THE PHARMACOLOGY OF INHIBITORS OF HEME PROTEIN-CATALYZED LIPID PEROXIDATION

血红蛋白催化的脂质过氧化作用有助于肌红蛋白 和血红蛋白从细胞的抗氧化环境中释放出来。其中包括一项重大贡献 肌红蛋白催化的脂质过氧化反应与横纹肌溶解引起的肾功能衰竭的关系， 心肌缺血时微血管收缩。血红蛋白引起的脂质过氧化反应与 与蛛网膜下腔出血、恶性疟疾和镰状细胞病的病理生理学有关。之间 脂质过氧化的产物是F2 -异前列烷，其是高效的血管收缩剂。我们 已经证明氧化血红素蛋白的过氧化物酶样功能催化的脂质过氧化 会被醋氨酚抑制在横纹肌溶解的大鼠模型中，F2-异前列腺素产生 肾内导致肾衰竭，对乙酰氨基酚显着减少脂质过氧化反应， 肾衰竭的程度明显降低。这些发现为开发甚至 更有效的抑制剂具有较低电离势和键离解焓的化合物已被 合成，并发现作为铁氧自由基的还原剂， 肌红蛋白和血红蛋白。这些化合物的进一步测试和新化合物的合成 系列提出。假设脂质过氧化的最佳抑制可以通过 抑制自由基引发剂的水溶性抗氧化剂与脂溶性抗氧化剂的组合 将检查链断裂的抗氧化剂。对乙酰氨基酚的作用将在 蛛网膜下腔出血，其中脂质过氧化的证据与迟发性血管痉挛的时间相关 以及神经功能缺损的严重程度。这将是一项试点研究，其中对乙酰氨基酚为基础的方案 通过测量F2异前列腺素水平评估其降低脂质过氧化的能力 在脑脊液中。次要终点将包括血管痉挛和脑缺血， 磁共振动脉造影和成像，以及评估神经系统的结果。结果 可以为更大规模的结果研究提供基础，并为开发更有效的 抑制蛛网膜下腔出血以及 其它疾病

Hemoprotein- catalyzed lipid peroxidation contributes to the pathophysiology of diseases in which myoglobin and hemoglobin are released from the antioxidant environment of cells. These include a major contribution of myoglobin-catalyzed lipid peroxidation to the renal failure produced by rhabdomyolysis and to microvascular constriction in myocardial ischemia. Lipid peroxidation induced by hemoglobin is correlated with the pathophysiology of subarachnoid hemorrhage, Falciparum malaria and sickle cell disease. Among the products of lipid peroxidation are the F2 -isoprostanes, which are highly potent vasoconstrictors. We have demonstrated that lipid peroxidation catalyzed by the peroxidase-like function of oxidized hemoproteins is inhibited by acetaminophen. In a rat model of rhabdomyolysis in which F2-isoprostanes generated intrarenally contribute to the renal failure, acetaminophen significantly reduced lipid peroxidation and markedly decreased the extent of renal failure. These findings provide a rationale for development of even more potent inhibitors. Compounds with lower ionization potential and bond dissociation enthalpy have been synthesized and found to have markedly increased potency as reductants of the ferryloxo radical of myoglobin and hemoglobin. Further testing of these compounds and synthesis of newer compounds in the series is proposed. The hypothesis that optimal inhibition of lipid peroxidation can be achieved by a combination of water soluble antioxidants that inhibit the radical initiator together with lipid soluble antioxidants that are chain breaking will be examined. The effect of acetaminophen will be evaluated in subarachnoid hemorrhage, in which evidence of lipid peroxidation correlates with time of delayed vasospasm and with severity of neurological deficits. This will be a pilot study in which acetaminophen based regimens will be tested for their ability to reduce lipid peroxidation assessed by measurement of F2 isoprostane levels in cerebrospinal fluid. Secondary endpoints will include vasospasm and brain ischemia as determined by magnetic resonance arteriography and imaging, as well as assessment of neurological outcome. The results could provide a basis for a larger outcome study, and a rationale for development of even more potent regimens for inhibiting hemoprotein-catalyzed lipid peroxidation in subarachnoid hemorrhage as well as in other diseases.