CN1349409A - 用glp－1进行代谢介入以提高缺血和再灌注组织的功能 - Google Patents
用glp－1进行代谢介入以提高缺血和再灌注组织的功能 Download PDFInfo
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- CN1349409A CN1349409A CN00806951A CN00806951A CN1349409A CN 1349409 A CN1349409 A CN 1349409A CN 00806951 A CN00806951 A CN 00806951A CN 00806951 A CN00806951 A CN 00806951A CN 1349409 A CN1349409 A CN 1349409A
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- Prior art keywords
- glp
- ischemia
- glucose
- peptide
- glucagon
- Prior art date
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Abstract
本发明涉及用包含与胰高血糖素样肽－1之受体结合的化合物的组合物治疗与缺血相关的再灌注,优选通过静脉给药所述化合物。本发明涉及用于此等治疗的方法及组合物。
Description
相关申请的交叉参考
本申请是1998年10月8日递交的60/103,498号临时申请的部分继续。
发明领域
本发明涉及用GLP-1进行代谢介入以治疗性地提高缺血和再灌注组织的功能。
发明背景
众所周知，缺血的后果是需氧器官组织的细胞损坏，无论是自发性冠状动脉闭塞时的内源性缺血，还是开心术、冠状分流手术或者心脏或其他器官如肺、肾、肝、胰腺和胃肠道的移植手术时的医源性缺血。导致缺血状况的程度和持续时间与细胞死亡量和/或可逆性细胞功能障碍有关。还已知的是，许多组织损伤事实上是在以前缺氧组织再灌注(血流重新开始)以及重新加氧时发生的。由于医学的发展，特别是在心肌梗死及其他心肌治疗方法如冠状分流、其他开心手术以及器官移植后治疗再灌注损伤，促进了最近对再灌注损伤的研究。
作为正常需氧呼吸的副产物，通常从线粒体电子转移链中失去电子。此等电子与分子氧相互作用，产生活性游离基超氧化物，该超氧化物在其他反应步骤中在过氧化氢和铁存在时产生极为活性而且毒性的羟基游离基。代谢活性的需氧组织具有防御机制，用于在这些活性氧物质与细胞器、酶或DNA相互作用之前分解毒性游离基，而该相互作用的后果是在没有所述保护机制时导致细胞死亡。这些防御机制包括使超氧化物歧化的酶超氧化物歧化酶(SOD)，分解过氧化氢的过氧化氢酶，以及作为非特异性游离基清除剂的肽谷胱甘肽。
虽然尚未完全理解，但认为在代谢组织缺血以及随后的再灌注时，发生复杂的过程。首先在缺血阶段，细胞内抗氧酶的活性出现下降，包括SOD、过氧化氢酶和谷胱甘肽的活性。还有迹象表明，黄嘌呤氧化酶的活性在缺血过程中同时在血管内皮组织中增加。产生氧游离基的能力增强(通过增强的黄嘌呤氧化酶活性)以及清除相同氧游离基的能力下降(通过SOD、过氧化氢酶和谷胱甘肽活性降低)，如果缺血细胞随后再灌注血液以及氧，则大大增加了这些缺血细胞对氧化性突发情况的敏感性。该氧化性突发情况通常在再灌注的数秒-数分钟内发生，有可能对内皮细胞以及构成缺血-再灌注器官基质的其他细胞导致可逆和不可逆性损伤。例如，如果心脏是该情况下的器官，可逆性氧化性损伤会使心肌晕眩(stunning)，而不可逆的损伤本身表现为心肌梗死。伴随该首先发生的氧化性突发情况，是对细胞膜的氧化性损伤。细胞膜中脂质氧化在中性白血病趋化性为缺血后区域中似乎发挥作用。此等经活化的中性白血病粘附在血管内皮上，诱导黄嘌呤脱氢酶在所述内皮细胞中转化为黄嘌呤氧化酶，并进一步加剧内皮完整性的丧失。经活化的中性白血病还从脉管系统中移出，进入心肌间隙空间，在此炎性细胞可直接杀死心肌细胞。另外，由于缺血-再灌注，正常钙从肌质网中的流动受到介入，产生可逆性心肌功能障碍，称为心肌晕眩。
缺血-再灌注过程的后果是可逆及不可逆性细胞损伤、细胞死亡以及器官功能下降。更具体而言，对于心肌再灌注损伤，其后果包括心肌晕眩、心律不齐、以及梗死，结果产生生龋中风和潜在的充血性心脏衰竭。
与有限时间缺血性缺氧相关的细胞损伤以及随后再灌注之间的反论是细胞损伤和死亡似乎不仅直接由于失氧期，而且还由于组织的重新加氧使得对缺氧期间氧化性损伤高度敏感。再灌注损伤开始于回流时立即产生的初始氧化性突发情况，而且随着相同的缺血后组织中炎症发展继续恶化数小时。使缺氧后的细胞对氧化性损伤的敏感性下降的努力，以及降低这些相同组织中炎性反应的努力，都表明降低了对缺氧后再灌注器官的可逆性及不可逆性损伤。降低初始氧化性突发情况以及随后与炎症有关的损伤的方法组合可对再灌注损伤提供协同保护作用。
在治疗患有缺血及MI的患者时，现在通常使用的常规治疗方法是使用溶栓剂如链激酶和t-PA以及血管成形术。第4,976,959号美国专利公开了给药t-PA和SOD以抑制在同时患有缺血的再灌注和/或透皮穿腔冠状血管成形术期间的组织损伤，恢复区域血流。因此，越来越多的患者都有经受再灌注损伤及其作用的可能性，特别是心脏病患者。
对除心脏外器官的再灌注损伤自身通常表现为功能效率大大降低，其后果是器官的早熟性退化或者简单关闭。另外，如果有显著的再灌注损伤，移植器官过程会增加排斥率。
如以上简单讨论的，虽然再灌注损伤的精确机理尚未完全清除，但在各种心脏病模型研究中汇集的大多数数据表明，产生源自于氧的游离基，包括超氧阴离子(O2)-、羟基游离基(·OH)和H2O2，是由于再灌注时重新引入分子氧，而且在组织坏死中起到重要的作用。降低这些氧衍生的游离基的产生的药物(包括别嘌呤醇和deferroxamine)或者增加这些物质的降解的药物如超氧化物歧化酶、过氧化氢酶、谷胱甘肽以及铜络合物，似乎可限制梗死面积，而且也可增强左心室功能从心脏晕眩中恢复。
特别是在急性心肌梗死期间使用代谢介入作为治疗方法是已知的，但并非无可争议。有许多试验和临床证据支持在急性MI后使用葡萄糖-胰岛素-钾(GIK)输注(代谢介入的主要形式)，特别是在瑞典DIGAMI研究(Malmberg，K.和DIGAMI研究组(1997)Prospective randomizedstudy of intensive insulin treatment on long term survival after acutemyocardial infarction in patients with diabetes mellitus.Brit.Med.J.314，1512-1515)成功后。DIGAMI研究强调了葡萄糖-胰岛素输注对于糖尿病患者中急性MI的效力，但该类型的治疗方法对于再灌注已不再被推荐或者使用。
因此可以看出仍需要安全有效而且对预防或者缓解缺血和再灌注对组织、特别是器官组织的有害作用具有更宽适用性的组合物，所述器官组织包括但不限于心肌。本发明的主要目的在于实现该需要。
本发明的另一个目的在于提供治疗缺血和再灌注但没有目前方法通常所具有的副作用的方法。
本发明的又一个目的是提供可用于静脉给药本发明组合物的药物学上可接受的载体组合物，但该组合物没有任何显著的非所希望的副作用，而且不会负面影响抗原或者免疫刺激性质。
从以下的进一步描述及所附的权利要求书，本发明的这些目的以及其他目的对本领域技术人员将更显而易见。
发明简述
需要治疗缺血和/或再灌注的个体用包括能够结合胰高血糖素样肽-1之受体的化合物的组合物进行治疗，优选通过静脉给药。本发明涉及用于此等治疗的方法及组合物。发明详细描述
GLP-1是葡萄糖依赖性促胰岛素激素，其有效地增强周围葡萄糖摄入，但不诱导危险的低血糖病。另外，GLP-1强烈地抑制胰高血糖素分泌，独立于其促胰岛素作用，而且由此强效地降低血浆游离脂肪酸(FFA)水平，大大超过用胰岛素治疗时的作用。高FFA水平有可能是心肌缺血期间的主要毒性因素。
我们现在发现GLP-1可作为用于治疗缺血-再灌注损伤的代谢方法。该发现是基于以下事实：有两种临床情况，其中缺血-再灌注是常规而且潜在危险的事情：用于急性MI的溶栓法，以及心脏手术期间缺血心麻痹后的心脏再灌注。另外，近来的试验和临床数据表明，缺血-再灌注现象对于用GIK输注的代谢疗法有特别的应答，甚至大大高于没有再灌注的离体缺血(Apstein，CS(1998)Glucose-insulin-potassium foracute myocardial infacfion.Remarkable results from a new prospective，randomized trial.Circulation 98，2223-2226)。
在过去的十年中，治疗伴随MI的急性缺血的两个重要治疗进展是引入了血栓溶解和β-阻断。但是，尽管该总的成功，血栓溶解的一些研究发现了早期过高死亡率，这归因于再灌注诱发的损伤以及心肌晕眩。产生晕眩的机理是复杂的，但一致的观点是认为其有可能与导致功能障碍性肌纤维膜Ca2+泵和胞液Ca2+过量负载的细胞内酸中毒有关。净结果是被损害的心肌收缩功能，导致机械效率下降，以及再灌注心室心律不齐。另外，最近的研究表明，细胞内酸中毒又是由于糖酵解和完全葡萄糖氧化之间的不平衡，其意义是在TCA循环中糖酵解率与丙酮酸(糖酵解的终产物)的氧化不匹配。由于丙酮酸转化为乳酸，该不匹配导致净H+产生。该不平衡的最大可能原因是存在高血浆游离脂肪酸(FFA)水平，其优先进入线粒体中，并抑制丙酮酸氧化。这是与灌注葡萄糖的心脏相比，灌注有FFA的心脏更不易在再灌注期恢复的机理。这在此已经发现，而且是以下治疗发明的基础之一：GLP-1抑制FFA，超过用胰岛素时的预期水平，其中用胰岛素时抑制50％，而GLP-1可抑制FFA高达90％。
这些考虑增强了我们对用胰高血糖素样肽治疗缺血-再灌注的信心。已知的是，在正常灌注并充足加氧期间，心脏依赖于需氧代谢，而且使用FFA作为其优选的燃料。相反，在缺血(血流下降)或者低氧(O2张力下降)期间，脂肪酸的β-氧化被损害(因为其是严格需氧的)，而且持续提供ATP更加依赖于无氧糖酵解。在缺血期间，葡萄糖-胰岛素是有益的，这是因为其能够增强葡萄糖的摄入并刺激糖酵解，由此提供ATP用于维持基本的膜功能，特别是离子转运的功能。另外，葡萄糖-胰岛素抑制脂肪组织的脂解，由此降低血浆FFA水平以及FFA向心肌中的摄入。由于对膜的直接去垢作用和cAMP的增加，以及acylcamitine的累积，高的FFA水平对于缺血心肌是毒性的。而acylcamitine的累积抑制Ca2+泵。净作用是干扰了离交换、胞液Ca2+过量负载、以及产生收缩功能障碍和心律不齐。
在再灌注期间，葡萄糖-胰岛素是有益的，这是因为如上所述，该疗法可缓解产生晕眩的代谢不平衡。这是通过直接刺激PDH并由此刺激丙酮酸氧化，以及间接通过降低FFA摄入并由此提高丙酮酸与FFA氧化的比例而实现的。
由以上讨论可以看出，葡萄糖-胰岛素增强葡萄糖摄入和代谢以及降低FFA水平的双重作用，在再灌注中具有显著的治疗效力。一些人已表达了以下忧虑：在深的、基本上零流动的缺血中，糖酵解最终产物，即、乳酸，会由于不充分的“清洗”而发生累积。乳酸累积又会导致高的细胞内质子浓度，而且不能氧化还原NADH；高的[H+]以及NADH/NAD+比例抑制生产性糖酵解。在此情况下，葡萄糖对于细胞则为毒性的，因为ATP实际上是在产生果糖-1，6-二磷酸酯时被消耗，而高的[H+]会加剧心肌细胞坏死(Neely，JR和Morgan，HE(1974)Relationship between carbohydrate and lipid metabolism and the energybalance of heart muscle.Ann.Rev.Physiol.36，413-459)。但是，这些忧虑并没有由于证明葡萄糖-胰岛素产生有益结果的试验及临床数据的重量而消除。虽然不希望囿于任何理论，对此可能的解释是，在人中，急性自发性缺血不是零流动缺血的症状，但相反代表了低流动缺血区域，其中残留的灌注对于基础转运和乳酸清洗是足够的。该事实现在为在缺血-再灌注中使用代谢疗法提供了强有力的生理学逻辑。
现代的心脏手术涉及心瓣替换或者冠状动脉分流接入(CABG)，通常需要低温心麻痹性暂停、主动脉交叉钳住以及手术期间的心肺分流。因此，常规心脏手术会有效地诱发选择性的全面缺血以及随后的再灌注，这潜在地使心脏暴露于所有可能的风险和损伤中，特别是对心肌缺血-再灌注。所以，防止心肌在心脏手术期间以及之后的损伤仍是最大问题。再灌注前的选择性心麻痹缺血明显与再血管化前在急性MI期间遇到的缺血-再灌注并行，而且因此许多以前考虑的病理学原则在心脏手术期间也是适用的。但是，在手术性心麻痹缺血-再灌注以及与MI有关的缺血-再灌注之间有一些显著不同。在手术期间，心脏停止(心麻痹)并输注冷(低温)的溶液，用于最佳地保护心肌。在手术完成后，重新激活心脏，并再灌注与体温相同温度的加氧血液。这产生了以下顺序：低温缺血以及常温再灌注，防止了H+和乳酸的高组织累积水平。另外，与急性MI不同，低温心麻痹是一种全身性的零流动缺血，然后是全身性再灌注。
在我们的以前申请(第60/103,498号，本申请是该在先申请的部分继续)中，已综述了葡萄糖-胰岛素输注的缺点以及用GLP-1输注替代它们的优点，后者更为安全。总之，GIK输注有低血糖和高血糖的显著风险，而且技术上要求较高并需要许多人力。低血糖的危险是显而易见的。
相反，这些风险在使用GLP-1输注时都不存在。胰高血糖素样肽(7-36)酰胺(GLP-1)是天然的、由肠中得到的、促胰岛素肽，其是所谓肠降血糖素作用的主要成分。GLP-1在胰内分泌细胞中发挥其主要作用，在胰内分泌细胞中其(1)以葡萄糖依赖性的方式调节胰岛素表达以及从β-细胞中的分泌；(2)刺激促生长素抑制素的分泌；以及(3)抑制胰高血糖素从α细胞中的分泌。虽然没有正式解决，但强的胰高血糖素抑制(glucagonostatic)作用假设是由于以下原因之-或者全部：(1)通过刺激α细胞上的GLP-1受体直接抑制，虽然这不太有可能；(2)通过小岛内释放促生长素抑制素旁分泌抑制胰高血糖素分泌；或者(3)通过小岛内释放胰岛素旁分泌抑制。无论何种细胞机理，GLP-1在其同时刺激胰岛素分泌以及抑制胰高血糖素释放的能力方面都是独特的。虽然治疗性输注胰岛素也抑制胰高血糖素的释放，但该作用没有GLP-1作用那么强，后者直接、小岛内旁分泌地抑制胰高血糖素分泌。
GLP-1强有力地刺激胰岛素释放以及抑制胰高血糖素分泌的双重能力，以及该促胰岛素性作用对葡萄糖的严格依赖性，使得该分子在治疗缺血-再灌注中具有独特的治疗效力。首先，GLP-1强烈刺激内源性胰岛素的分泌，并因此可用于实现对代谢治疗缺血-再灌注中胰岛素输注有益的作用。虽然高剂量的GIK输注通常包含25-33％葡萄糖和50-100U胰岛素/L，但需要引入高血糖以实现治疗效力，相反仅提供用于安全给药高剂量胰岛素的代谢环境，都仍不清除。有可能的是，需要足够的葡萄糖血液浓度以保证底物转运，但这并不一定意味着需要高血糖，而且不应偏离胰岛素除葡萄糖摄入外还具有重要作用这一事实。因此，治疗性GLP-1输注有可能仅需要中等(如5％)的葡萄糖共同输注，以维持葡萄糖血液浓度略高于生理浓度，引发胰岛素释放。葡萄糖不是必须的安全措施，因为小于等于3.5mM的血液浓度消除GLP-1的胰岛素刺激活性，由此完全避免低血糖的危险。
其次，GLP-1发挥强有力的胰高血糖素抑制作用，与其促胰岛素作用一起对FFA产生强的抑制作用。葡萄糖-胰岛素输注的主要优点之一是降低了循环中FFA的浓度，以及抑制FFA摄入。当产生晕眩时，FAA及其代谢物对缺血心肌以及在再灌注期间具有直接毒性作用。因此降低FFA浓度是缺血-再灌注中代谢介入的主要治疗目标、缺血-再灌注中代谢介入的目标。因为胰高血糖素对于脂肪组织脂解以及FFA产生是有力的刺激因素，GLP-1介导的胰高血糖素抑制作用进-步增强了胰岛素诱导的FFA循环浓度降低。因此，GLP-1治疗在这方面优于葡萄糖-胰岛素输注。的确，健康自愿者中的初步数据表明GLP-1静脉输注将降低血浆FFA水平至低于对照值的10％。
GLP-1应在绝大多数患者中是有效的，不需要同时给药葡萄糖。但是，小部分患者有可能需要葡萄糖/GLP-1以引发足够的胰岛素反应。另外，还有可能需要给药钾以校正在葡萄糖与GLP-1共同给药时钾在细胞内室中的过度转移。
除GLP-1或其生物类似物外，治疗法还包括使用游离基清除剂如谷胱甘肽、褪黑素、维生素E、以及超氧化物歧化酶。在此等组合中，再灌注损伤风险被进一步减弱。
术语“GLP-1”或者胰高血糖素样肽，包括模拟物，而且在本发明中包括胰高血糖素样肽以及结合胰高血糖素样肽-1(GLP-1)受体蛋白如GLP-1(7-36)酰胺受体蛋白并对胰岛素分泌具有与GLP-1(7-36)酰胺相应的生物作用的相关肽和胰高血糖素样肽-1的类似物，所述GLP-1(7-36)酰胺是GLP-1的天然生物活性形式。见Goke，B和Byrne，M，Diabetic Medicine，1996，13：854-860。GLP-1受体是例如存在于产生胰岛素的胰β-细胞上的细胞表面蛋白。胰高血糖素样肽及类似物包括具有促胰岛素活性的物质以及作为GLP-1受体分子激动剂(即、活化)而且对产生胰岛素的β-细胞具有第二信使活性的物质。在以下文献中描述了通过其受体表现活性的胰高血糖素样肽的激动剂：EP 0708179A2；Hjorth，S.A.等人，J.Biol.Chem.269(48)：30121-30124(1994)；Siegel E.G.等人，Amer.Diabetes Assoc.57th Scientific Sessions.Boston(1997)；Hareter，A.等人，Amer.Diabetes Assoc.57th ScientificSessions，Boston(1997)；Adelhorst，K.等人，J.Bioil.Chem.269(9)：6275-6278(1994)；Deacon C.F.等人，16th International Diabetes FederationCongress Abstracts，Diabetologia Supplemetn(1997)；Irwin，D.M.等人，Proc.Natl.Acad.Sci.USA.94：7915-7920(1997)；Mosjov，S.，Int.J.PeptideProtein Res.40：333-343(1992)。胰高血糖素样分子包括表达GLP-1激动剂(即、GLP-1受体分子的活化剂)及其在产生胰岛素的β-细胞上存在的第二信使活性的多核苷酸。也是激动剂的GLP-1模拟物包括例如具体设计成活化GLP-1受体的化学合成的化合物。胰高血糖素样肽-1拮抗剂也是已知的，例如参见：Watanabe，Y等人，J.Endocrinol.140(1)：45-52(1994)，并包括exendin(9-39)胺，其是exendin类似物，为GLP-1受体的强效拮抗剂(见例如WO 97/46584)。最近一些出版物公开了Black Widow GLP-1和Ser2 GLP-1，见G.G.Holz，J.F.Hakner/Comparative Biochemistry and Physiology，Part B 121(1998)177-184；以及Ritzel等人，A synthetic glucagon-like peptide-1 analog withimproved plasma stability，J.Endocrinol 1998 Oct.159(1)：93-102。
其他实施方案包括化学合成的胰高血糖素样多肽以及基本上同源性的任何多肽或片段。“基本上同源性”是指核酸及氨基酸序列，代表具体的受试序列，例如突变序列，由于一个或多个取代、缺失或者增加而由参考序列发生变化，其净效果不在参考序列和受试序列之间产生不利的功能相异性。为本发明的目的，具有超过50％同源性、优选超过90％同源性、在增强β细胞对血浆葡萄糖浓度应答方面具有相同生物活性、以及具有相同表达特性的序列被认为是基本上同源的。为测定同源性，成熟序列的截短不应被考虑。同源性较低但具有可比生物活性以及相同表达特性的序列被认为是等价的。
哺乳动物GLP肽和胰高血糖素是由相同基因编码的。在回肠中，表型被处理为两种主要类别的GLP肽激素，即、GLP-1和GLP-2。已知有四种由表型肽处理得到的GLP-1相关肽。GLP-1(1-37)具有以下序列；His Asp Glu Phe Glu Arg His Ala Glu Gly Thr Phe Thr SerAsp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp LeuVal Lys Gly Arg Gly(SEQ ID NO：1)。GLP-1(1-37)通过翻译后处理被酰胺化，产生GLP(1-36)NH2，其具有以下序列：His Asp Glu PheGlu Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu GlyGin Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Gls Gly Arg(NH2)(SEQ IDNO：2)；或者其经酶解后产生具有以下序列的GLP-1(7-37)：His AlaGlu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala LysGlu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly(SEQ ID NO：3)。GLP-1(7-37)也可被酰胺化，产生GLP-1(7-36)酰胺，其是GLP-1分子的天然形式，而且具有以下序列：His Ala Glu Gly Thr Phe Thr Ser AspVal Ser Ser Tyr Leu Glu Gly Gin Ala Ala Lys Glu Phe Ile Ala Trp Leu ValLys Gly Arg(NH2)(SEQ ID NO：4)，而且为GLP-1分子的天然形式。
肠L细胞分别以1-5的比例分泌GLP-1(7-37)(SEQ ID NO：3)和GLP-1(7-36)NH2(SEQ ID NO：4)。这些截短形式的GLP-1在原位具有短的半衰期，低于10分钟，而且被氨基二肽酶IV灭活，分别产生Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln AlaAla Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly(SEQ ID NO：5)；以及Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala AlaLys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg(NH2)(SEQ ID NO：6)。肽Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala LysGlu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly(SEQ ID NO：5)和Glu GlyThr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu PheIle Ala Trp Leu Val Lys Gly Arg(NH2)(SEQ ID NO：6)被认为可以影响肝葡萄糖产生，但不刺激胰岛素由胰腺中的产生或者释放。
在Gila畸形体毒液中有六种肽与GLP-1是同源性的。在表1中显示了它们的序列与GLP-1序列的对比。表1a.HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRNH2b.HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSNH2c. DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSNH2d.HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSNH2e.HSDATFTAEYSKLLAKLALQKYLESILGSSTSPRPPSSf.HSDATFTAEYSKLLAKLALQKYLESILGSSTSPRPPSg.HSDAIFTEEYSKLLAKLALQKYLASILGSRTSPPPNH2h.HSDAIFTQQYSKLLAKLALQKYLASILGSRTSPPPNH2a＝GLP-1(SEQ.ID NO：4).b＝Exendin 3(SEQ.ID NO：7).c＝Exendin 4(9-39(NH2(SEQ.ID NO：8).d＝Exendin 4(SEQ.ID NO：9).e＝Helospectin I(SEQ.ID NO：10).f＝Helospectin II(SEQ.ID NO：11).g＝Helodermin(SEQ.ID NO：12).h＝Q8，Q9Helodermin(SEQ.ID No：13).
表1中概括区域表示的主要同源性是：肽c和h分别衍生于b和g。所有6种天然肽(a、b、d、e、f、和g)在1、7、11和18位是同源的。GLP-1和exendin3及4(a、b和d)进一步在4、5、6、8、9、15、22、23、25、26和29位是同源的。在2位，A、S和G在结构上是类似的。在3位，残基D和E(Asp和Glu)在结构上是类似的。在22和23位，F(Phe)和I(Ile)在结构上分别类似于Y(Tyr)和L(Leu)。同样，在26位，L和I在结构上是等价的。
因此，在GLP-1的30个残基中，exendin 3和4在15位是相同的，而且在5个其他位置处是等价的。仅在残基16、17、19、21、24、27、28和30处基团结构变化是明显的。Exendin在羧基端还具有额外的残基。
GLP-1样肽可通过固相化学肽合成法制备。GLP-1也可通过常规的重组技术来制备，其中可使用例如Sambrook和Maniaitis中描述的标准程序。在此所用术语“重组”是指蛋白得自于重组(如微生物或者哺乳动物)表达体系，而所述表达体系可进行遗传改性，包含用于GLP-1或其生物活性类似物的表达基因。
GLP-1样肽可由重组细胞培养基中通过以下方法回收并纯制：硫酸铵或乙醇沉淀、酸抽提、阴离子或阳离子交换色谱、磷酸纤维素色谱、疏水性相互作用色谱、亲和性色谱、羟基磷灰石色谱以及卵磷脂色谱。对于最终纯制步骤，可使用高效液相色谱(HPLC)。
本发明的多肽可为天然纯制形式，或者是化学合成产物，或者是通过重组技术由原核或真核宿主(例如细菌、酵母、高级植物、昆虫和哺乳动物细胞在培养基中或者于体内)产生的物质。取决于重组制备程序中所使用的宿主，本发明的多肽通常是非糖基化的，但也可是糖基化的。
GLP-1活性可通过标准方法测定，通常是通过受体结合活性筛选法测定，该方法涉及提供在其表面上表达GLP-1受体的合适细胞，例如胰岛瘤细胞系，如RINmSF细胞或者INS-1细胞。也可参见：Mosjov，S.(1992)和EP 0708170A2。除使用放射免疫分析法测定示踪物与膜的特异性结合外，也可测定cAMP活性或者葡萄糖依赖性的胰岛素产生。在一个方法中，使用编码本发明受体的多核苷酸，以转染细胞，并由此表达GLP-1受体蛋白。因此，例如，这些方法可用于筛选受体激动剂，其中包括使所述细胞与待筛选的化合物相接触，然后测定该化合物是否产生信号，即、活化受体。
多克隆及单克隆抗体可用于检测、纯制和鉴别在本发明方法中使用的GLP-1样肽。诸如ABGA1178的抗体检测完整未剪接的GLP-1(1-37)或者N端截短的GLP-1(7-37)或(7-36)酰胺。其他抗体检测前体分子C端的末端，其是通过减法来计算生物活性的截短肽的量，即、GLP-1(7-37)或者(7-36)酰胺(Orskov等人，Diabetes，1993，42：658-661；Orskov等人，J.Clin.Invest.1991，87：415-423)。
其他筛选技术包括在测量由于受体活化导致的细胞外pH或离子交换的体系中使用表达GLP-1受体的细胞，例如经转染的CHO细胞。例如，潜在的激动剂与表达GLP-1蛋白受体的细胞接触，然后测量第二信使应答，如信号传导或者离子或pH变化，以测定该潜在的激动剂是否有效。
本发明的胰高血糖素样肽受体结合蛋白可与合适的药物载体组合使用。此等组合物包括治疗有效量的所述多肽以及药物学上可接受的载体或赋形剂。所述载体包括但不限于盐水、缓冲盐水、葡萄糖、水、甘油、乙醇、乳糖、磷酸盐、甘露醇、精氨酸、海藻糖以及它们的混合物。剂型应适合于给药方式，而且本领域技术人员可容易确定。GLP-1肽也可与本领域中体内增强所述肽的半衰期的已知物质组合使用，以增强或者延长肽的生物活性。例如，在给药前，分子或者化学基团可共价键地连接在本发明的组合物上。或者，增强剂可与所述组合物共同给药。另外，所述物质可包括已知抑制GLP-1样肽的酶降解的分子，并可与GLP-1肽组合物共同给药或者在其后给药。所述分子可例如通过口服或者注射给药。
给药GLP-1或其类似物以及在此所述的载体体系的患者，特别是那些在计划手术之前或者在缺血情况后头4个小时内进行治疗的患者，观察他们具有非常低的心律不齐、较低的组织损伤以及较少的不适感，而且没有副作用。
由以上考虑来看，显然输注GLP-1可在心肌再灌注上发挥主要的治疗作用。GLP-1可通过IV或者皮下给药进行连续输注，其中优选的给药水平是，静脉(IV)给药为0.1pmol/kg/min-10pmol/kg/min，皮下(SC)给药为0.1pmol/kg/min-75pmol/kg/min，而对于IV单次注射(团块)为0.005nmol/kg-20nmol/kg，SC为0.1nmol/kg-100nmol/kg。如果需要将血液葡萄糖水平维持在大于等于5mM(以维持有效的胰岛素分泌)，GLP-1输注可与葡萄糖(5％)共同给药。类似地，也可以考虑共同给药钾(K+)，这取决于激活膜Na+/K+ATP酶使K+迁移至细胞内空间的程度。在家或者救护车中，在例如急性自发性缺血后尽可能早地于缺血后期以及再灌注治疗前开始GLP-1治疗，而且之后继续进行。如果是心脏手术，GLP-1输注应在手术前12-24小时前、开始麻醉至主动脉交叉夹紧的手术期间、以及手术后松开夹钳后至少72小时立即开始。如以上所述，共同给药游离基清除剂可进一步有助于再灌注恢复。
从以上描述可以看出，本发明可实现所有目的。
Claims (23)
1、一种用于缓解由于缺血后血流再灌注导致的器官组织损伤的方法，其包括：向需要此等治疗的个体给药有效量的组合物，该组合物包括结合胰高血糖素样肽-1之受体的化合物以及药物载体。
2、如权利要求1所述的方法，其中，所述胰高血糖素样肽-1是GLP-1或其生物活性类似物。
3、如权利要求1所述的方法，其中，所述药物载体选自于以下组中：盐水、缓冲盐水、葡萄糖、水、甘油、乙醇、乳糖、磷酸盐、甘露醇、精氨酸、海藻糖以及它们的混合物。
4、如权利要求1所述的方法，其中，给药剂量为0.1pmol/kg/min-10pmol/kg/min。
5、如权利要求4所述的方法，其中，共同给药葡萄糖。
6、如权利要求5所述的方法，其中，共同给药钾。
7、如权利要求4所述的方法，其中，共同给药游离基清除剂。
8、如权利要求1所述的方法，其中，在缺血情况后4小时内开始给药。
9、如权利要求8所述的方法，其中，缺血情况后4小时内开始给药而且之后继续进行。
10、如权利要求1所述的方法，其中，通过静脉给药。
11、如权利要求1所述的方法，其中，通过皮下或者微压注射、深度肺吸入、外部泵或植入泵、缓释注射、以及其他持续释放装置、口服、和药贴、颊和其他透皮及透膜装置给药。
12、如权利要求1所述的方法，其中，器官组织是心肌。
13、如权利要求8所述的方法，其中，在情况发生后尽可能快地给药。
14、一种用GLP-1进行代谢介入以提高缺血及再灌注组织的功能的方法，所述方法包括：向需要此等治疗的个体给药有效量的组合物，该组合物包括结合胰高血糖素样肽-1之受体的化合物以及药物载体。
15、如权利要求14所述的方法，其中，所述胰高血糖素样肽-1是GLP-1或其生物活性类似物。
16、如权利要求14所述的方法，其中，所述药物载体选自于以下组中：盐水、缓冲盐水、葡萄糖、水、甘油、乙醇、乳糖、磷酸盐、甘露醇、精氨酸、海藻糖以及它们的混合物。
17、如权利要求14所述的方法，其中，给药剂量为0.1pmol/kg/min-10pmol/kg/min。
18、如权利要求17所述的方法，其中，共同给药葡萄糖。
19、如权利要求14所述的方法，其中，在缺血情况后4小时内开始给药。
20、如权利要求19所述的方法，其中，缺血情况后4小时内开始给药而且之后继续进行。
21、如权利要求14所述的方法，其中，需要通过代谢介入来缓解的组织损伤是由于选自于以下组中的手术医疗过程产生的：心脏手术、器官移植、创伤性截肢以及再接肢。
22、如权利要求14所述的方法，其中，所述手术医疗过程涉及缺血性再灌注，而该再灌注与肠梗塞和心肌梗死同时发生。
23、一种用于用GLP-1进行代谢介入以提高缺血及再灌注组织的功能的组合物，其包括：有效量的GLP-1以及药物学有效的载体。
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