Abstracts

Rationale: The intranasal transmucosal route provides a convenient mode of midazolam delivery. Indeed, intranasal midazolam has been studied for over a decade as a pediatric sedative and for treating acute seizure clusters and status epilepticus. However, we considered whether the administration of midazolam directly into the lungs could provide better absorption and more direct delivery to the brain. The lung is highly vascularized and the thin alveolar epithelium represents a large absorptive surface that presents a minimal barrier to drug absorption. The intrapulmonary route therefore offers more rapid systemic delivery than does intranasal dosing and avoids first pass metabolism in the liver. Methods: Midazolam was administered to mice via a tracheal cannula and by conventional intraperitoneal (i.p.) injection. The convulsant pentylenetetrazol (PTZ) was administered i.p (80 mg/kg). PTZ and a second chemoconvulsant kainic acid were administered intravenously (i.v.) at increasing doses to evaluate midazolam effects on seizure threshold. Results: Midazolam (100 mg/kg, i.p.) induced loss of righting reflex within 8 min. Midazolam at much lower doses (100-1000 mcg/kg, i.p.) protected mice against clonic and tonic seizures and death induced by i.p. PTZ. Intratracheal midazolam was markedly more potent and more rapidly acting than with i.p. administration, providing protection against seizures and death at doses of 25-200 mcg/kg. Intratracheal midazolam at low doses also elevated the seizure threshold for i.v. PTZ and kainic acid. Intratracheal administration of cresyl violet dye revealed uniform distribution of the solution throughout the lungs. Conclusions: Intratracheal midazolam provides potent and rapid seizure protection, indicating that intrapulmonary midazolam enters the alveoi and is rapidly absorbed into the blood stream and delivered to the brain. Midazolam administered by inhalation could be used to treat seizures. The pulmonary route of administration may offer advantages over intranasal delivery.