ABSTRACT
PURPOSE: Patient sedation and analgesia are vital for safety and comfort during extracorporeal membrane oxygenation (ECMO). However, adsorption by the circuit may alter drug pharmaco-kinetics and remains poorly characterized. This study is the first to examine the concentrations of DEX and MDZ in the presence of drug-drug interactions using an in vitro extracorporeal circuit system that incorporates a polymer-coated polyvinyl chloride tube, but not a membrane oxygenator. METHODS AND RESULTS: Nine in vitro extracorporeal circuits were prepared using polymer-coated PVC tubing. Once the circuits were primed and running, either a single drug or two drugs were injected as boluses into the circuit with three circuits per drug. Drug samples were drawn following injection at 2, 5, 15, 30, 60, and 120 min and at 4, 12, and 24 h. They were then analyzed using high-performance liquid chromatography with mass spectrometry. When compared with an injection of DEX alone, the combination of DEX and MDZ is highly changed, with DEX and MDZ affecting the availability of free drugs in the circuit. CONCLUSIONS: The change of DEX and MDZ concentrations was confirmed by a combination of both drugs as compared with either single-infusion DEX or MDZ in an in vitro extracorporeal circuit. Drug-drug interactions developed between DEX and MDZ through albumin in an extracorporeal circuit; as a result, the unbounded drugs might change in the circuit.
ABSTRACT
Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal function, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic efficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects.