Chlorpromazine-promethazine combo induces protective hypothermia in primate stroke model and Phase I patients

The three-species program first blocked the middle cerebral artery in mice, then administered C+P. Oxygen-consumption fell, glucose metabolism shifted to ketones, and infarct size dropped without the shivering seen with external cooling. Neurological scores improved across cold, ambient, and warm housing conditions. In rhesus monkeys the same intravenous regimen achieved sustained 33–34 °C hypothermia, lowered metabolic rate, and produced significantly smaller lesions on MRI compared with vehicle controls. Human data came from an open-label Phase I escalation in 32 acute ischemic stroke patients; the 100 mg dose lowered temperature and energy expenditure without serious adverse events. Therapeutic hypothermia trials have repeatedly failed to translate because surface cooling triggers thermoregulatory defenses and logistical delays. C+P bypasses those defenses pharmacologically, offering a portable intervention that could be given in the ambulance or emergency department before endovascular thrombectomy. The metabolic switch to fat oxidation may further limit reperfusion injury, an effect not captured by temperature alone. Larger efficacy trials must now measure 90-day modified Rankin Scale scores and confirm that infarct-volume reduction predicts functional gain rather than merely radiographic change.