Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials.

AIMS: To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin). METHODS: We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks' treatment with aleglitazar 150 µg/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26. RESULTS: Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and -0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication. CONCLUSIONS: Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables.

Cadmium induces apoptosis in a human T cell line.

Cadmium, a potent toxic metal, poses a serious environmental threat but the mechanisms of its toxicity remain unclear. In the present study, we investigated the nature of cadmium-induced cell death in the human T cell line CEM-C12. Cadmium was time- and dose-dependently toxic for CEM-C12 cells, cell death being preceded by chromatin condensation and DNA fragmentation. Quantification of the latter indicated an increase above 4 microM cadmium, with maximal fragmentation at 8 to 10 microM. By contrast, when CEM-C12 cells were exposed to higher cadmium concentrations (50 microM), cell death increased without concomitant chromatin condensation or DNA fragmentation. Thus, cadmium at low and high concentration kills CEM-C12 cells by apoptosis and necrosis, respectively. Addition of cycloheximide reduced the apoptotic effect of cadmium, suggesting that cadmium-induced apoptosis is an process depending on protein synthesis. Verapamil, a calcium/potassium channel blocker, markedly increased the viability of CEM-C12 cells treated by low cadmium concentrations and prevented DNA fragmentation. The apoptotic effect of cadmium suggests a possible mechanism for lymphocyte damage occurring after in vivo exposure to cadmium.

Immunoregulatory functions of paf-acether. IX. Modulation of apoptosis in an immature T cell line.

We investigated the ability of a phospholipid cytokine, paf-acether to modulate programmed cell death in an immature human T cell line CEM-C12. Paf-acether alone did not cause cell death, but when it was added to CEM-C12 cells in the presence of calcium ionophore, a marked increase in cell mortality and DNA fragmentation was observed compared with calcium ionophore alone. This effect was dose-dependent between 2 and 10 microM paf-acether and specific in that lysophosphatidylcholine had a minimal effect. Thus, in association with another signal, paf modulates apoptotic processes in an immature human T cell line. This may be relevant to intrathymic lymphocyte maturation.