A 9-Month Toxicity and Toxicokinetic Assessment of Subcutaneous Pegylated Human C-peptide (CBX129801) in Cynomolgus Monkeys.

C-peptide is formed in the biosynthesis of insulin and is therefore deficient in patients with type 1 diabetes mellitus. A pegylated form of human synthetic C-peptide (CBX129801) has been developed to extend the half-life of the native peptide and is undergoing clinical investigation as replacement therapy to treat diabetic peripheral neuropathy. This monkey study was conducted to evaluate the toxicity of CBX129801 with weekly subcutaneous dosing for 39 weeks at dose levels of 0 (vehicle), 0.4, 1.33, and 4.0 mg/kg/wk. No systemic adverse effects were observed at any dose with maximal CBX129801 plasma concentrations of 735 to 1050 nmol/L during the dosing period (physiological range is 1-3 nmol/L). CBX129801-related effects were limited to minimal macrophagic vacuolization at the injection sites and in the associated draining (axillary) lymph nodes; these local effects largely resolved by the end of a 7-week recovery period. No systemic macrophagic vacuolization was observed. Additionally, there was no histological evidence for plaque formation in the major arteries of these nondiabetic animals.

Prevention of descending pneumonia in rts with perflubron-delivered tobramycin.

OBJECTIVES: Patients undergoing emergent endotracheal intubation are at increased risk for developing pneumonia. Although numerous strategies have been investigated to reduce ventilator-associated pneumonia (VAP), the incidence of VAP and its associated mortality remains high. This investigation tested the hypothesis that LiquiVent (Alliance Pharmaceutical, San Diego, CA-LV) delivered antibiotics (via spray-dried microspheres-SDM) would improve survival in a rat model of descending gram-negative pneumonia. METHODS: Wistar rats (n = 49) were randomized to receive prophylaxis with 1). nothing (controls); 2). intramuscular (IM) tobramycin, 3). intratracheal LV plus SDM shells (vehicle), 4). intratracheal LV plus SDM shells plus IM tobramycin, or 5). intratracheal LV plus SDM containing 1 mg/kg of tobramycin. All interventions were given 24 hours before a bacterial challenge with 10(8) colony-forming units of intratracheal Klebsiella pneumoniae. Mortality at ten days was the sole outcome measure. Survival in individual groups was compared with controls by Fisher's exact test with Bonferroni correction for multiple comparisons. RESULTS: All animals in the control group died of pneumonia within ten days of bacterial inoculation (0% survival). Prophylaxis with either IM tobramycin or SDM vehicle plus IM tobramycin provided no protection (0% survival). This is in sharp contrast to the cohort receiving pretreatment with tobramycin-containing SDM delivered via LV, in which 60% of the animals survived to study completion (p < 0.05). CONCLUSIONS: Prophylaxis with SDM containing antibiotics delivered in low-dose LV provided significant protection in a rat model of descending gram-negative pneumonia. These data support the hypothesis that perfluorocarbon-delivered intratracheal antimicrobials may be useful in the prevention of VAP.