انت الان في كلية الصيدلة

OBESITY BY DR SHEREEN M.AL-HUSSEINY تاريخ الخبر: 09/02/2023 | المشاهدات: 454

مشاركة الخبر :

Anti- Obesity Drugs ( AOD΄s): To Design a Near Ideal Drug)
Problems associated with older AODs
Most of these problems pertain to adverse cardiovascular effects (sibutramine, fenfluramine, dexfenfluramine, rainbow pills), increased suicidal risk (rimonabant) or enhanced likelihood of drug dependence and abuse (methamphetamine).
As such, certain drugs are recommended only for short-term use, due to addictive potential or emergence of tachyphylaxis (phentermine, amfepramone, cathin hydrochloride).
What should be overcomed to design a near ideal AOD?
An ideal AOM should sizeably and sustainably correct excess weight while reducing the risk of CVD and other comorbidities, devoid of the potential for abuse, tachyphylaxis and other adverse effects that have historically plagued this field.
Direct modulation with central nervous system (CNS) signalling pathways requires selective targeting of cellular circuits, which remains a technological stretch, as historic attempts have shown more than once.
For optimal weight loss efficacy, it seems apparent that drug therapy would have to target both energy intake and expenditure. However, intervention in central ‘survival’ mechanisms is a delicate endeavour that has led to withdrawal of many AOMs.
The vision

A recurrent question is whether pharmacology can ever be as efficacious in lowering body fat at tolerable doses as bariatric surgery, or alternatively might it in time prove superior.
Challenges confronting AOM development

Heterogeneity of patient cohorts: Obesity is a heterogeneous condition constituted by rare monogenetic and, more commonly, polygenic aetiology associated with neurobehavioural, endocrine and metabolic causes.
Neuroendocrine considerations: Various peripherally derived endocrine factors regulate food intake by jointly acting on defined neurocircuits in the hypothalamus and other brain regions.
. Although this tightly controlled system is pivotal for survival, it has emerged as a major obstacle to achieving sizeable body weight reduction, as it progressively defends against negative energy balance and undernutrition as it progressively defends against negative energy balance and undernutrition.
Another obstacle in weight loss pharmacology is that persistent elevation of adiposity signals such as leptin and insulin results in desensitization, leading to an impaired responsiveness of this homeostatic system (leptin supplementation shows remarkable efficacy in lowering body weight in individuals with congenital leptin deficiency, but is largely ineffective in more common polygenetic forms of obesity
Translation of pharmacology from animals to humans: whereas weight loss effects generally translate from rodents to humans, maximal efficacy is historically two to four times lower in humans relative to rodents.

Novel and emerging obesity therapies
Despite numerous disappointments, several prominent therapeutic targets have captured the attention of the scientific community.
Four target areas (leptin, ghrelin, mitochondrial uncouplers and growth differentiation factor 15 (GDF15)) were initiated and advanced with obesity constituting the primary therapeutic purpose.

By contrast, the research pertaining to incretins and, most notably, GLP1, as well as amylin, was predominately focused on diabetes that evolved through concurrent empirical observations of body weight lowering. However, the maturation of incretin biology has led to late-phase AOM candidates that potently activate GLP1R and/or GIPR to establish a much elevated, new benchmark for performance.
Weight loss drugs in clinical development
GLP1/glucagon dual agonists, GIP/GLP1 dual agonists, GIP/GLP1/glucagon tri-agonists, GIPR agonists, GLP1 R agonist, Glucagon analogue, Leptin sensetizers, Amylin/calcitonin dual agonists, Amylin analogues, Drugs targeting the ghrelin pathway, Mitochondrial uncoupler, Other appetite suppressants, GIP, glucose-dependent insulinotropic polypeptide