Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats.

Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFβRI inhibitor, BMS-986260, in rats and dogs.

Toxicity of Pexacerfont, a Corticotropin-Releasing Factor Type 1 Receptor Antagonist, in Rats and Dogs.

Pexacerfont is a corticotropin-releasing factor subtype 1 receptor antagonist that was developed for the treatment of anxiety- and stress-related disorders. This report describes the results of repeat-dose oral toxicity studies in rats (3 and 6 months) and dogs (3 months and 1 year). Pexacerfont was well tolerated in all of these studies at exposures equal to or greater than areas under the curve in humans (clinical dose of 100 mg).

Assessment of the Siksika chronic disease nephropathy-prevention clinic.

Objective: To determine if a community-based multifactorial intervention clinic led by a nurse practitioner would improve management of First Nations people at risk of developing chronic kidney disease.

Design: Qualitative descriptive study.

Setting: A nephropathy-prevention clinic in Siksika Nation, Alta.

Left ventricular endocardial pacing: a transarterial approach.

Introduction: We tested the feasibility of a new technique of direct left ventricular endocardial lead placement across the aortic valve in a chronic (six month) pig model. The potential for aortic valve damage, systemic embolization, and pacing lead maturation and function within the left ventricle are unknown.

Methods: Ten minipigs were successfully implanted with a transaortic left ventricular lead (Medtronic CapSureFix, Minneapolis, MN, USA) placed in the left ventricular apex via the carotid artery.

Urine acidification has no effect on peroxisome proliferator-activated receptor (PPAR) signaling or epidermal growth factor (EGF) expression in rat urinary bladder urothelium.

We previously reported prevention of urolithiasis and associated rat urinary bladder tumors by urine acidification (via diet acidification) in male rats treated with the dual peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist muraglitazar. Because urine acidification could potentially alter PPAR signaling and/or cellular proliferation in urothelium, we evaluated urothelial cell PPARalpha, PPARdelta, PPARgamma, and epidermal growth factor receptor (EGFR) expression, PPAR signaling, and urothelial cell proliferation in rats fed either a normal or an acidified diet for 5, 18, or 33 days. A subset of rats in the 18-day study also received 63 mg/kg of the PPARgamma agonist pioglitazone daily for the final 3 days to directly assess the effects of diet acidification on responsiveness to PPARgamma agonism.

Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR alpha/gamma agonist: Evidence for urolithiasis as the inciting event in the mode of action.

Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed.

Immediate and 1-year survival of out-of-hospital cardiac arrest victims in southern New Jersey: 1995-2000.

Most studies report the out-of-hospital cardiac arrest (OHCA) survival to hospital discharge. One-year survival and neurological outcomes in southern New Jersey in 1996-2000 were analyzed using a retrospective data review. There were 1,597 cases of OHCA.