Improved actions of nitrates and statins with L-arginine

描述(申请人提供)：该项目旨在开发更安全、更有效和持久的：1)硝酸甘油或单硝酸异山梨酯治疗心绞痛和充血性心力衰竭；2)他汀类药物[普伐他汀或辛伐他汀]联合L-精氨酸(L-精氨酸)治疗不稳定型心绞痛和中风。硝基血管扩张剂是非常有效的，但由于对其血管扩张作用的耐受性迅速发展，其在慢性治疗中的有效性受到限制。NitrO Systems，Inc.发现了GTN诱导的血管扩张和耐受的另一种依赖内皮细胞(EC)的机制，这种耐受可以通过补充L精氨酸来预防。资料显示，GTN激活内皮型一氧化氮合酶(ENOS)，使其底物L精氨酸产生NO。已知的是，在以血管功能障碍为特征的疾病中，细胞内L精氨酸的供应可能会受到限制，作为eNOS底物的L精氨酸的可获得性降低可能会由于形成超氧阴离子(Soa)和其他活性氧物种而导致内皮损伤，补充L精氨酸可以防止内皮功能障碍。他汀类或HMG辅酶A还原酶抑制剂通过与降脂无关的机制激活enqs并抑制血小板聚集。他汀类药物也促进了SOA的形成。假设细胞外持续升高的L-精氨酸水平是硝酸酯类药物和他汀类药物的最佳治疗效果所必需的，补充L-精氨酸将通过减少soa的形成来增强药物作用。具体目的为：1.测定GTN、ISMN、PRA、SIM在EC中激活一氧化氮合酶、产生SOA的能力及补充L精氨酸对其抑制作用。2.测定补充L-精氨酸对动物SOA形成和亚硝酸盐耐受性的影响。3.研制静脉滴注复方L-精氨酸制剂和口服复方丹参滴丸与L-精氨酸联合缓释制剂。4.研制SIM与L-精氨酸联合口服缓释制剂。

DESCRIPTION (provided by applicant): This project seeks to develop safer, more effective and enduring: 1) nitrate therapy for angina and congestive heart failure using nitroglycerin (GTN) or isosorbide mononitrate (ISMN) and 2) statin therapy [pravastatin (PRA) or simvastatin (SIM)] for unstable angina and stroke, by their combination with L-arginine (L-arginine). Nitrovasodilators are highly effective acutely, but their usefulness for chronic therapy is limited due to the rapid development of tolerance to their vasodilating effects. NitrOSystems, Inc. has discovered an additional endothelial cell (EC)-dependent mechanism of GTN-induced vasodilation and tolerance and that tolerance can be prevented by treatment with supplemental L-arginine. Data show that GTN activates EC nitric oxide synthase (eNOS) to produce NO from its substrate L-arginine. It is known that the intracellular supply of L-arginine can become limiting in diseases characterized by vascular dysfunction, that diminished availability of L-arginine as a substrate for eNOS can result in EC damage due to formation of superoxide anion (SOA) and other reactive oxygen species and that treatment with supplemental L-arginine can prevent EC dysfunction. Statins or HMG CoA reductase inhibitors, by mechanisms unrelated to lowering lipids, activate eNQS and inhibit platelet aggregation. Formation of SOA is also increased by statins. It is hypothesized that sustained elevated extracellular levels of L-arginine are required for optimal therapeutic effects of nitrates and the statins and that supplemental L-arginine will potentiate drug actions by reducing formation of SOA. Specific aims are to: 1. Determine the ability of GTN, ISMN, PRA, SIM to activate NOS and produce SOA in EC and the ability of supplemental L-arginine to prevent SOA formation. 2. Determine the ability of supplemental L-arginine to prevent SOA formation and nitrite tolerance in animals. 3. Develop an IV formulation of GTN in combination with L-arginine and an oral combined sustained release formulation of ISMN and L-arginine. 4. Develop an oral combined sustained release formulation of SIM and L-arginine.