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Aim: The purpose of this study was to characterize a novel, non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR)gamma agonist, RWJ-348260, via both in vitro and in vivo approaches., Methods: The in vitro PPARgamma activities of RWJ-348260 were assessed in PPARgamma-GAL4 co-transfection assay, PPARgamma receptor binding assay, aP2 gene induction assay and preadipocyte differentiation assay. The in vivo efficacy of the compound was determined in rodent genetic diabetes models [ob/ob mouse, db/db mouse and Zucker diabetic fatty (ZDF) rat] following multiple days of oral administration., Results: RWJ-348260 selectively activated PPARgammain vitro. In vivo, RWJ-348260 produced significant decreases in plasma glucose, HbA1c, insulin and triglyceride levels. RWJ-348260 also dose-dependently improved oral glucose tolerance. In db/db mice, the compound up-regulated PPARgamma target genes in white adipose tissues. RWJ-348260 produced a lower extent of hepatocyte lipid deposition and a smaller increase in liver weight compared to rosiglitazone in db/db mice. While RWJ-348260 effectively normalized hyperglycaemia and dyslipidaemia, it did not change haematocrit, transaminase, alkaline phosphatase, total bilirubin levels or liver weights in ZDF rats., Conclusions: RWJ-348260 is a potent PPARgamma agonist with efficacious antidiabetic activity in diabetic animal models. The compound has an improved side-effect profile compared to rosiglitazone.

Twenty-one healthy, middle-aged volunteers and 8 patients with chronic lung disease were given live, attenuated influenza virus vaccine by nasal spray. Forced vital capacity, 1-sec forced expiratory volume, ratio of 1-sec forced expiratory volume to forced vital capacity, residual volume, ratio of airway conductance to lung volume, maximal expiratory flows after exhalation of 50 and of 75 per cent of the forced vital capacity, closing volume, slope of Phase III, volume of isoflow, single-breath diffusing capacity for CO, and arterial blood gases were measured before and 3, 7, 10, and 21 days after exposure. Vaccination was well tolerated by the healthy volunteers without change in pulmonary function. In contrast, the patients tended to develop increased respiratory symptoms and had a slight decrease in mean forced expiratory volume in 1 sec 3 weeks after vaccination.

Twenty healthy hospital workers produced maximal expiratory flow-volume curves before and after three vital capacity inhalations of an 80 percent helium and 20 percent oxygen mixture (HE+O2) in the morning and afternoon for four days during one week. Ten healthy trade union apprentices underwent the same tests, twice on one day and again one month later. Measurements made from curves (and their mean coefficients of variation) were: VisoV (105 percent) FVC (3 percent), FEF50% (6 percent), FEF75% (8 percent), the ratio of FEF50% breathing He+O2 to FEF50% breathing air (6 percent), and the ratio of FEF75% breathing He+O2 to FEF75% breathing air (9 percent). Differences among separate observers contributed significantly to the high variability of the VisoV. Diurnal changes and training effects over the week of study were not significant. In conclusion, VisoV is poorly reproducible compared with the FVC and expiratory flow rates at low lung volumes breathing air and He+O2. This should be considered when interpreting results in a given individual.