論文 - 杉本　幸雄

The effects of cephem antibiotics and related compounds on the aldehyde dehydrogenase in rat liver mitochondria

Kamei Chiaki, Sugimoto Yukio, Tasaka Kenji

Biochemical Pharmacology   36 ( 12 )   1933 - 1939   1987年6月

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掲載種別：研究論文（学術雑誌）  

The effects of cephem antibiotics and their related compounds on aldehyde dehydrogenase obtained from rat liver mitochondria were studied. A pH of 8.8 and reaction temperature 24° were the conditions for measurement of enzyme activity. The apparent Michaelis constant Km values for NAD, acetaldehyde and propionaldehyde were 3.8 × 10-5 M, 4.0 × 10-5 M and 2.5 × 10-5 M, respectively. Cefamandole, cefoperazone and cefmetazole, having a 1-methyl-5-thiotetrazol group at position 3 of the cephem ring, caused a relatively potent inhibition of aldehyde dehydrogenase. Cefmetazole and cefoperazone also showed a significant inhibition on highly purified yeast aldehyde dehydrogenase; the extent of inhibition on yeast enzyme was almost the same as that on rat mitochondrial aldehyde dehydrogenase. The decrease in enzyme activity effected by 1-methyl-1H-tetrazol-5-thiol (MTT) was greater than those of 1H-tetrazol (TZ), 1H-tetrazol-5-thiol and 1-(2-dimethylaminoethyl)-1H-tetrazol-5-thiol, but was, of course, less than that of disulfiram. Cefamandole, cefmetazole and MTT showed competitive inhibition with NAD, while TZ was uncompetitive inhibitor with respect to both NAD and acetaldehyde. Enzyme inhibition caused by disulfiram, cefmetazole and MIT increased timedependently and the addition of 2-mercaptoethanol into the medium effectively and completely restored enzyme inhibition. These results suggest that thiol group at position 5 of 1H-tetrazol ring is responsible for the type of inhibition with NAD, and methyl group at position 1 of 1H-tetrazol ring is important to exhibit a potent inhibition on aldehyde dehydrogenase. © 1987.

DOI： 10.1016/0006-2952(87)90491-6

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Antihypertensive effects of nisoldipine and reference drugs in certain types of hypertensive rats

K. Tasaka, C. Kamei, H. Tagami, T. Hokonohara, Y. Sugimoto

Arzneimittel-Forschung/Drug Research   37 ( 3 )   316 - 321   1987年

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掲載種別：研究論文（学術雑誌）  

The hypotensive effects of nisoldipine (Bay k 5552), compared with those of nifedipine, nicardipine and hydralazine, in normotensive rats (NR), spontaneously hypertensive rats (SHR), DOCA-NaCl hypertensive rats (DNR) and renal hypertensive rats (RHR), were studied. The changes in plasma renin activity (PRA) after treatment with nisoldipine and these reference drugs were also studied. The results of this study revealed that: 1. Nisoldipine caused more potent antihypertensive effects in SHR, DNR and RHR than in NR. 2. The antihypertensive effects of nisoldipine in SHR were almost equipotent to those of nifedipine, nicardipine and hydralazine. However, in NR, DNR and RHR, the effects of nisoldipine were weaker than those of the reference drugs. 3. The positive chronotropic effects of nisoldipine were less remarkable than those elicited by nifedipine, nicardipine and hydralazine in all types of hypertensive rats, except SHR. 4. As did nifedipine and nicardipine, nisoldipine caused an increase of the plasma renin activity in NR and SHR, though its potency was weaker than those of nifedipine and nicardipine.

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Effects of various cephem antibiotics on ethanol metabolism and their structure‐activity relations

Chiaki Kamei, Yukio Sugimoto, Nobuaki Muroi, Kenji Tasaka

Journal of Pharmacy and Pharmacology   38 ( 11 )   823 - 828   1986年11月

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掲載種別：研究論文（学術雑誌）  

The effects of various cephem antibiotics and related compounds on ethanol metabolism were studied in association with their chemical structures. In rats, cefoperazone, cefbuperazone, cefamandole, latamoxef, cefmetazole, cefotetan, cefmenoxime and cefminox which have the [(1‐methyl‐1H‐tetrazol‐5‐yl) thio] methyl group at position 3 of the cephem ring caused a significant increase in the blood acetaldehyde concentration. In the last three compounds, disulfiram‐like activity was less potent than that evaluated in the preceding compounds. Cefazolin and ceftezole having a 1H‐tetrazol group at position 7 also showed a disulfiram‐like activity. A single administration of 1H‐tetrazol also increased the blood acetaldehyde concentration. Both blood ethanol and acetaldehyde values were increased significantly on administration of these drugs. In beagle dogs, cefoperazone induced a less remarkable but much more sustained increase in the blood acetaldehyde. These results indicate that the 1H‐tetrazol group, as well as the [(1‐methyl‐1H‐tetrazol‐5‐yl) thio] methyl group, is responsible for inducing a disulfiram‐like action and that there is a difference in the potency of the disulfiram‐like activity among the drugs having a [(1‐methyl‐1H‐tetrazol‐5‐yl)thio] methyl group at position 3 of the cephem ring in relation to those in which the side chain is substituted at position 7. Copyright © 1986, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.2042-7158.1986.tb04502.x

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