Aegera Therapeutics, Inc.

Ins2C96Y Akita mice represent a model of spontaneous early-onset diabetes mellitus, expressing a mutant non-functional isoform of insulin. These mice are characterized by a reduced number of pancreatic beta cells resulting in hypoinsulinemia and hyperglycemia. We obtained longitudinal measures of morning fasting blood glucose levels and gait performance. Sciatic nerve electrophysiology was also performed and the performance of these mice on spatial memory tasks was measured longitudinally. We observed a progressive increase in fasting blood glucose levels that was proportionally associated with increased gait disturbances. Diabetes induced a decrease in the sensory nerve conduction velocity up to the age of 40 weeks. Glucose transporter (GLUT) 3 levels were reduced in the hippocampus of the aged Ins2C96Y Akita mice. However, we failed to detect any significant deficits during reference, reversal or probe tests in the Morris water maze or in a spontaneous alternation task up to the age of 34 weeks old. We found that, up to the age of 34 weeks old, uncontrolled hyperglycemia produced peripheral neuropathy and reduced hippocampal GLUT3 levels in the absence of any effect on spatial memory processing.

Mice that lack tumor necrosis factor-alpha (TNF) receptors are more susceptible than wild-type animals to brain injury produced by kainic acid or transient focal ischemia suggesting that the rapid production of TNF that occurs after these insults serves a neuroprotective role. The mechanisms by which TNF reduces neuronal loss after brain injury may involve the up-regulation of proteins that maintain calcium homeostasis or reduce free radical generation. We report here that systemic administration of kainic acid rapidly elevates expression of mRNA encoding neuronal apoptosis inhibitor protein (NAIP) in the hippocampus and that this increase does not occur in mice that lack TNF receptors. Given that NAIP overexpression can reduce neuronal injury by blocking apoptosis, our findings suggest that induction of the naip gene may contribute to the neuroprotective properties of TNF.

The objectives of this study were to evaluate both the compatibility and the stability of hydromorphone when mixed with different drugs and to provide recommendations for appropriate conservation conditions.Four drug mixtures used for palliative care were stored in polypropylene syringes at different temperatures (25°C and 4°C) up to 96 h.These mixtures were: M1: hydromorphone 10.00 mg mL-1, midazolam 1.00 mg mL-1, famotidine 0.40 mg mL-1; M2: hydromorphone 10.00 mg mL-1, metoclopramide 0.50 mg mL-1, haloperidol 0.50 mg mL-1; M3: hydromorphone 10.00 mg mL-1, ketorolac 1.50 mg mL-1, metoclopramide 0.50 mg mL-1, famotidine 0.40 mg mL-1; and M4: hydromorphone 10.00 mg mL-1, dimenhydrinate 5.00 mg mL-1, haloperidol 0.50 mg mL-1, famotidine 0.40 mg mL-1, scopolamine 0.04 mg mL-1.Drug mixtures were prepared in NaCl 0.9%, to obtain a 100 mL final solution containing the maximum daily dose of each component.For the separation and quantification of active ingredients fast, precise, accurate, and sensitive methods were developed.Drugs were separated using a high performance liquid chromatog.-diode array detector (HPLC-DAD) with a Zorbax Eclipse XDB C18 column under gradient elution.Just after preparing the mixture of drugs and then after 4, 8, 12, 24, 48, 72, and 96 h, the phys. appearance of each solution was observed and drug concentrations were controlled.Stability was assumed if the loss after 96 h was < 10% of the initial concentration