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Background and Purpose: Potent synthetic nonsteroidal liver X receptor (LXR) agonists like T0901317 induce triglyceridaemia and fatty liver, effects not observed with some natural and synthetic steroidal, relatively weak agonists of LXR. To determine if potency is responsible for the lack of side effects with some steroidal agonists, we investigated the in vivo effects of a novel steroidal LXR agonist, ATI-111, that is more potent than T0901317., Experimental Approach: Eight week old male LDLR(-/-) mice fed an atherogenic diet were orally treated with vehicle or ATI-111 at 3 and 5 mg·kg(-1) ·day(-1) for 8 weeks, and effects on plasma and liver lipid levels, expression of genes involved in lipid metabolism and on atherogenesis were analysed., Key Results: ATI-111 increased the expression of genes involved in lipid transport, such as ABCA1, ABCG1 and ABCG5/G8, in intestine and macrophages; decreased ABCG1, apoE; and slightly increased ABCA1 and ABCG5/G8 expression in liver. ATI-111 markedly increased sterol regulatory element-binding protein (SREBP)-1c mRNA in some tissues, whereas acetyl-coenzyme A carboxylase and fatty acid synthase expression was unaffected or only slightly increased in intestine and liver. ATI-111 inhibited the conversion of SREBP-1c precursor form to its active form. Compared with vehicle-treated mice, the levels of hepatic lipids and liver-secreted nascent lipoproteins were not altered, while a significant decrease in plasma cholesterol and triglyceride levels was observed in ATI-111-treated mice. ATI-111 significantly inhibited atherogenesis in three separate vascular sites., Conclusions and Implications: ATI-111 is a promising candidate for further development as a treatment of certain vascular diseases as it lacks the significant side effects associated with nonsteroidal LXR agonists, the induction of fatty liver and hypertriglyceridaemia., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

An intramuscular dose of 18 mg/kg bodyweight of this steroid anaesthetic produced surgical anaesthesia with rapid induction, safe, efficient maintenance and rapid recovery without side effects.

Alphaxalone-alphadolone (Althesin), diluted and administered as a controlled infusion, was used as a sedative for 30 patients in an intensive therapy unit. This technique allowed rapid and accurate control of the level of sedation. It had three particularly useful applications: it provided "light sleep," allowed rapid variation in the level of sedation, and enabled repeated assessment of the central nervous system.Sedation was satisfactory for 86% of the total time, and no serious complications were attributed to the use of the drug. Furthermore, though alphaxalone-alphadolone was given for periods up to 20 days there was no evidence of tachyphylaxis or delay in recovery time.

A mixture of 3H-15alpha-hydroxyandrostenedione and 14C-15alpha-hydroxydehydroisoandrosterone was injected intravenously into two subjects in the third trimester of pregnancy and, in a second study, directly into two fetuses in utero during transfusion for erythroblastosis fetalis. The urine was collected for 4-5 days and steroid conjugates in the urine were hydrolyzed into sulfate and glucosiduronate fractions. From the glucosiduronate fraction 15alpha-hydroxyestriol, 15alpha-hydroxyestradiol, 15alpha-hydroxyandrostenedione and 15alpha-hydroxydehydroisoandrosterone were isolated. No metabolites were identified in the sulfate fraction of the urine. A marked difference was observed in the metabolism of 15alpha-hydroxyandrostenedione and 15alpha-hydroxydehydroisoandrosterone which is dependent on the route of administration of the substrates. Both substrates were converted to 15alpha-hydroxyestriol and 15alpha-hydroxyestradiol, and the 3H/14C ratios and percentage conversions suggest that 15alpha-hydroxyandrostenedione seems to be a better precursor of the urinary 15alpha-hydroxylated estrogens than 15alpha-hydroxydehydroisoandrosterone. The 3H/14C ratios also suggest that 15alpha-hydroxydehydroisoandrosterone was converted to 15alpha-hydroxyestriol via 15alpha-hydroxyandrostenedione, and that the formation of 15alpha-hydroxyestradiol from 15alpha-hydroxydehydroisoandrosterone via 15alpha-hydroxyandrostenedione is a pathway of minor importance. Finally, 15alpha-hydroxydehydroisoandrosterone was recovered from the urine only when the precursors were injected into the maternal circulation. Also, an unknown metabolite containing only 14C was detected in the glucosiduronate fraction of the urine of each subject.

The erythropoietic effect of 5beta-pregnane-3beta-hydroxy-20-one, a naturally occurring steroid metabolite of progesterone, was evaluated in the squirrel monkey by ferrokinetic studies. red cell survival, and blood volume measurements. The intramuscular administration of this steroid in pharmacologic doses shortened the (59)Fe plasma clearance and increased the plasma iron turnover, thereby indicating an increase in erythropoiesis. A normal (59)Fe red cell uptake was observed, and the bone marrow maturation time was not altered. Red cell survival was the same in the treated and control groups. After five weekly injections of the steroid, the monkeys increased their red cell mass by 57%. A significant increase in white blood cells and a slight elevation of platelet counts in the treated monkeys also suggest a possible direct stimulation of hemopoietic stem cells by the steroid metabolite. These observations indicate that some steroid metabolites can stimulate an early increase in iron turnover (within 48 h) that is not secondary to hemolysis. The increased red cell mass indicates effective erythropoiesis in primates.