Aleglitazar, a balanced PPARα/γ agonist, has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin.

BACKGROUND: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones. OBJECTIVE: To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar. RESEARCH DESIGN AND METHODS: In a two-cohort, open-label, randomised, three-period crossover study, 44 healthy subjects received once-daily oral doses of aleglitazar 300 µg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and aleglitazar co-administered with each statin for 7 days. Plasma concentrations of each drug were measured and pharmacokinetic parameters determined on day 7 in each period. MAIN OUTCOME MEASURES: Peak observed plasma concentration (C(max)) and total exposures (AUC(0 - 24)) of aleglitazar, atorvastatin and rosuvastatin. RESULTS: C(max) and AUC(0 - 24) to aleglitazar were similar, whether administered alone or in combination with a statin. Total exposure to either statin was unaffected by co-administration with aleglitazar. C(max) treatment ratios for both statins exceeded the conventional no-effect boundary (1.25) when administered with aleglitazar. CONCLUSIONS: Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.

Evidence for incorporation of free-floating mesothelial cells as a mechanism of serosal healing.

Regeneration of the mesothelium is unlike that of other epithelial-like surfaces, as healing does not occur solely by centripetal migration of cells from the wound edge. The mechanism of repair of mesothelium is controversial, but it is widely accepted, without compelling evidence, that pluripotent cells beneath the mesothelium migrate to the surface and differentiate into mesothelial cells. In this study we examined an alternative hypothesis, using in vivo cell-tracking studies, that repair involves implantation, proliferation and incorporation of free-floating mesothelial cells into the regenerating mesothelium. Cultured mesothelial cells, fibroblasts and peritoneal lavage cells were DiI- or PKH26-PCL-labelled and injected into rats immediately following mesothelial injury. Implantation of labelled cells was assessed on mesothelial imprints using confocal microscopy, and cell proliferation was determined by proliferating cell nuclear antigen immunolabelling. Incorporation of labelled cells, assessed by the formation of apical junctional complexes, was shown by confocal imaging of zonula occludens-1 protein. Labelled cultured mesothelial and peritoneal lavage cells, but not cultured fibroblasts, implanted onto the wound surface 3, 5 and 8 days after injury. These cells proliferated and incorporated into the regenerated mesothelium, as demonstrated by nuclear proliferating cell nuclear antigen staining and membrane-localised zonula occludens-1 expression, respectively. Furthermore, immunolocalisation of the mesothelial cell marker HBME-1 demonstrated that the incorporated, labelled lavage-derived cells were mesothelial cells and not macrophages as it had previously been suggested. This study has clearly shown that serosal healing involves implantation, proliferation and incorporation of free-floating mesothelial cells into the regenerating mesothelium.