JM-1232(-) and propofol, a new combination of anesthetics with short-acting and non-cumulative preferable properties

Abstract Background Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice.Methods Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected.Results The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36–4.10] for JM-1232(-) and 9.88 [8.03–11.58] mg kg-1 for propofol. Co-administration of 0.05 and 0.1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21–2.51] and 1.00 [0.46–1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia.Conclusions The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.

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Co-administration of JM-1232(-) reduces the dose of propofol required for hypnosis with minimal prolongation of recovery time even after repeated injections

10.21203/rs.2.331/v1 ◽

2019 ◽

Author(s):

Saori Taharabaru ◽

Michiko Higashi ◽

Naoyuki Matsuda ◽

Maiko Satomoto ◽

Tomohiro Tamura ◽

...

Keyword(s):

Recovery Time ◽

Receptor Agonist ◽

Benzodiazepine Receptor ◽

Additive Effects ◽

Additive Interaction ◽

Male Adult ◽

Adult Mice ◽

Righting Reflex ◽

Benzodiazepine Receptor Agonist ◽

Hypnotic Dose

Abstract Background: Drug interaction is an important and effective phenomenon in the area of anesthesiology because of drugs combinations potentially possessing novel properties. The characteristics of anesthesia with co-administration of JM-1232(-), benzodiazepine receptor agonist, and propofol, the most popular anesthetics, was studied using mice. Methods: Male adult mice were each administered JM-1232(-), propofol and various combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, double and triple the ED50 dose of propofol with JM-1232(-) were injected to compare hypnosis time. The injections were repeated 4 times and each hypnosis time was compared. Separately, flumazenil was administered immediately after the last dose was injected. Results: The ED50s ([95% confidence interval]) for hypnosis were 3.76 [3.36 - 4.10] for JM-1232(-) and 9.88 [8.03 - 11.58] mg kg-1 for propofol. Co-administration of 0.05- and 0.1-mg kg-1 of JM-1232(-) reduced the ED50 of propofol to 1.76 [1.21 - 2.51] and 1.00 [0.46 - 1.86] mg kg-1. The interaction of the drug combinations for hypnosis was supra-additive. Hypnosis time was significantly shorter in the groups given the mixtures as compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with sole hypnotics. Flumazenil antagonized the supra-additive effects of the mixtures. Conclusions: The combination of JM-1232(-) and propofol shows supra-additive interaction and the reduced hypnotic dose translates to faster recovery even after multiple injections. Keywords: JM-1232(-), Propofol, Supra-additive interaction, Flumazenil.

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