OXIDATION OF AGRANULOCYTOSIS CAUSING DRUGS BY MYELOPEROXIDASE

髓过氧化物酶对引起粒细胞增多症的药物的氧化

• 批准号: 3755463
• 负责人: R P MASON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3755463
• 关键词: cardiotonic agents; congestive heart failure; drug adverse effect; electron spin resonance spectroscopy; granulocytopenia; heart disorder chemotherapy; inflammation; myeloperoxidase; oxidation

Myeloperoxidase, an abundant neutrophil protein involved in microbial killing and inflammatory tissue damage, is capable of oxidizing biological molecules and drugs in the presence of H2O2. The required H2O2 is supplied in vivo as a secondary product of the respiratory burst. Hypochlorous acid (HOCl) is also a potent oxidant and can be formed in the presence of myeloperoxidase, H2O2 and Cl-. OPC-8212 is a new positive inotropic agent currently undergoing clinical trials in the US for use in the treatment of congestive heart failure. In previous trials, OPC-8212 has been linked to the onset of agranulocytosis in 14% of the patients receiving the drug. Of those patients displaying signs of agranulocytosis, 75% had received an influenza vaccine either just prior to or during the trial, which may have stimulated the neutrophils. To probe this system, EPR (electron paramagnetic resonance spectroscopy) and oxygen uptake will be used. To elucidate whether it is the myeloperoxidase responsible for the oxidation of this drug or the secondary oxidant, hypochlorous acid, two buffer systems, a phosphate buffer containing no chloride ions and a phosphate buffered saline solution were used.

髓过氧化物酶是一种丰富的中性粒细胞蛋白，参与微生物的代谢。 杀死和炎性组织损伤，能够氧化生物 分子和药物在H2 O2的存在下。 所需的H2 O2为 作为呼吸爆发的次级产物在体内提供。 次氯酸（HOCl）也是一种有效的氧化剂，可以在 髓过氧化物酶、H2 O2和Cl-的存在。 OPC-8212是一种新型正性肌力药物，目前正处于临床应用阶段 在美国用于治疗充血性心力衰竭的试验。 在 在先前的试验中，OPC-8212与粒细胞缺乏症的发病有关 在14%的接受药物治疗的患者中。 在那些表现出 有粒细胞缺乏症的迹象，75%的人接受过流感疫苗， 就在审判之前或审判期间，这可能刺激了 中性粒细胞 为了探测这个系统，EPR（电子顺磁共振） 光谱学）和氧摄取。 为了阐明它是否 是髓过氧化物酶负责这种药物的氧化或 二次氧化剂，次氯酸，两种缓冲体系，磷酸盐 不含氯离子的缓冲液和磷酸盐缓冲盐水 使用溶液。