No abstract

The dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic β cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in-class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007, although approval in the US is still pending), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011 and is undergoing regulatory review in Japan and the EU. As the number of DPP-4 inhibitors on the market increases, potential differences among the different members of the class become important when deciding which agent is best suited for an individual patient. The aim of this review is to provide a comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors, and to pinpoint pharmacological differences of potential interest for their use in therapy. Despite their common mechanism of action, these agents show significant structural heterogeneity that could translate into different pharmacological properties. At the pharmacokinetic level, DPP-4 inhibitors have important differences, including half-life, systemic exposure, bioavailability, protein binding, metabolism, presence of active metabolites and excretion routes. These differences could be relevant, especially in patients with renal or hepatic impairment, and when considering combination therapy. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. Data on nonglycaemic parameters are scant at present and do not allow a comparison among DPP-4 inhibitors. Several phase III trials of DPP-4 inhibitors are currently ongoing; these trials, along with post-marketing surveillance data, will hopefully increase our knowledge about the long-term efficacy and safety of DPP-4 inhibitor therapy, the effect on pancreatic cell function and peripheral glucose metabolism, and the effect on cardiovascular outcomes in patients with type 2 diabetes.

No abstract

We studied the efficiency of plasmid/liposome complexes, Moloney murine leukemia virus-derived (MMLV) retroviruses, pseudotyped vesicular stomatitis virus protein-G (VSV-G)-containing retroviruses, and adenoviruses in delivering genes into the rabbit carotid artery using a silastic collar applied to the adventitia. This method was used for gene transfer because (a) it provides a gene delivery reservoir; (b) no intraluminal manipulations are performed; (c) installation of the collar induces arterial smooth muscle cell (SMC) proliferation and enhances retroviral gene transfer efficiency where target cell proliferation is required. The transfer of the beta-galactosidase (lacZ) marker gene to the adventitia and media occurred with all gene transfer systems. Adenoviruses also transferred the beta-galactosidase gene to some endothelial cells. After 5 days, adenoviral vectors produced the highest gene transfer efficiency with up to 10%+/-6% of cells showing beta-galactosidase activity. Pseudotyped VSV-G retroviruses were also effective in achieving gene transfer in 0.05%+/-0.03% of cells in the adventitia and media. Plasmid/liposome complexes and MMLV retroviruses infected 0.05%+/-0.03% and <0.01%+/-0.01% of cells, respectively. It is concluded that replication-deficient adenoviruses, VSV-G pseudotyped retroviruses, and plasmid/liposome complexes can be used for gene transfer to the arterial wall using the collar method. Because the endothelium remains anatomically present throughout the experiments, the model may be useful for the gene transfer studies involving diffusible or secreted gene products that primarily act on the endothelium. Effects on medial SMC and even endothelium can be achieved from the adventitial side, suggesting an alternative route for the delivery of therapeutically useful genes into the arterial wall.

Plasma-membrane composition plays a crucial role in most of the cellular functions that depend on membrane processes. In virtually all cell types the proteolytic processing of Alzheimer amyloid precursor protein (APP) to generate soluble APP (sAPP) is believed to occur at the plasma membrane or in its immediate proximity. Alteration of this metabolic pathway has been linked to the pathogenesis of Alzheimer's disease. We analysed the effect of membrane cholesterol enrichment on APP metabolism. Incubation of COS cells with increasing concentrations of nonesterified cholesterol carried by rabbit β-very low-density lipoprotein caused a dose-dependent inhibition of sAPP release : 70 % inhibition with 10 µg\ml non-esterified cholesterol. A less pronounced inhibitory effect was observed on treatment with