PHARMACOLOGIC AGENTS FOR THE PRESERVATION OF DONOR LIVER

因为器官排斥反应的控制得到了极大的改善 引入环孢素-A，肝移植已成为公认的 某些肝病的一种治疗形式。然而，现实的 肝脏对缺血的耐受性仍然是一个限制因素。尝试 在克服这一计划时包括使用低温疗法， 细胞内型溶液和各种灌流技术。那里有 然而，没有系统地调查使用 解决肝脏特殊需求的药理药物 缺血症。肝脏的缺血会导致能量储备的耗尽， 细胞电解质平衡的丧失，有毒物质的产生 最终导致肝细胞和微循环衰竭。建议数 研究将确定肝脏在低温期间的特殊需求 并构成一种系统的肝脏发育途径 利用各种药物干预的保存液 特别针对肝脏在缺血期间的各种需求。是这样的 一种方法提供了巨大的潜在有效性的优势以及 应用的简单性。因此，与复杂的灌流技术不同， 肝功能的药物稳定可以很容易和快速地实现 应用于临床，将进一步提高中药的疗效。 可长期保存的灌流技术。目前，血液是 从供体肝脏中洗出林格氏乳酸盐，然后输注 冷防腐剂，通常是柯林斯溶液。在植入之前 受者的肝脏再次被林格氏乳酸盐冲洗。我们的 假说是在这些溶液中加入不同的试剂 具体解决肝脏在缺血期间的需要会延长 允许的缺血时间。将进行测试的干预措施包括 糖异生抑制剂、ATP-MgC12、钙拮抗剂、自由基 清道夫，高渗甘露醇和血栓素抑制剂。这些特工 将添加到防寒冲刷和保鲜解决方案中 保存大鼠肝脏。它们的有效性将由以下因素决定 评估广泛的细胞和器官功能主要使用 冷保存后的离体肝灌流模型。这将是 允许在敏感的和非敏感的 具有成本效益的方式。这种方法应该能改善肝脏状况。 可以迅速应用于临床的保存技术。

Because of vastly improved control of organ rejection since the introduction of Cyclosporin-A, liver transplantation has become an accepted form of therapy for certain liver diseases. However, the realtive intolerance of the liver to ischemia remains a limiting factor. Attempts at overcoming this program include the use of hypothermia, intracellular-type solutions and various perfusion techniques. There has not, however, been a systematic investigation into the use of pharmacological agents to address the specific needs of the liver during ischemia. Ischemia in the liver results in depletion of energy stores, loss of cellular electrolyte balance, production of toxic substances and ultimately hepatocellular and microcirculatory failure. The proposed studies will determine the specific needs of the liver during hypothermic ischemia and constitute a systematic approach to the development of a liver preservation solution that utilizes various pharmacologic interventions to specifically attack the various needs of the liver during ischemia. Such an approach offers the advantages of great potential effectiveness plus simplicity of application. Thus, unlike elaborate perfusion technique, pharmacologic stabilization of hepatic function could be easily and rapidly applied to clinical practice and would further enhance the efficacy of perfusion techniques for longer term preservation. Currently, blood is washed out of the donor liver Ringer's lactate followed by infusion of the cold preservative, usually a Collins solution. Prior to implanting in the recipient, the liver is again flushed with Ringer's lactate. Our hypothesis is that the addition of various agents to these solutions to specifically address the needs of the liver during ischemia will prolong the allowable ischemic time. The interventions to be tested include gluconeogenesis inhibitors, ATP-MgC12, Ca2+ antagonists, free radical scavengers, hypertonic mannitol and thromboxane inhibitors. These agents will be added to the washout and preservation solutions for the cold preservation of rat livers. Their efficacy will then be determined by evaluating a broad spectrum of cellular and organ functions primarily using the isolated perfused liver model following cold preservation. This will allow evaluation of a large number of permutations in a sensitive and cost-effective manner. This approach should produce improved liver preservation techniques that can quickly be applied clinically.