Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration.

Melatonin is a highly effective treatment in different animal models of excitotoxicity or ischemia/reperfusion injury. Due to a lack of patentability, commercial sponsors are not interested in funding clinical evaluations of melatonin. Investigators may initiate small-scale clinical evaluation, and intravenous (i.v.) administration is appropriate in acute stroke patients. Institutional Review Boards may require proper preclinical evaluation of the preparation. In this pharmacokinetic and safety study, melatonin in propylene glycol was evaluated in adult male Sprague-Dawley rats. Following a single i.v. injection at 5 or 15 mg/kg, plasma concentrations of melatonin increased to 39 and 199 million pg/mL at 2 min and 128,000 and 772,000 pg/mL at 120 min. Within 60 min of injection, the blood pressure, heart rate and body temperature remained unaffected. Melatonin at 5 mg/kg did not influence the complete blood counts at 60 min, but melatonin at 15 mg/kg had some effects on the differential white cell and platelet counts. Melatonin at 5 or 15 mg/kg slightly elevated some liver enzymes at 60 min of injection, and melatonin at higher dose also elevated plasma creatinine and lactate dehydrogenase levels. At 24 hr after completion of six daily injections of melatonin, there was a 5.5% reduction in body weight. Gross postmortem examination and histological examination of the brain, kidney, liver and spleen did not reveal any evidence of toxicity. In conclusion, melatonin in propylene glycol markedly elevates plasma levels of melatonin with no serious toxicity. This preparation should be further evaluated in human patients.

Melatonin reduces infarction volume in a photothrombotic stroke model in the wild-type but not cyclooxygenase-1-gene knockout mice.

Cyclooxygenase (COX)-2 plays a harmful role in cerebral ischemic/reperfusion injury, but the role of COX-1 is uncertain. In the present study, cerebral infarct was induced by photothrombosis. Intraperitoneal injections of melatonin at 15 g/kg or its vehicle were made at 0.5 hr before stroke and 24 and 48 hr after stroke. Cerebral blood flow (CBF) in the penumbra was monitored during stroke using a laser Doppler flowmeter. Sensorimotor behavior was evaluated using the turning in an alley and falling from a pole tests at 1 hr before stroke and 24 and 48 hr after stroke. Infarct volume was determined from the T2-weighted magnetic resonance images at 72 hr after stroke. During the first 15 min of stroke, CBF decreased in the penumbra in both homozygous COX-1-gene knockout and wild-type mice. Melatonin treatment improved the penumbral CBF in the wild-type mice. Mild poststroke impairment in sensorimotor behavior was detected by the turning in an alley test in which the COX-1-gene knockout mice performed better. Melatonin treatment did not affect the poststroke sensorimotor behavior. The relative infarct volume at 72 hr after stroke was 8.1% and 8.4% in the COX-1-gene knockout and wild-type mice, respectively. Melatonin treatment reduced the relative infarct volume to 6.3% in the latter but not in the former (8.2%). Thus, COX-1-gene knockout does not affect the brain's susceptibility to photothrombotic stroke. Melatonin treatment reduces infarct size in the wild-type mice following photothrombotic stroke partly via maintenance of penumbral CBF in which the COX-1-gene may play a role.