A new rocuronium formulation not causing vascular pain in a flexor reflex model of anesthetized rats.

PURPOSE: Intravenous administration of the brand formulation of rocuronium bromide, currently used as a muscle relaxant, has been associated with vascular pain accompanied by withdrawal movements of the arm and wrist. The purpose of this study was to identify the cause of vascular pain induced by the brand formulation and to develop a new rocuronium formulation, not causing vascular pain, using a vascular pain-evoked flexor reflex response model of anesthetized rats. METHODS: A rat flexor reflex model, monitored by electromyography, was used to evaluate a flexor reflex response as the index of vascular pain. A catheter for drug administration was inserted into the superficial caudal epigastric artery. A needle electrode was inserted into a muscle in the femoral area to obtain an electromyogram (EMG) value. The integrated EMG values obtained after the administration of each test drug were compared to the baseline value and quantified. RESULTS: The acetate buffer contained in the solvent could cause flexor reflex response. Furthermore, the flexor reflex response increased in an acid concentration-dependent manner. Based on these results, we prepared a new rocuronium formulation using a low-acid-concentration buffer solution and found that it decreased the integrated EMG value in the rat model. The integrated EMG value acquired using the brand formulation was reduced by pretreatment with the TRPA1 channel inhibitor. CONCLUSION: Our findings suggest that the high acid concentration in the brand formulation buffer solution is the cause of vascular pain. The rocuronium formulation developed using a low-acid-concentration buffer solution might help eliminate vascular pain in the clinic.

Novel water-soluble sedative-hypnotic agents: isoindolin-1-one derivatives.

We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(-), 5(-), 27(-), and 47(-) [JM-1232(-)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(-) [JM-1232(-)] is being considered as the most potential candidate for clinical trials in humans.