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.
Eltanolone, a new intravenous steroid anaesthetic agent was administered intravenously in a dose of 0.6 mg.kg-1 over 45 s to eight healthy male volunteers to evaluate some of its pharmacokinetic and pharmacodynamic effects. Drug concentration-time data were analysed by PCNONLIN, a non-linear regression programme, showing data consistent with a three-compartment model with initial distribution half-life t1/2 lambda 1 between 0.3 and 2 min, intermediate distribution half-life t1/2 lambda 2 between 12 and 29 min and terminal half-life t1/2 lambda z between 72 and 212 min. The total body clearance of eltanolone was rapid and with individual values in the range 1.6-2.3 l.h-1.kg-1. Eltanolone was initially distributed into a relatively large central compartment V1 between 0.09 and 0.98 l.kg-1 and then extensively further distributed (Vss between 1.80 and 5.44 l.kg-1 and V between 4.87 and 11.87 l.kg-1). The excretion of unchanged of eltanolone in urine was very small, the renal clearance was less than 0.5% of the total clearance. Induction of anaesthesia was trouble free with onset and duration of anaesthesia between 1-2 min and 6-13 min, respectively. There was slight respiratory depression, a small transient increase in heart rate, and a maximum reduction in arterial blood pressure of 23%, as compared with the resting level. Pain on injection and venous sequelae were not seen. Involuntary movements were seen in one subject. We conclude that eltanolone has a favourable pharmacokinetic profile with relatively rapid half-lives, large distribution volumes and rapid total body clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
The anticonvulsive activity (ED50), acute toxicity (LD50), and minimal neurotoxicity (TD50) of diazepam in an emulsion form (Diazemuls) were compared with two different water-based diazepam solutions (Valium and Stesolid). The diazepam preparations were administered intravenously to male mice. After determination of time of peak drug activity, the ED50's were established against pentetrazol-induced convulsions, at peak drug activity. The most important difference between the three diazepam preparations was a significantly higher LD50 of diazemuls (275 mg/kg) compared to valium (49 mg/kg) and stesolid (51 mg/kg). ED50 was: diazemuls 0.24 mg/kg, valium 0.14 mg/kg and stesolid 0.10 mg/kg. The therapeutic indices (LD50/ED50) were thus calculated to be 1146 for diazemuls, 350 for valium and 510 for stesolid. Time of peak drug activity and TD50 were equal for all three drugs. No signs of pain on injection or necrosis were observed following diazemuls, whereas this was common after valium and stesolid.
SummaryThe anuesthetir. properiie.r oj-pregnanolorie Key wordsAnaesthetics, intravenous; pregnanolone, Althesin, propofol. thiopcntone. Hypnotic&. benzoriiazepine;\; midazolamAlthesin, a mixture of the two 5r reduced progesterone derivatives, alphaxolone and alphadolone. appeared to have many of the properties of the ideal intravenous anaesthetic. I ,* However, a high incidence of hypcrsensitivity reactions terminated its clinical use. The solubilising agent Cremophor EL was suspected as the causative agent even though a contribution of the steroids could not be e~c l u d e d .~ Pregnanolone emulsion is a new steroid preparation for intravenous administration, with anaesthetic properties comparable to those of A l t h e~i n .~The preparation differs from Althcsin in several ways. The active ingredient, pregnanolone, is a 5B reduced metabolite of progesterone, a naturally occurring ~t e r o i d ,~ and the preparation does not contain Cremophor EL. It is solubilised in soya bean oil and emulsified in a similar way to diazepam in the form of Diazemuls.The present study in rats evaluates the anaesthetic properties of pregnanolone emulsion in relation to thc rcquirements of the ideal intravenous anaesthetic as outlined recently by Dundee,6 and compares its properties to those of Althesin, propofol, midazolam and thiopentone.
The acute cardiovascular effects of pregnanolone emulsion, a new steroid preparation for intravenous anaesthesia, were investigated in artificially ventilated dogs. The anaesthetic was administered as repeated intravenous bolus injections, doubling the dosage with each injection. The plasma concentration of pregnanolone, and the haemodynamic, respiratory and metabolic variables were determined after each injection. Cardiac output and heart rate increased from the first bolus dose of the anaesthetic (0.5 mg/kg), which produced anaesthesia lasting 10 to 15 min. Both continued to increase after administration of 1.0, 2.0 and 4 mg/kg, whereas reductions of systemic arterial pressure and estimated myocardial contractility were observed only at the two highest dosages. A decrease in vascular resistance was calculated in the systemic circulation, whereas vascular resistance increased in the pulmonary circulation. A state of circulatory shock followed administration 8, 16 and 32 mg/kg of the anaesthetic.
SummaryThc r~niiesthetic uctivitj of' pregnanolonc (a nietoholitc gf' progcsteronc) Serious, and in some cases fatal, allergic reactions due to the Cremophor EL causcd this otherwise excellent drug to be withdrawn from clinical use.
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