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Summary Background Obesity is a major issue in Australia and globally. Many individuals struggle to maintain weight loss with lifestyle modification, and adjunctive pharmacotherapy may help. Historically, there have been limited pharmacotherapies for managing obesity. In addition, previous treatments such as phentermine-fenfluramine, rimonabant and sibutramine were withdrawn due to safety issues, resulting in lingering safety concerns. Methods This is a narrative review of published data examining four new pharmacotherapy options for weight management in Australia. Of four new therapeutic options, three may be approved in Australia shortly and one — liraglutide 3.0mg — was approved in December 2015. Liraglutide is a glucagon-like peptide-1 receptor agonist that appears to act by increasing satiety and reducing food intake. Lorcaserin is a selective agonist of the serotonin 2C receptor, which mediates anorectic activity. The naltrexone/bupropion extended release (ER) combination utilises synergistic effects of the two component drugs, mediated via neurons in the hypothalamus, to reduce energy intake. Phentermine/topiramate ER combines the appetite suppressant phentermine with topiramate, an anti-epileptic with appetite-suppressant effects. All can result in meaningful improvements in obesity-related diseases, including diabetes and cardiovascular disorders) in large phase 3 trials, with efficacy demonstrated over 3 years for liraglutide 3.0 mg and 1–2 years for the rest. Conclusions The landscape of obesity treatment is changing rapidly. Of the new therapeutic options presented, all options have associated adverse events requiring long-term safety data, but the availability of new options is a welcome development.

Hydroxamic acid-based histone deacetylase inhibitors (HDACi) are a class of epigenetic agents with potentially broad therapeutic application to several disease states including post angioplasty mediated neointimal hyperplasia (NIH). Precise spatiotemporal control over the release of HDACi at the target blood vessel site is required for the safe and successful therapeutic use of HDACi in the setting of drug eluting balloon catheter (DEBc) angioplasty treatment of NIH. We aimed to develop and characterise a novel photoactive HDACi, as a potential coating agent for DEBc. Metacept-3 1 was caged with a photo-labile protecting group (PPG) to synthesise a novel UV365nm active HDACi, caged metacept-3 15. Conversion of caged metacept-3 15 to active/native metacept-3 1 by UV365nm was achievable in significant quantities and at UV365nm power levels in the milliwatt (mW) range. In vitro evaluation of the biological activity of pre and post UV365nm activation of caged metacept-3 15 identified significant HDACi activity in samples exposed to short duration, mW range UV365nm. Toxicity studies performed in human umbilical vein endothelial cells (HUVEC's) identified significantly reduced toxicity of caged metacept-3 15 pre UV365nm exposure compared with native metacept-3 1 and paclitaxel (PTX). Taken together these findings identify a novel photo-activated HDACi, caged metacept-3 15, with pharmacokinetic activation characteristics and biological properties which may make it suitable for evaluation as a novel coating for targeted DEBc angioplasty interventions.

Abdominal aortic aneurysm (AAA) is a common disease associated with significant cardiovascular morbidity and mortality. The pathogenesis of AAA is poorly defined, making targeting of new therapies problematic. Current evidence favours an interaction of multiple environmental and genetic factors in the initiation and progression of AAA. Epigenetics is the term used to define the properties of the genome that are not explained by the primary sequence, but are due to the modifications of DNA and/or associated proteins. Previous research indicates the association of gene specific promoter DNA hyper-methylation and global DNA hypo-methylation with atherosclerosis. Evidence also suggests an important role for epigenetic processes such as histone acetylation in cardiovascular diseases including atherosclerosis and restenosis. Altered DNA methylation or histone acetylation occur in inflammation, cellular proliferation and remodelling processes and therefore maybe relevant to the pathology of AAA. Important risk factors for AAA, including cigarette smoking, older age, male gender and hypertension, have been linked with epigenetic effects and thus could act in this way to promote AAA. In this review, we discuss the potential role of epigenetic mechanisms in AAA. Since epigenetic alterations are to some extent reversible, further study of this area may identify new treatment targets for AAA.

Summary PAI-2, the most enigmatic member of the serine protease inhibitor gene superfamily, is generally recognised as an inhibitor of urokinase (u-PA) and, to a lesser extent, tissue-type plasminogen activator. The role of plasminogen activator inhibitor type-2 (PAI-2) in the regulation of a u-PA-mediated proteolysis is well established. However, the predominantly cytosolic location of PAI-2 has raised much speculation as to the role this serpin plays in intracellular proteolysis and in particular in the events leading to cellular differentiation and apoptosis. In vitro studies have highlighted the fact that PAI-2 is one of the most tumour necrosis factor (TNF) responsive genes so far described suggesting that PAI-2 may also play a significant role in TNF biology.

Clopidogrel is a widely used anti-platelet agent for the prevention of arterial thrombosis. Clopidogrel is administered as a pro-drug and metabolised to its active metabolite by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. The active metabolite is responsible for the anti-platelet activity of clopidogrel. Recent studies demonstrate that single nucleotide polymorphisms, (SNP's), in the gene for CYP2C19 result in significantly reduced production of the active metabolite of clopidogrel. Additional studies demonstrate that patients with SNP's in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5, have reduced production of the active metabolite of clopidogrel, reduced inhibition of platelet aggregation and increased incidence of coronary, cerebrovascular, and coronary stent thrombosis. We have been interested in determining the CYP2C19 genotype in cases of coronary stent thrombosis whilst on clopidogrel treatment and provide two case reports of coronary stent thrombosis whilst taking clopidogrel with subsequent CYP2C19 genotyping. As patients at risk of atherothrombosis in general, and stent thrombosis in particular, may be receiving or considered for anti-platelet therapy including clopidogrel, genotyping for CYP2C19 SNP's may be of benefit in the selection of appropriate anti-platelet therapy.