Malignant hyperthermia (MH) is an autosomal dominant disorder which is potentially lethal in susceptible individuals on exposure to commonly used inhalational anaesthetics and depolarising muscle relaxants. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. Susceptibility was first localised to chromosome 19q13.1 and the skeletal muscle ryanodine receptor, RYR1 (the calcium release channel of the sarcoplasmic reticulum). Defects in this gene have been identified which cosegregate with the MHS phenotype and evidence as to their potential causal roles has accumulated. MH has, however, been shown to be genetically heterogeneous, additional loci on chromosomes 3q, 17q and 7q being proposed. Pedigrees remain in Europe where linkage status is still unclear. In a collaborative search of the human genome conducted with three pedigrees whose disease status was classified according to the European IVCT protocol we have evidence to suggest that at least two further loci exist for MH susceptibility. One of these locates to chromosome 1q, the site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the dihydropyridine receptor. The second region resides on chromosome 5p to where no known candidate has been mapped to date. The third family exhibited inconclusive results which suggests the existence of at least one other locus. This study adds to the evidence for considerable genetic heterogeneity in MH and will provide a route to further our understanding of the molecular pathology of the condition.

Aims Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P-glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose-dependently in vivo by cremophor EL, an 'inactive' pharmaceutic aid known to inhibit PGP in vitro. Methods In a randomized, placebo-controlled, double-blind, four phase cross-over design single doses of oral saquinavir (Invirase 1 , 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (C max ), time to reach C max (t max ) and terminal elimination half-life (t 1/2 ). Results Cremophor EL dose-dependently increased C max , AUC(0,4 h), and AUC(0,?) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13-fold for both C max and AUC(0,4 h) and 5-fold for AUC(0,?). The terminal half-life and the time to reach C max (t max ) were unchanged. Conclusions Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.

Although in vitro contracture testing for malignant hyperthermia diagnosis is well standardized, with a relatively high sensitivity and specificity, false test results cannot be excluded and may be associated with serious disabilities for the concerned individuals. In this multicenter study, 4-chloro-m-cresol was evaluated as a new test substance for the in vitro contracture testing. Its use improves the accuracy of in vitro diagnosis of malignant hyperthermia susceptibility.

Prolonged microgravity alters the regulation of the peripheral vasculature. The influence of reduced food intake, as often observed in astronauts, on vascular function is unclear. In a randomized, four-phase, crossover study, the effect of simulated microgravity (13 days of bed rest), energetic restriction (-25%, fat reduced), and their combination on endothelium-dependent and -independent vasodilation was compared with ambulatory control conditions. Using venous occlusion plethysmography, cumulative intra-arterial dose-response curves to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators were constructed in 10 healthy male volunteers before and on day 13 of each of the four intervention periods. Bed rest combined with normoenergetic nutrition impaired the dose-response to acetylcholine (ANOVA, P = 0.004) but not to sodium nitroprusside, whereas hypoenergetic diet under ambulatory conditions improved responses to acetylcholine (P = 0.044) and sodium nitroprusside (P < 0.001). When bed rest was combined with hypoenergetic diet, acetylcholine responses did not change. Similarly, under control conditions, no change was observed. Individual changes in the total cholesterol-to-HDL ratio were correlated with changes in endothelial and vascular smooth muscle relaxation. In conclusion, short-term bed rest impairs endothelium-dependent arterial relaxation in humans. A hypoenergetic, low-fat diet modulates serum lipids, improves endothelium-dependent and -independent relaxation, and may antagonize the unfavorable effects of simulated microgravity on endothelial function.

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The sulfated bile alcohol scymnol sulfate (ScyS), 3α,7α,12α,24ξ,26,27-hexahydroxy-5β-cholestane-26(27)-sulfate, is the major bile salt in bile of an elasmobranch, the little skate. To investigate hepatic transport of bile alcohols in skate liver, [3H]ScyS and a potential precursor, 3α,7α,12α-trihydroxy-5β-cholestane (chtriol), were used as model compounds. Their transport into isolated hepatocytes was partially saturable, temperature sensitive, and Na+ independent. The uptake of ScyS was inhibited by cholyltaurine, and uptake of cholyltaurine was inhibited by ScyS in a competitive manner. In contrast, uptake of chtriol was not inhibited by cholyltaurine, suggesting separate transport systems. ScyS and chtriol showed a choleretic effect in isolated perfused livers. When ScyS was added to the perfusate of isolated perfused livers, >25% was found in bile within 7 h. When chtriol was added to the perfusate, 10% of the dose was secreted into the bile mainly in the form of polar metabolites, whereas only nonmetabolized chtriol remained in the livers. The slow bile flow of 40–50 μl/h and the high recovery in the liver suggest that metabolism may be the rate-limiting step in the hepatic elimination of chtriol. The major metabolites secreted into bile were identified by mass spectrometry and chromatography as scymnol and ScyS. To study the enterohepatic circulation, [3H]ScyS or [3H]chtriol was administered into the duodenum of free-swimming skates, and bile was collected through exteriorized indwelling cannulas over a 4-day period. More than 90% of the radioactivity was recovered from bile, indicating that there was a highly effective absorption in the intestinal epithelium, as well as specific transport mechanisms for hepatic uptake and biliary secretion of these compounds. This is the first direct demonstration of an enterohepatic circulation for a bile alcohol sulfate in fish liver.

Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations have been completed, the CV risks associated with the use of NSAIDs, especially in high-risk patients, will likely continue to be controversial. Nevertheless, the benefits of their short-term (e.g., perioperative) use in patients without CV risks probably outweigh their potential CV adverse effects. Finally, careful risk/benefit assessment should be undertaken and both COX-2 selective inhibitors and NS-NSAIDs should be used with caution in patients with CV risk factors.

The use of intravenous guanethidine blocks is an accepted treatment for established reflex sympathetic dystrophy (RSD). Some units administer intravenous guanethidine peri-operatively with the intention of protecting their patients from post-operative dystrophy. There have been no studies confirming this protective effect of peri-operative guanethidine. Between 1992 and 1994 we performed a prospective randomized double blind study in 71 patients undergoing fasciectomy for Duputyren's disease. Peri-operative guanethidine did not prevent post-operative RSD in our series.