更他氯胺--必威体育精装版肌松药.pptVIP

Study design - Cardiopulmonary effects of CW002 Male beagles Each animal studied twice First: Estimation of ED95 from multiple doses and confirmation of cysteine reversal Second: Assessment of cardiopulmonary effects with incremental dosing based upon multiples of ED95 Systemic and pulmonary hemodynamics along with left ventricular volume, inotropy, and lusitropy Breath to breath measurement of ventilatory pressure and compliance During incremental dosing protocol, blood drawn for histamine analysis before and after bolus injection L-cysteine as a drug: Efficacy and safety Study design – Cysteine reversal of CW002 Male beagles Each animal studied 4 times CW002 at 9XED95 followed by 10, 20, 50 or 100 mg/kg cysteine Invasive assessment of cardiopulmonary effects at 100 mg/kg For each experiment, cysteine given 1 minute after CW002, with dose repeated 10 minutes later to assess residual cysteine effects Clinical experience with L-cysteine N-acetyl L-cysteine FDA approved for treatment of acetaminophen toxicity L-cysteine incorporated in TPN of neonates at doses of 50-100 mg/kg per day Wide application of both the parent compound and the N-acetyl derivative in conditions where increased glutathione production beneficial Multiple reports indicate neuroprotection Preclinical toxicology for L-cysteine reversal of CW002 LD50 in rats: 1.8 g/kg oral, 1.16 IV, 1.4 SQ, 1.6 IP Toxicology studies (FDA guidelines) at Charles River Laboratories: Conscious rats, 750 mg/kg IV bolus Conscious dogs, 400 mg/kg IV bolus Anesthetized dogs, 200 mg/kg IV bolus to reverse CW002, awakened then sacrificed 2 days or 2 weeks later No clinical, biochemical, or histological evidence of organ toxicity However…. A variety of studies in rodents have indicated neuroexcitation and neurotoxicity Role of high, sustained CNS levels in the pathogenesis of some neurodegenerative diseases? N-acetyl L-cysteine used for acetaminophen toxicity reported to have incidence of cardiopulmonary side effects *