Tesofensine

Abstract: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity. This development is preceded by increased understanding of the underpinnings of energy regulation and neurohormonal pathways involved in energy homeostasis. Though there are approved anti-obesity drugs available in the USA, newer drugs are now in the pipeline for development given the urgent need. This review focuses on anti-obesity drugs in the pipeline including centrally acting agents (setmelanotide, neuropeptide Y antagonist [velneperit], zonisamide-bupropion [Empatic], cannabinoid type-1 receptor blockers), gut hormones and incretin targets (new glucagon-like-peptide-1 [GLP-1] analogues [semaglutide and oral equivalents], amylin mimetics [davalintide, dual amylin and calcitonin receptor agonists], dual action GLP-1/glucagon receptor agonists [oxyntomodulin], triple agonists [tri-agonist 1706], peptide YY, leptin analogues [combination pramlintide-metreleptin]), and other novel targets (methionine aminopeptidase 2 inhibitor [beloranib], lipase inhibitor [cetilistat], triple monoamine reuptake inhibitor [tesofensine], fibroblast growth factor 21), including anti-obesity vaccines (ghrelin, somatostatin, adenovirus36). With these new drugs in development, anti-obesity therapeutics have potential to vastly expand allowing better treatment options and personalized approach to obesity care.

Abstract: For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT(2C) receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individual's natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite.

Abstract: For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate, which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in Phase III trials for obesity, and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist, which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues.

Abstract: Adverse events; Antiobesity; Antiobesity drugs; Anxiety; Bupropion; Cannabinoid receptor; CB1 receptor; Central; Contrave; Depression; Drugs; Ecopipam; Lorcaserin; μ-opioid receptor; Naltrexone; Obesity; Psychiatric; Psychological; Rimonabant; Sedation; Sibutramine; Side effects; Sleep; Taranabant; Tesofensine; Topiramate; Treatments; Zonisamide. SUMMARY Introduction: Central neurochemical systems including the monoamine, opi- oid, and cannabinoid systems have been promising targets for antiobesity drugs that modify behavioral components of obesity. In addition to modulating eating behavior, centrally acting antiobesity drugs are also likely to alter emo- tional behavior and cognitive function due to the high expression of recep- tors for the neurochemical systems targeted by these drugs within the fronto- striatal and limbic circuitry. Methods: This paper reviewed the neuropsychi- atric adverse effects of past and current antiobesity drugs, with a central mech- anism of action, linking the adverse effects to their underlying neural sub- strates and neurochemistry. Results: Antiobesity drugs were found to have varying neuropsychiatric adverse event profiles. Insomnia was the most com- mon adverse effect with drugs targeting monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some positive effects on mood and anxiety and may have added therapeutic benefits in obese patients with comorbid depression and anxiety symptoms. Sedation and tiredness were the most common adverse effects reported with drugs targeting the m-opioid re- ceptors (i.e., naltrexone) and combination therapies targeting the opioid and monoamine systems (i.e., Contrave TM ). Cognitive impairments were most fre- quently associated with the antiepileptic drugs, topiramate and zonisamide, consistent with their sedative properties. Drugs targeting the cannabinoid sys- tem (rimonabant and taranabant) were consistently associated with symp- toms of anxiety and depression, including reports of suicidal ideation. Simi- lar adverse events have also been noted for the D1/D5 antagonist ecopipam. Conclusion: These findings highlight the need to assess neuropsychiatric ad- verse events comprehensively using sensitive and validated methods early in the clinical development of candidate antiobesity drugs with a central mecha- nism of action.