Stereospecific oxidation of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, by aldehyde oxidase.

In a previous paper by the authors on RS-8359, a new selective and reversible monoamine oxidase A (MAO-A) inhibitor, it was reported that the (S)-enantiomer of RS-8359 is rapidly eliminated from rats, monkeys and humans as a result of the formation of a 2-oxidative metabolite. The present study investigates the properties of the enzyme responsible for the 2-oxidation of RS-8359. Subcellular localization, cofactor requirement and the inhibitory effects of typical compounds were studied using rat liver preparations. In addition, the enzyme was purified from rat liver cytosol for further characterization. The enzyme activity was localized in the cytosolic fraction without the need for any cofactor and was extensively inhibited by menadione, chlorpromazine and quinacrine. The purified enzyme was also a homodimer with a monomeric molecular weight of 140 kDa and it had an A280/A450 ratio of 5.1 in the absorption spectrum. The results suggest that the enzyme responsible for the biotransformation of RS-8359 to give the 2-keto derivative is aldehyde oxidase (EC 1.2.3.1). The reaction of aldehyde oxidase is highly stereoselective for the (S)-configuration of RS-8359 and the (9R)-configuration of cinchona alkaloids.

The effects of single and fractionated doses of mepivacaine on the extent of thoracic epidural block.

BACKGROUND AND OBJECTIVES: The effects of single and fractionated doses of local anesthetic on the extent of thoracic epidural blockade has not yet been determined. This single blinded and randomized study was designed to examine the effects of the initial dose and timing of the additional dose of local anesthetic on the sensory block level of the thoracic epidural anesthesia. METHODS: Eighty-nine patients, who received thoracic epidural anesthesia followed by general anesthesia, were randomly divided into 4 groups: Group I received 5 mL of mepivacaine; Group II, 10 mL; Group III, 5 mL twice, with an interval of 5 minutes; and Group IV, 5 mL twice, with an interval of 10 minutes. After 15 minutes of either a single bolus or after the second bolus drug administration, the level of sensory block to coldness and pinprick were determined by an individual who was uninformed of the groups. RESULTS: The median (range) number of spinal segments with sensory block to coldness in Groups I, II, III, and IV were 8 (5 to 12), 12 (7 to 17)*, 11 (7 to 16)*, and 9 (6 to 17)# (*P < .05 v Group I, #P < .05 v Group II), respectively. The number of segments with sensory block to pinprick in the 4 groups were 7 (4 to 11), 11 (6 to 14)*, 10 (6 to 14)*, and 9 (4 to 16)*#, respectively. These differences were mainly due to the differences of the lower sensory block level. CONCLUSIONS: We concluded that the timing of the second administration of mepivacaine was one of the factors for the spread of the drug into thoracic epidural space. The more extensive sensory block level occurred by shorter time interval of the second drug administration.