PHARMACOLOGIC AGENTS FOR THE PRESERVATION OF DONOR LIVER

由于自2000年以来，对器官排斥的控制得到了极大的改善， 随着环孢素A的引入，肝移植已成为公认的 某些肝病的治疗形式。 然而，现实 肝脏对局部缺血的不耐受性仍然是一个限制因素。 尝试 包括使用低温疗法， 细胞内型溶液和各种灌注技术。 一直 然而，没有系统地调查使用 药理学试剂，以解决肝脏的特定需求， 缺血 肝脏缺血导致能量储存的耗尽， 细胞电解质平衡丧失，产生有毒物质， 最终导致肝细胞和微循环衰竭。 拟议 研究将确定在低温期间肝脏的具体需求。 缺血，并构成一个系统的方法，以发展的肝脏 利用各种药理学干预的保存溶液， 特别是在局部缺血期间攻击肝脏的各种需求。 等 一种方法提供了巨大的潜在有效性的优点， 应用的简单性。 因此，与复杂的灌注技术不同， 肝功能的药物稳定可以容易和快速地 应用于临床实践，将进一步提高疗效， 长期保存的灌注技术。 目前，血液 从供体肝脏中冲洗出林格氏乳酸盐，然后输注 冷防腐剂，通常是柯林斯溶液。 在植入之前， 接受者，肝脏再次用林格氏乳酸盐冲洗。 我们 假设是，向这些溶液中加入各种试剂， 专门针对肝脏缺血期间的需要， 允许的缺血时间。 待测试的干预措施包括 糖异生抑制剂、ATP-MgC 12、Ca 2+拮抗剂、自由基 清除剂、高渗甘露醇和血栓素抑制剂。 这些试剂 将被添加到冲洗和保存解决方案的寒冷 保存大鼠肝脏。 然后将通过以下方式确定其功效： 评估细胞和器官功能的广泛范围，主要使用 冷保存后的离体灌流肝脏模型。 这将 允许在敏感的和 成本效益的方式。 这种方法应该能改善肝脏 可以快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.