Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

摘要: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment survivors out hospital cardiac arrest. However, this type therapy cumbersome and associated with several side-effects. We investigated feasibility using a transient receptor potential vanilloid 1 (TRPV1) agonist obtaining drug-induced sustainable hypothermia. First, we screened heterogeneous group TRPV1 agonists secondly tested hypothermic properties selected candidate by dose-response studies. Finally in large animal. screening was conscious rats, experiments rats cynomologus monkeys, finally young cattle (calves body weight as an adult human). were administered continuous intravenous infusion. Screening: Dihydrocapsaicin (DHC), component chili pepper, displayed desirable profile regards to duration, depth control rats. Dose-response experiments: In both monkeys DHC caused dose-dependent immediate decrease temperature. Thus infusion at doses 0.125, 0.25, 0.50, 0.75 mg/kg/h maximal ΔT (°C) compared vehicle -0.9, -1.5, -2.0, -4.2 within approximately hour until 6 stopped. Finally, calves able maintain > -3°C more than 12 hours. Our data support hypothesis that dihydrocapsaicin testing primary or adjunct method inducing maintaining