Toxicity Studies of Potent Antisickling Agent 5HMF

强效抗镰刀剂5HMF的毒性研究

• 批准号: 7108317
• 负责人: Robert Swift
• 金额: $ 47.32万
• 依托单位: XECHEM, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108317
• 关键词: aldehydes; biological models; blood /lymphatic pharmacology; blood tests; clinical research; dogs; dosage; drug administration rate /duration; drug design /synthesis /production; drug screening /evaluation; erythrocytes; furans; hemoglobin Ss; human tissue; hypoxia; intravenous administration; laboratory rat; methanol; oral administration; oxygen consumption; pharmacokinetics; protein binding; sickle cell anemia; sickling inhibitor; toxicology

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a hereditary blood disorder, affecting millions of patients worldwide, leading to high medical costs and a shortened life expectancy. Although many approaches to prevent the symptoms of sickle cell disease (SCD) have been and currently are being explored, no method is approved for clinical use except administration of hydroxyurea, which is frequently toxic due to undesirable side effects, for sustained use by many patients. Thus, new methods for treatment of sickle cell disease are sorely needed. A safe and effective antisickling agent can reduce the effects of SCD, reduce medical costs and increase the life expectancies of sufferers of the disease. This SBIR phase I application is a drug development plan for preclinical studies of 5-hydroxymethyl-2-furaldehyde (5HMF). 5HMF has been studied extensively, both in vitro and in vivo in a battery of preliminary tests by NHLBI SCD Reference Laboratory. It binds to HbS within RBCs and prevents sickling, both in vitro and in vivo. Preliminary in vivo studies with Tg sickle mice show that 5HMF is orally active with high bioavailability and has high red cell membrane permeability. 5HMF prolongs the life of severe hypoxic transgenic sickle cell (Tg) mice significantly and inhibits hypoxia induced sickling. Thus, 5HMF possesses a unique feature of antisickling action and clearly warrants further pre-clinical and toxicological investigation. Therefore, our specific aims include: (1) Comparison of the effect of 5HMF on the position of the oxygen equilibrium curves of human blood samples and those obtained from Sprague-Dawley rats and Beagle dogs that are treated with various doses of 5HMF, by multipoint tonometry, (2) Determination of the single dose acute toxicity, pharmacokinetics and pharmacodynamics of 5HMF in Sprague-Dawley rats and Beagle dogs, following oral/intravenous administration of 5HMF, and (3) Determination of the repeat-dose toxicity and pharmacokinetics of 5HMF in Sprague-Dawley rats and Beagle dogs, following oral/intravenous administration of 5HMF for 14 consecutive days. The toxicological response and tissue distribution will be assessed in proposed animal models. Our long term ultimate goal is to develop a safe and effective antisickling agent as either an oral or IV-delivered therapeutic for SCD. The Phase I SBIR preclinical, in vivo animal efficacy and toxicology studies should clearly identify 5HMF as the new antisickling agent. The goals of phase II SBIR proposal will be to initiate Phase I study of 5HMF to establish the safety, tolerance and efficacy of 5HMF, by the most favored mode of delivery, in healthy human volunteers and sickle cell patients.

描述（由申请人提供）：镰状细胞病（SCD）是一种遗传性血液疾病，影响着全球数百万患者，导致高昂的医疗费用和缩短的预期寿命。虽然许多预防镰状细胞病（SCD）症状的方法已经和目前正在探索中，但没有一种方法被批准用于临床使用，除了给药羟基脲，由于不良副作用，羟基脲通常是有毒的，用于许多患者的持续使用。因此，迫切需要治疗镰状细胞病的新方法。一种安全有效的抗镰状细胞凝集剂可以减少SCD的影响，降低医疗费用，延长患者的预期寿命。该SBIR I期申请是5-羟甲基-2-呋喃醛（5HMF）临床前研究的药物开发计划。NHLBI SCD参考实验室在体外和体内进行了一系列初步试验，对5HMF进行了广泛的研究。它与红细胞内的HbS结合，在体外和体内都能防止镰状细胞坏死。初步的Tg镰状小鼠体内研究表明，5HMF具有口服活性，生物利用度高，具有较高的红细胞膜通透性。5HMF可显著延长重度缺氧转基因镰状细胞（Tg）小鼠的寿命，抑制缺氧诱导的镰状细胞凋亡。因此，5HMF具有独特的抗镰状细胞作用，显然值得进一步的临床前和毒理学研究。因此，我们的具体目标包括：(1)采用多点血压法比较不同剂量5HMF对人血氧平衡曲线与Sprague-Dawley大鼠和Beagle犬血氧平衡曲线位置的影响；(2)口服/静脉给药5HMF对Sprague-Dawley大鼠和Beagle犬单剂量5HMF急性毒性、药代动力学和药效学的影响；(3)连续14天口服/静脉给药5HMF后，测定5HMF对Sprague-Dawley大鼠和Beagle犬的重复给药毒性和药代动力学。毒理学反应和组织分布将在拟议的动物模型中进行评估。我们的长期最终目标是开发一种安全有效的抗SCD药物，作为SCD的口服或静脉给药治疗。SBIR I期临床前、体内动物疗效和毒理学研究应明确确定5HMF为新的抗镰状细胞病药物。II期SBIR提案的目标是启动5HMF的I期研究，以确定5HMF在健康人类志愿者和镰状细胞患者中的安全性、耐受性和有效性，通过最有利的递送方式。