Pharmacotherapies for Obesity: Past, Current, and Future Therapies

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs

Fenitrothion: toxicokinetics and toxicologic evaluation in human volunteers.

An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the acceptable daily intake (ADI)] and 0.36 mg/kg/day (72 X ADI) administered as two daily divided doses for 4 days in 12 human volunteers was designed and undertaken after results from a pilot study. On days 1 and 4, blood and urine samples were collected for analysis of fenitrothion and its major metabolites, as well as plasma and red blood cell cholinesterase activities, and biochemistry and hematology examination. Pharmacokinetic parameters could only be determined at the higher dosage, as there were insufficient measurable fenitrothion blood levels at the lower dosage and the fenitrooxone metabolite could not be measured. There was a wide range of interindividual variability in blood levels, with peak levels achieved between 1 and 4 hr and a half-life for fenitrothion of 0.8-4.5 hr. Although based on the half-life, steady-state levels should have been achieved; the area under the curve (AUC)(0-12 hr) to AUC(0-(infinity) )ratio of 1:3 suggested accumulation of fenitrothion. There was no significant change in plasma or red blood cell cholinesterase activity with repeated dosing at either dosage level of fenitrothion, and there were no significant abnormalities detected on biochemical or hematologic monitoring

Anti-Obesity Drugs: A Review about Their Effects and Safety

The current recommendations for the treatment of obese people include increased physical activity and reduced calories intake. When the behavioral approach is not sufficient, a pharmacologic treatment is recommended. In past years, numerous drugs have been approved for the treatment of obesity; however, most of them have been withdrawn from the market because of their adverse effects. In fact, amphetamine, rimonabant and sibutramine licenses have been withdrawn due to an increased risk of psychiatric disorders and non-fatal myocardial infarction or stroke. Even if orlistat is not as effective as other drugs in reducing body weight, orlistat is presently the only available choice for the treatment of obesity because of its safety for cardiovascular events and positive effects on diabetic control. Hopefully, more effective and better tolerated anti-obesity drugs will be developed through an improved understanding of the multiple mechanisms and complex physiological systems targeting appetite

Challenges for Australia's Bio/Nanopharma Policies: trade deals, public goods and reference pricing in sustainable industrial renewal

Industrial renewal in the bio/nanopharma sector is important for the long term strength of the Australian economy and for the health of its citizens. A variety of factors, however, may have caused inadequate attention to focus on systematically promoting domestic generic and small biotechnology manufacturers in Australian health policy

Vaccination against GIP for the treatment of obesity.

BACKGROUND: According to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR(-/-)) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity. METHODOLOGY/PRINCIPAL FINDINGS: In order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance. CONCLUSIONS/SIGNIFICANCE: This study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans

Sparsity enables estimation of both subcortical and cortical activity from MEG and EEG

Subcortical structures play a critical role in brain function. However, options for assessing electrophysiological activity in these structures are limited. Electromagnetic fields generated by neuronal activity in subcortical structures can be recorded noninvasively, using magnetoencephalography (MEG) and electroencephalography (EEG). However, these subcortical signals are much weaker than those generated by cortical activity. In addition, we show here that it is difficult to resolve subcortical sources because distributed cortical activity can explain the MEG and EEG patterns generated by deep sources. We then demonstrate that if the cortical activity is spatially sparse, both cortical and subcortical sources can be resolved with M/EEG. Building on this insight, we develop a hierarchical sparse inverse solution for M/EEG. We assess the performance of this algorithm on realistic simulations and auditory evoked response data, and show that thalamic and brainstem sources can be correctly estimated in the presence of cortical activity. Our work provides alternative perspectives and tools for characterizing electrophysiological activity in subcortical structures in the human brain

Medicinal importance of grapefruit juice and its interaction with various drugs

Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P – 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P – glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P – 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug – grapefruit juice eraction with their mechanisms of action and have presented the clinical implications of these interactions

Sibutramine on cardiovascular outcome.

S ibutramine, a combined norepi-nephrine and serotonin reuptakeinhibitor, is effective in the man-agement of obese patients requiring phar-macotherapy as part of a multimodal approach to weight loss. It improves in-sulin resistance markers, glucose metab-olism, and atherogenic dyslipidemia in both diabetic and nondiabetic patients, most of these effects resulting fromweight loss. However, sibutramine exerts a pe-ripheral sympathomimetic effect that induces a moderate increase in heart rate and attenuates the reduction in blood pressure attributable to weight loss or even slightly increases blood pressure. Since 2002, several cardiovascular adverse event