PHARMACOLOGY OF ANTIBIOTIC-RELATED HYPOPROTHROMBINEMIA

几种常用的β-内酰胺类抗生素，包括头孢芒多， 头孢哌酮和莫沙拉坦与糖尿病的发生有关 低凝血酶原血症，一种可能导致严重出血的副作用。这个 这里提出的研究将检验这样的假设： 与这些抗生素相关的低凝血酶原血症是 丹参的一个共同结构特征的药理活性 抗生素，1-甲基-5-硫代四氮唑(MTT侧)组。这个四甲基偶氮唑蓝小组 已被证明可以抑制凝血因子中依赖维生素K的步骤 大鼠肝脏谷氨酸的伽玛羧化合成 微体系统。对其作用机制的进一步体外分析 提出了抑制机制。此外，四甲基偶氮唑盐的进一步代谢以及 不同硫醇侧基对其他β-内酰胺类抗生素的作用能力 抑制羧化体系将被研究。对…的考试 与低凝血酶原血症相关的药物系统中的行为 将生产硫脲、抗甲状腺药物和双硫胺等药物。活体内 将在大鼠身上进行实验，通过以下方式进一步确定这种机制 β-内酰胺类抗生素、硫醇基团和硫脲类药物 低凝血酶原血症。并不是所有患者都在服用含四甲基偶氮唑蓝的抗生素 出现低凝血酶原血症；因此，该动物模型将用于 识别和评估可能使患者易感的潜在风险因素 到低凝血酶原血症。例如，对凝血的影响，由于 改变动物的谷胱甘肽状态，以及 将检查饮食中维生素K的水平。从调查结果来看 四甲基偶氮唑盐抑制凝血因子的体外分析 合成，并根据动物风险因素测定的结果 模型，则有可能预测 在特定患者中使用特定抗生素的低凝血酶原血症。这样的一种 了解将导致更安全地使用β-内酰胺类抗生素和 解释与这些药物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.