PHARMACOLOGY OF ANTIBIOTIC-RELATED HYPOPROTHROMBINEMIA

几种常用的β内酰胺抗生素包括头孢孟多， 头孢哌酮和莫昔拉坦与 低凝血酶原血症，这是一种可能导致严重出血的副作用。 的 这里提出的研究将检验假设， 与这些抗生素相关的低凝血酶原血症是 的一个共同的结构特征的药理活性， 抗生素，1-甲基-5-硫代四唑（MTT）侧基。 这个MTT小组 已显示抑制凝血因子中的维生素K依赖步骤 合成，大鼠肝脏中谷氨酸的γ羧基化 微粒体系统 进一步体外分析其作用机制 提出了抑制。 此外，MTT的进一步代谢以及 其他β内酰胺抗生素中不同的巯基侧基 抑制羧化系统将进行研究。 审查 与低凝血酶原血症相关的药物在该系统中的行为 如硫脲类抗甲状腺药物和双硫仑。 体内 将在大鼠中进行实验以进一步确定机制， β-内酰胺抗生素、巯基和硫脲药物产生的 低凝血酶原血症。 并非所有使用含MTT抗生素的患者 出现低凝血酶原血症;因此，动物模型将用于 识别和评估可能使患者易感的潜在风险因素 低凝血酶原血症 例如，对血液凝固的影响， 改变动物的谷胱甘肽状态，以及 维生素K的饮食水平，将被检查。 从结果的 拟定的MTT诱导的凝血因子抑制的体外分析 合成，并从动物中的风险因素测定结果 模型，可以预测 低凝血酶原血症与给定的抗生素在给定的患者。 这样的 了解将导致更安全地使用β内酰胺抗生素， 解释与这些和相关药物相关的低凝血酶原血症。

Several commonly used beta lactam antibiotics including cefamandole, cefoperazone, and moxalactam, have been associated with the development of hypoprothrombinemia, a side effect which may lead to serious bleeding. The research proposed here will examine the hypothesis that the hypoprothrombinemia associated with these antibiotics is a consequence of the pharmacologic activity of a common structural feature of the antibiotics, the 1-methyl-5-thiotetrazole (MTT) side group. This MTT group has been shown to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma carboxylation of glutamic acid in a rat liver microsomal system. Further in vitro analysis of the mechanism of this inhibition is proposed. Also the further metabolism of MTT as well as the ability of different thiol side groups in other beta lactam antibiotics to inhibit the carboxylation system will be investigated. An examination of the behavior in this system of drugs associated with hypoprothrombinemia such as thiourea antithyroid drugs and disulfiram will be made. In vivo experiments will be conducted in rats to further define the mechanism by which beta lactam antibiotics, thiol groups, and thiourea drugs produce hypoprothrombinemia. Not all patients on MTT-containing antibiotics develop hypoprothrombinemia; therefore the animal model will be used to identify and evaluate potential risk factors which may predispose patients to hypoprothrombinemia. For example, the effects on blood clotting due to altering the glutathione status of the animal, as well as variations in the dietary levels of vitamin K, will be examined. From the results of the proposed in vitro analysis of the MTT-induced inhibition of clotting factor synthesis, and from the results of risk factor determination in an animal model, it may be possible to predict the relative risk of hypoprothrombinemia with a given antibiotic in a given patient. Such an understanding will lead to the safer use of beta lactam antibiotics and explain the hypoprothrombinemia associated with these and related drugs.