Although sevoflurane is the most commonly used inhalational anesthetic agent, the popularity of desflurane is increasing to a similar level. The main beneficial property of desflurane is the relatively fast emergence of the patient from the anesthetic state after halting its supply compared with anesthesia using other anesthetic agents. However, there has been no comprehensive comparison of the effects of these two anesthetic agents on alterations in liver gene expression profiles in animals, including humans, to assess the levels of hepatotoxicity that is induced at least in some extent by inhalational anesthesia. Thus, we compared alterations in the global gene expression profiles in the livers of rats subjected to inhalational anesthesia by sevoflurane or desflurane by a next-generation sequencing method. Our data revealed that both anesthetic agents significantly activated a similar set of genes including those related to drug metabolism and circadian rhythm. Furthermore, many genes downregulated by sevoflurane were also downregulated by desflurane. However, many of the genes related to the cholesterol biosynthetic process were specifically repressed by sevoflurane, but not by desflurane.
Introduction
TS-142 is a novel dual orexin receptor antagonist (DORA) developed for the treatment of insomnia. Here we report its pharmacokinetic profile in the healthy subjects and its efficacy and safety in patients with insomnia.
Methods
A phase1 study was conducted to clarify pharmacokinetic profile, in which various doses of TS-142 (1–30 mg) were orally administered once to thirty two healthy subjects. Subsequently, a phase 2a study utilizing polysomnography (PSG) was carried out in patients with primary insomnia, in which 5, 10, or 30 mg of TS-142, or placebo was randomly administered in a double-blind manner. Karolinska Sleepiness Scale (KSS) and Digit Symbol Substitution Test (DSST) were also examined in the morning after PSG.
Results
Following single administration of TS-142, plasma concentration of unchanged compound reached maximum within 2.50 h (median), and then eliminated rapidly, giving mean elimination half-life between 1.32 and 3.25 h. Twenty-three patients with insomnia completed the Phase2a study. Both latency to persistent sleep (LPS) and wake after sleep onset (WASO) were significantly improved with TS-142 at all doses, in comparison with placebo (-42, -42 and -45 for LPS [min] and -28, -35 and -55 for WASO [min] in 5, 10, 30 mg, respectively). KSS and DSST administered in the morning indicated no serious hangover effects. No serious adverse events were observed in these trials.
Conclusion
The phase 1 trial showed favorable pharmacokinetic profiles. The phase 2a trial demonstrated that TS-142 was efficacious in objective sleep onset and maintenance with minimal next-day residual effects. TS-142 was generally well tolerated in both studies.
Support
Taisho Pharmaceutical. Co., Ltd.
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