Nagai B
Hokkaido Igaku Zasshi. 1982 Nov;57(6):706-21.
Clinical and experimental studies were performed on the mechanisms of metabolic acidosis observed in the children with epilepsy who had long been treated with anticonvulsants such as phenobarbital (PB) or diphenylhydantoin (DPH). The effect of the anticonvulsants was studied on the erythrocyte carbonic anhydrase isozymes (CA-B and CA-C) and on the calcium ion metabolism. The results obtained were as follows: (1) Ten cases with metabolic acidosis were found in 37 cases of epilepsy (27%). Hypocalcemia and high alkaline phosphatase activity in the serum were observed in the acidotic cases. The specific activity of erythrocyte CA-B isozyme was significantly lower in the acidotic cases as compared to those in nonacidotic cases or normal individuals, suggesting that the metabolic acidosis may bring about an inhibition of this enzyme. (2) In vitro experiments were performed to further study the effect of DPH on the erythrocyte CA-B and CA-C. Incubation of the enzymes with DPH resulted in an inhibition of their activities. Affinity binding of DPH to the enzymes was studied using a gel filtration method. The binding of DPH was not replaced by the presence of salicylate, indicating that the binding is non-specific. The addition of ethylenediamine tetraacetic acid did not show any influence on the binding, suggesting that the binding is not chelate-bound with zinc ion which locates at the active center of the enzyme. The binding of DPH was not competitive with respect to acetazolamide which is known to have an affinity for the active center of the enzyme. These results suggest that the binding site of DPH for the enzyme is in the vicinity of its active center, however definitely different from those of acetazolamide. PB was supposed to behave in the same manner as DPH for carbonic anhydrases. (3) This study lead to the conclusion that a long term treatment with PB or DPH specifically inhibits the activity of carbonic anhydrases in erythrocytes. The inhibition of the enzyme activity may result in the metabolic acidosis. Imbalanced calcium ion metabolism was supposed to be induced by the acidosis. The considerable care is requisite for a long-term treatment of anticonvulsants.
对长期使用苯巴比妥（PB）或苯妥英钠（DPH）等抗惊厥药物治疗的癫痫患儿所出现的代谢性酸中毒机制进行了临床和实验研究。研究了抗惊厥药物对红细胞碳酸酐酶同工酶（CA - B和CA - C）以及钙离子代谢的影响。所得结果如下：（1）37例癫痫患儿中有10例出现代谢性酸中毒（27%）。酸中毒患儿血清中出现低钙血症和高碱性磷酸酶活性。与非酸中毒患儿或正常个体相比，酸中毒患儿红细胞CA - B同工酶的比活性显著降低，提示代谢性酸中毒可能导致该酶受到抑制。（2）进行体外实验以进一步研究DPH对红细胞CA - B和CA - C的影响。酶与DPH孵育导致其活性受到抑制。使用凝胶过滤法研究了DPH与酶的亲和结合。水杨酸的存在并未取代DPH与酶的结合，表明该结合是非特异性的。添加乙二胺四乙酸对结合没有任何影响，提示该结合不是与位于酶活性中心的锌离子形成螯合结合。DPH的结合相对于已知对酶活性中心有亲和力的乙酰唑胺不具有竞争性。这些结果表明DPH与酶的结合位点在其活性中心附近，但肯定不同于乙酰唑胺的结合位点。PB对碳酸酐酶的作用方式被认为与DPH相同。（3）本研究得出结论，长期使用PB或DPH会特异性抑制红细胞中碳酸酐酶的活性。酶活性的抑制可能导致代谢性酸中毒。酸中毒可能导致钙离子代谢失衡。长期使用抗惊厥药物时需要格外小心。
