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

• 批准号: 9891845
• 负责人: Joseph Stone Doggett
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 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/9891845
• 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

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.

弗吉尼亚州的科学家们发现了抗寄生虫喹诺酮类药物，对疟疾非常有效， 弓形虫病疟疾是一种潜在的致命感染，对退伍军人来说是一种部署危险。的许多 患有艾滋病毒或接受造血干细胞或实体器官移植的退伍军人有 当他们免疫抑制的时候会发展成弓形虫脑炎。目前的疟疾治疗方法， 疟疾的预防措施受到抗药性蔓延的限制。治疗弓形虫病的药物 副作用的发生率在HIV和移植患者中更常见和更成问题。这项建议 建立在已经确定ELQ-422作为一种主要的抗寄生虫喹诺酮类前药的研究基础上， 弓形虫病和疟疾的动物模型，并且在细胞测定和功效实验中没有毒性。的 临床前试验的下一步是在动物身上进行药物安全性试验。为了达到这一目的，最大耐受剂量 并且将在大鼠中确定ELQ-422的未观察到的不良作用水平。展示一个可接受的 ELQ-422在大鼠中的治疗指数将允许大动物测试和随后的临床试验。ELQ-422 预期是安全的;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的烷氧基碳酸酯前体部分 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 生物利用度该前体部分也将应用于一系列ELQ衍生物，这些衍生物将被合成以 优化最近发现的ELQ，其效力是ELQ-316的100倍， ELQ-422的成分。这些新的前药将在细胞和酶测定的级联中进行测试， 功效和毒性，随后是功效和药代动力学的体内研究。铅化合物从这些 将以与ELQ-422相同的方式评价大鼠实验的安全性。ELQ-422及其 已经发现活性组分ELQ-316与阿托伐醌（ATV）在急性模型中具有协同作用， 弓形虫病和限制人类巴贝虫病动物模型中耐药性的发展， 类似于疟疾的感染。协同作用的基本机制将通过比较 比较了ELQ+ATV的杀细胞浓度和寄生虫抑制的浓度依赖性动力学 每一种化合物。此外，ELQ和ATV对彼此的药代动力学效应将被 测定将在体内测试ELQ+ATV作为疟疾预防和抗潜伏性疟疾的协同作用。 弓形虫感染。总的来说，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价，并确定治疗策略，将提高临床适用性 抗寄生虫的喹诺酮类药物