Toxicity Studies of Potent Antisickling Agent 5HMF

描述(申请人提供)：镰状细胞病(SCD)是一种遗传性血液疾病，影响全球数百万患者，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)症状的方法已经并正在探索中，但除了羟基尿素(由于不良副作用而经常中毒)被许多患者持续使用外，没有一种方法被批准用于临床。因此，迫切需要治疗镰状细胞病的新方法。安全有效的抗精神病药可以减轻SCD的影响，降低医疗成本，延长患者的预期寿命。这项SBIR I期应用是5-羟甲基-2-呋喃甲醛(5HMF)临床前研究的药物开发计划。NHLBI SCD参考实验室在体内和体外对5HMF进行了广泛的初步研究。在体外和体内，它与红细胞内的HBs结合，并防止镰刀状生长。对TG镰刀鼠的初步体内研究表明，5HMF具有口服活性和高生物利用度，并具有高红细胞膜通透性。5HMF能显著延长重度低氧转基因镰状细胞(TG)小鼠的寿命，并抑制低氧诱导的镰刀效应。因此，5HMF具有独特的抗恶心作用，值得进一步的临床前研究和毒理学研究。因此，我们的具体目标包括：(1)用多点眼压计比较5HMF对不同剂量5HMF治疗的SD大鼠和Beagle犬血样氧平衡曲线的位置的影响；(2)测定口服和静脉注射5HMF后5HMF在SD大鼠和Beagle犬的单剂量急性毒性、药动学和药效学；(3)连续14天口服和静脉注射5HMF后，测定5HMF在SD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呕吐剂，作为口服或静脉注射治疗SCD的药物。第一阶段的SBIR临床前、体内动物疗效和毒理学研究应该清楚地确定5HMF是新的抗感冒剂。第二阶段SBIR提案的目标是启动5HMF的第一阶段研究，以确定5HMF在健康志愿者和镰状细胞患者中的安全性、耐受性和有效性，采用最受欢迎的给药方式。

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.