Pregnanolone emulsion A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent

Abstract

SummaryFigdor et al.' demonstrated in 1957 that a series of structurally related pregnanes, without notable endocrine action, were anaesthetically active when administered to mice. The most active of these pregnanes was pregnanolone (3a-hydroxy-5/l-pregnane-20-one), which is a naturally occurring metabolite of progesterone, first isolated from urine of pregnant women in 1937.' The anaesthetic effect of pregnanolone has been demonstrated in several animal speciesZ3 but its lack of water solubility prevented its development in clinical practice. Pregnanolone is now prepared in a stable emulsion which may prove to be suitable for clinical use. It is solubilised in soya bean oil and emulsified in a similar way to diazepam in the form of Diazemuls.A wide species variation in toxicity and tolerance of pregnanolone emulsion was observed in preclinical studies. Administration of a single bolus injection of 40 mg/kg did not cause any (or only marginal) mortality in the mouse and the rat. No organ toxicity was noted after repeated daily intravenous injections in several species: rat 16 mglkg for 4 days and 7 mg/kg for 28 days; dog 12 mg/kg for 4 days and 3 mg/kg for 28 days; monkey 28 mg/kg for 14 days and 21 mg/kg for 28 days. Hepatic lesions restricted to the biliary system, manifested as morphological changes and increased serum enzymes, occurred after daily administration of 40-64 mg/kg for 4 days and after 14 mg/kg for 28 days in the rat. In the dog the threshold dose for hepatobiliary changes at repeated doses was about 7 mg/kg. The liver damage was clearly related to the dose, but also to the duration of the treatment, and was reversible at least in its initial state (toxicological report, not published). The anaesthetic and anticonvulsive properties of pregnanolone in animals are encouraging and very similar to those of Althesin.-This study reports the findings of a preliminary and limited clinical investigation with pregnanolone emulsion in male volunteers.

Altered Postural Control during the Luteal Phase in Women with Premenstrual Symptoms

“…In animal studies, it is shown that some of the effects of alcohol are mediated via increased productions of allopregnanolone [10, 24, 25]. In humans, a high dose of pregnanolone is hypnotic and anesthetic [1, 26]. In parallel with inducing sedation, allopregnanolone has also been shown to induce disturbances in motor function [27, 28].…”

Patients with Premenstrual Syndrome Have a Different Sensitivity to a Neuroactive Steroid during the Menstrual Cycle Compared to Control Subjects

“…Administered intravenously in doses of 0.4–0.6 mg/kg, it produces anesthesia of short duration with minimal effects on hemodynamic and respiratory parameters [9]. Pregnanolone has also been reported to have hypnotic activity [10] and basic research on this class of compounds has demonstrated that compounds closely related to pregnanolone possess hypnotic [11], antiepileptic [12] and anxiolytic activity [13]. Brain and plasma levels of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) temporally follow circulating levels of progesterone produced by the corpus luteum [14].…”

Soporific Effect of the Neurosteroid Pregnanolone in Relation to the Substance’s Plasma Level: A Pilot Study

“…Indeed, alphaxalone has been used successfully as an intravenous sedative-hypnotic in human subjects [8]. Like alphaxalone, preliminary human pharmacodynamic and pharmacokinetic studies reveal that pregnanolone is capable of inducing anesthesia of short duration (plasma ti/2 = 0.9-1.4 h) after intravenous infusion [9], The anes thetic effect was accompanied by minimal effects on hemodynamic and respiratory parameters although exci tation of short duration was observed during induction. The evaluation of pregnanolone as an orally administered sedative-hypnotic agent has been hampered by its low water solubility.…”