Advanced Preclinical Testing of a Broad-Spectrum Antiparasitic Quinolones for Veteran Health

广谱抗寄生虫喹诺酮类药物对退伍军人健康的高级临床前测试

基本信息

批准号：
10265392
负责人：
Joseph Stone Doggett
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265392
关键词：
Active Sites Acute Adverse reactions Animal Model Animal Testing Animals Antimalarials Antiparasitic Agents Babesiosis Binding Bioavailable Biological Assay Biological Availability Blood Tests Brain Brain Injuries Canis familiaris Carbonates Caring Cells Cellular Assay Clinical Clinical Research Clinical Treatment Clinical Trials Country Cyst Cytochromes b Dose Drug Kinetics Drug resistance Drug usage Enzymes Esters Event Formulation Growth HIV Health Health Personnel Hematopoietic stem cells Histopathology Human In Vitro Individual Infection K-Series Research Career Programs Kinetics Lead Malaria Maximum Tolerated Dose Medicine Military Personnel Modeling Mus No-Observed-Adverse-Effect Level Oral Organ Organ Transplantation Parasites Parasitic Diseases Parasitic infection Pharmaceutical Preparations Plasma Plasmodium Plasmodium falciparum Preclinical Testing Prodrugs Property Prophylactic treatment Proteins Provider Qi Quinolones Rattus Relapse Research Risk Safety Scientist Series Site Solid Specificity Sporozoites Sprague-Dawley Rats Stem cell transplant Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Toxicity Tests Toxoplasma Toxoplasma gondii Toxoplasmosis Transplant Recipients Transplantation United States Veterans atovaquone base brain tissue clinical application drug candidate drug development drug discovery drug efficacy efficacy study efficacy testing experimental study hazard human model immunosuppressed improved in vivo in vivo evaluation intraperitoneal medication safety novel therapeutics pre-clinical prevent programs renal damage research clinical testing resistance mutation safety testing side effect stem cells synergism toxoplasmic encephalitis treatment strategy

项目摘要

VA scientists have discovered antiparasitic quinolones that are highly effective against malaria and toxoplasmosis. Malaria is a potentially fatal infection that is a deployment hazard for veterans. The many veterans who have HIV or who undergo hematopoietic stem cell or solid organ transplant are at risk of developing Toxoplasma encephalitis when they are immunosuppressed. Current treatments for malaria and prophylaxis for malaria are limited by the spread of drug resistance. Medicines for toxoplasmosis have high rates of side effects that are more common and problematic in HIV and transplant patients. This proposal builds on research that has identified ELQ-422 as a lead antiparasitic quinolone prodrug that is effective in animal models of toxoplasmosis and malaria, and is not toxic in cellular assays and efficacy experiments. The next step in preclinical testing is drug safety testing in animals. To achieve this, the maximum tolerated dose and no observed adverse effect level of ELQ-422 will be determined in rats. Demonstrating an acceptable therapeutic index of ELQ-422 in rats will allow for large animal testing and subsequent clinical trials. ELQ-422 is anticipated to be safe; however, identifying alternate antiparasitc quinolones is necessary in the event that ELQ-422 does not have an acceptable therapeutic index. The alkoxy carbonate ester promoiety of ELQ-422 that increases ELQ bioavailability close to 4 times will be applied to ELQs that were potent but limited by bioavailability. The promoiety will also be applied to a series of ELQ derivatives that will be synthesized to optimize a recently discovered ELQ that is 100 times more potent than ELQ-316, which is the active component of ELQ-422. These new prodrugs will be tested in a cascade of cellular and enzyme assays for efficacy and toxicity followed by in vivo studies of efficacy and pharmacokinetics. Lead compounds from these experiments will be evaluated for safety in rats in the same manner as ELQ-422. Finally, ELQ-422 and its active component ELQ-316 have been found to be synergistic with atovaquone (ATV) in acute models of toxoplasmosis and limit the development of drug-resistance in an animal model of human babesiosis, an infection that is similar to malaria. The underlying mechanism of synergy will be examined by comparing the cytocidal concentration and the concentration dependent kinetics of parasite inhibition of ELQ+ATV compared to each compound alone. In addition, the pharamacokinetic effects of ELQs and ATV on each other will be determined. The synergistic effect of ELQ+ATV will be tested in vivo as malaria prophylaxis and against latent Toxoplasma gondii infection. Overall, the proposed research will advance new broad-spectrum antiparasitic quinolones toward clinical evaluation and define treatment strategies that will enhance the clinical applicability of antiparasitic quinolones.

退伍军人管理局科学家发现了抗寄生虫喹诺酮类药物，对疟疾和疟疾非常有效弓形体病。疟疾是一种潜在致命的感染，对退伍军人来说是一种危险。许多感染艾滋病毒或接受造血干细胞或实体器官移植的退伍军人面临感染风险当免疫抑制时，会发生弓形虫脑炎。目前治疗疟疾和疟疾的预防因耐药性的传播而受到限制。治疗弓形体病的药物具有高在艾滋病毒和移植患者中更常见和更成问题的副作用的发生率。这个提议基于已确定 ELQ-422 是一种主要抗寄生虫喹诺酮前药的研究，该药物可有效弓形体病和疟疾的动物模型，并且在细胞测定和功效实验中无毒性。这临床前测试的下一步是动物药物安全性测试。为了实现这一目标，最大耐受剂量并且在大鼠中未测定观察到的 ELQ-422 不良反应水平。表现出可接受的 ELQ-422在大鼠中的治疗指数将允许进行大型动物测试和随后的临床试验。 ELQ-422 预计是安全的；然而，在以下情况下，有必要确定替代的抗寄生虫喹诺酮类药物： ELQ-422 没有可接受的治疗指数。 ELQ-422的烷氧基碳酸酯部分将 ELQ 生物利用度提高近 4 倍，将应用于有效但受以下因素限制的 ELQ：生物利用度。该促进剂还将应用于一系列 ELQ 衍生物，这些衍生物将被合成为优化了最近发现的 ELQ，其效力比 ELQ-316 强 100 倍，ELQ-316 是活性物质 ELQ-422 的组成部分。这些新的前药将在一系列细胞和酶测定中进行测试功效和毒性，然后是功效和药代动力学的体内研究。来自这些的铅化合物将以与 ELQ-422 相同的方式评估大鼠实验的安全性。最后，ELQ-422及其活性成分 ELQ-316 已被发现与阿托伐醌 (ATV) 在急性模型中具有协同作用弓形虫病并限制人类巴贝斯虫病动物模型中耐药性的发展，与疟疾类似的感染。将通过比较来检验协同作用的根本机制 ELQ+ATV 的杀细胞浓度和寄生虫抑制的浓度依赖性动力学比较单独针对每种化合物。此外，ELQ 和 ATV 相互之间的药代动力学效应将是决定。 ELQ+ATV 的协同效应将在体内测试作为疟疾预防和对抗潜伏疟疾的效果。弓形虫感染。总体而言，拟议的研究将推进新的广谱抗寄生虫药喹诺酮类药物的临床评估和确定治疗策略，以增强临床适用性抗寄生虫喹诺酮类药物。