have been identified as potential drug candidates for the management of obesity. Cellular and molecular studies have shown that these natural products suppress appetite and reduce food intake, reduce intestinal absorption of fats, attenuate lipid synthesis and accumulation, stimulate lipolysis, promote oxidation of fatty acids and reduce inflammation.

This chapter will focus on the molecular targets and mechanisms involved in weight regulation, provide an insight into the isolation of bioactive compounds from medicinal plants, and the multi targeted strategies for the control of obesity.

Obesity is a chronic condition that is causally related to serious medical illnesses. Plants, especially those used in Ayurveda, can provide biologically active molecules and lead structures for the development of drugs with enhanced activity and reduced toxicity. Natural products, particularly medicinal plants, are believed to harbor potential anti-obesity agents that can act through various mechanisms, either by preventing weight gain, or by promoting weight loss. Their mechanisms of action include inhibition of key lipid and carbohydrate hydrolyzing and metabolizing enzymes, modification of serum lipoprotein and apolipoproteins, blockage of intestinal absorption, disruption of adipogenesis and adipogenic factors, suppression of appetite etc. The chapter gives an account of medicinal plants used in antiobesity drug formulations in Ayurveda and their mechanisms of action, like Holoptelea integrifolia, Averrhoa bilimbi, Terminalia chebula, Picrorhiza kurroa, Acorus calamus etc. The knowledge and detailed study about these plants will help to control obesity and to increase awareness on the importance of medicinal plants in addressing the issue.