PubMed · 11780170
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R Hürlmann. 2001-11-09. [Premedication before endoscopy].. https://doi.org/10.1055/s-2001-18327-2
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General anesthetics allosterically modulate the activity of neuronal gamma-aminobutyric acid, type A (GABAA), receptors. Previous mutational studies from our laboratory and others have shown that the regions in transmembrane domain 1 (M1) and pre-M1 of alpha and beta subunits in GABA receptors are essential for positive modulation of GABA binding and function by the intravenous (IV) general anesthetics. Mutation of beta2Gly-219 to Phe corresponded in rho nearly eliminated the modulatory effect of IV anesthetics in alpha1/beta2/gamma2S combination. However, the general anesthetics retained the ability to directly open the channel of mutant G219F, and the apparent affinity for GABA was increased, and desensitization rate was reduced. In this study, we made additional single mutations such as 219 Ser, Cys, Ile, Asp, Arg, Tyr, and Trp. The larger side chains of the replacement residues produced the greatest reduction in enhancement of GABA currents by IV anesthetics at clinical concentrations (Trp > Tyr = Phe > Arg > Asp > Ile > Cys > Ser = wild type). Compared with a 2-3-fold response in wild type, pentobarbital and propofol enhanced less than 0.5-fold; etomidate and alphaxalone modulation was reduced from more than 4- to 1-fold in G219F, G219Y, and G219W. A linear correlation was observed between the volume of the residue at position 219 and the loss of modulation. An identical correlation was found for the effect of modulation on left-shift in the GABA EC50 value; furthermore, the same rank order of residues, related to size, was found for reduction in the maximal direct channel-gating by pentobarbital (1 mm) and etomidate (100 mum) and for increased apparent affinity for direct gating by the IV anesthetics.
OBJECTIVE: NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4. METHODS: Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, alpha-hydroxymidazolam, were investigated. RESULTS: Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The C(max) values of midazolam and alpha-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9. CONCLUSION: This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.
OBJECTIVES: To evaluate the long-term safety and efficacy of nightly sodium oxybate for the treatment of narcolepsy. DESIGN: A multicenter, 12-month, open-label trial. PARTICIPANTS: 118 narcolepsy patients previously enrolled in a 4-week double-blind sodium oxybate trial. INTERVENTIONS: Patients were administered 6 g sodium oxybate nightly, taken in equally divided doses at bedtime and 2.5 to 4 hours later. The study protocol permitted the dose to be increased or decreased in 1.5-g increments at 2-week intervals based on efficacy response or adverse experiences but staying within the range of 3 to 9 g nightly. MEASURES: Narcolepsy symptoms and adverse events were recorded in daily diaries. Safety measures included physical and laboratory examinations repeated at 6 and 12 months. The primary efficacy measure was the change in weekly cataplexy attacks from baseline. Secondary measures included daytime sleepiness using the Epworth Sleepiness Scale (ESS), inadvertent naps/sleep attacks, nighttime awakenings, and the overall change in disease severity as rated by the investigators (Clinical Global Impression of Change; CGI-c). RESULTS: Sodium oxybate, in doses of 3 to 9 g nightly, produced overall improvements in narcolepsy symptoms, which were significant at 4 weeks and maximal after 8 weeks. Reported improvements included a significant decrease in frequency of cataplexy attacks (p < 0.001); diminished daytime sleepiness (p < 0.001); and patient descriptions of nocturnal sleep quality, level of alertness, and ability to concentrate (for each p < 0.001). Adverse events were generally mild and patients showed no evidence of tolerance. CONCLUSION: Sodium oxybate is an effective and well-tolerated treatment for narcolepsy.