Risk and safety assessment of exogenous human brain natriuretic peptide in cynomolgus monkeys (Macaca fascicularis)--a subchronic study.

Safety evaluation of synthetic human brain natriuretic peptide (shBNP) was carried out in cynomolgus monkeys (Macaca fascicularis) by 2-week intravenous toxicity studies. System exposure was also assessed throughout the whole administration. Three test groups received doses of 432, 1440 and 4320 microg/kg/day of shBNP, with a high infusion rate of 36 mL/kg/hr for 30 min compared to the clinical protocol of continuous infusion over 24h. Commercially available recombinant human brain natriuretic peptide (rhBNP) of 1440 microg/kg/day was used as positive control. The 2-week repeated intravenous doses of shBNP resulted in reversible increased serum LDH and CPK in monkeys receiving 1440 and 4320 microg/kg/day dose with no pertinent histopathological changes. Some changes related to the pharmacologic effects of BNP including hypotension was observed after administration. No treatment-related mortalities or renal dysfunction were found. Controversy about the safety issue of BNP as an exogenous hormone concerning ventricular remodeling and myocardial cell apoptosis, coupled with our results, were also discussed. The no-observed-adverse-effect level (NOAEL) was considered to be 432 microg/kg /day, which is about 20 times higher than the commonly used clinical dose. The results of the present study advocate the safety of shBNP in cynomolgus monkeys at levels used in the study.

A central role for R7bp in the regulation of itch sensation.

Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gß5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.

N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population.

BACKGROUND: Mortality rates are higher in renal transplant recipients (RTR) than in the general population (GP). It is unknown what risk factors account for this difference. METHODS: We prospectively followed a cohort of 606 RTR for 3026 person-years, during which 95 died. A GP cohort of 3234 subjects was followed for 24,940 person-years, during which 130 died. RESULTS: All investigated risk factors, except ethnicity, body mass index, and total cholesterol, differed significantly between cohorts, with an adverse risk profile in the RTR. The age-adjusted and gender-adjusted hazard ratio for mortality in RTR was 6.2 (95% confidence interval [CI] 4.6-8.3) compared with GP, which was reduced to 2.4 (95% CI 1.6-3.6), 4.3 (95% CI 3.0-6.1), and 5.0 (95% CI 3.5-7.3) after additional adjustment for differences in N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine clearance, and need for antihypertensive medication, respectively (all P<0.001), whereas adjustment for variables more related to atherosclerosis, including history of cardiovascular disease, diabetes, and high-density lipoprotein cholesterol, did not affect the difference in mortality between RTR and GP. Associations of NT-proBNP, creatinine clearance, and the use of antihypertensive medication with mortality were significantly steeper in RTR than in GP. Risk for mortality was similar for RTR and GP with low NT-proBNP (<100 pg/mL). CONCLUSIONS: Elevated NT-proBNP, low creatinine clearance, and need for antihypertensive medication are stronger risk factors for mortality in RTR than in GP. The increased mortality seen in the RTR population may well be related to cardiac failure rather than "accelerated atherosclerosis."