A Computer Modeling Approach

计算机建模方法

• 批准号: 8790397
• 负责人: MITCHELL W MUTZ
• 金额: $ 75万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790397
• 关键词: Acute; Adverse effects; Africa; Africa South of the Sahara; AmBisome; Amphotericin B; Animal Model; Antifungal Agents; Arrhythmia; Calcineurin; Calcineurin inhibitor; Cell Survival; Cessation of life; Chemicals; Clinical; Computer Simulation; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Disease; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Exhibits; FDA approved; FK506; Fluconazole; Flucytosine; General Population; Generations; Generic Drugs; Goals; HIV; HIV Seropositivity; Headache; Health; Healthcare; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Industrial fungicide; Infection; Inhibitory Concentration 50; Interleukin-2; Intracranial Hypertension; Knowledge; Lead; Leukopenia; Libraries; Lipids; Maintenance Therapy; Mammalian Cell; Maximum Tolerated Dose; Membrane; Methods; Nausea and Vomiting; Neoadjuvant Therapy; North America; Organ Transplantation; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Process; Property; Proteins; Relative (related person); Resistance; Resources; Sales; Solid; Southeastern Asia; Structure-Activity Relationship; Survival Rate; Symptoms; Therapeutic; Time; Toxic effect; Transplant Recipients; Treatment Protocols; Treatment outcome; Triazoles; Tuberculosis; Work; analog; biological adaptation to stress; combat; compliance behavior; cost effective; cytotoxicity; improved; in vitro activity; in vivo; inhibitor/antagonist; mortality; mouse model; nephrotoxicity; novel; phase 1 study; posaconazole; public health relevance; resistant strain; screening; theories

DESCRIPTION: Cryptococcal meningitis (CM) continues to be a significant cause of mortality among HIV positive individuals, and a major worldwide health concern. The estimated mortality rate for HIV-infected acute CM patients is 20% within 3 months after infection in North America, despite patient access to good health care resources. In sub- Saharan Africa alone, the effects of CM are devastating: an estimated 530,000 annual deaths among HIV positive patients compared with 350,000 annual deaths for tuberculosis in the general population. CM symptoms include severe headaches, nausea, and vomiting related to increased intracranial pressure. The first line therapeutic to treat CM is currently Amphotericin B (AmB), a fungicidal i.v. administere agent, and is sometimes co-administered with flucytosine. AmB and alternative lipid formulations are administered intravenously and cause side effects including nephrotoxicity, leukopenia, and cardiac arrhythmia. Although multiple factors contribute to the high mortality rates of CM, the discovery of an orally available, efficacious alternative to AmB would add an important treatment option to combat this devastating illness. We propose exploiting fungal calcineurin, an essential membrane stress response protein, to create a new class of antifungals. Through the work of our collaborator, Joe Heitman, and others, it has been shown that targeting fungal calcineurin has great potential in treating cryptococcal disease, both as monotherapy and in combination with other antifungals including fluconazole and AmB. Calcineurin inhibitors (CI's) exhibit superior in vitro potency compared with AmB against Cryptococcus neoformans. In addition, combining a fungal CI with a fungistatic triazole such as fluconazole or posaconazole results in a fungicidal combination which would likely reduce the time period required for maintenance therapy and help avoid the increased incidence of resistant cryptococcal strains. The work proposed here will be a continuation of a Phase I project where we were able to demonstrate in vivo efficacy vs. a drug resistant strain of C. neoformans employing a novel fungal calcineurin inhibitor. Aim 1. Generate closely related analogs of the 6 early lead compounds from Phase I. Aim 2. Characterize compounds in vitro for advancement. Iterate library as required. Aim 3. Characterize compounds in vivo for pharmacokinetics and efficacy.

描述：隐球菌脑膜炎（CM）仍然是艾滋病毒阳性个体死亡的重要原因，以及全球范围内的主要健康问题。尽管患者获得了良好的医疗保健资源，但在北美感染后3个月内，艾滋病毒感染的急性CM患者的估计死亡率为20％。仅在撒哈拉以南非洲，CM的影响是毁灭性的：艾滋病毒阳性患者估计每年530,000例死亡，而每年350,000例死亡人口死亡。 CM症状包括严重的头痛，恶心和与颅内压升有关的呕吐。治疗CM的第一行治疗方法是目前两性霉素B（AMB），一种杀真菌i.v.管理剂，有时与氟替汀共同管理。 AMB和替代脂质制剂静脉注射，并引起副作用，包括肾毒性，白细胞减少和心律不齐。尽管多种因素导致了CM的高死亡率，但发现了一种口服，有效的AMB替代品将增加一种重要的治疗选择，以打击这种毁灭性的疾病。我们建议利用真菌钙调神经酶（一种必不可少的膜应激反应蛋白，以创建新的抗真菌剂。通过我们的合作者乔·海特曼（Joe Heitman）和其他人的工作，已经表明，靶向真菌钙调蛋白具有巨大的潜力，可以作为单一疗法以及与其他抗真菌药（包括氟康唑和AMB）结合使用。与针对新生型的AMP相比，钙调神经磷酸酶抑制剂（CI）表现出优异的体外效力。此外，将真菌CI与真菌三唑（例如氟康唑或postaconazole）结合起来会导致杀真菌组合，这可能会缩短维持治疗所需的时间段，并有助于避免耐药性加密局菌株的发生率增加。这里提出的工作将是I期项目的延续，我们能够在体内疗效与使用新型真菌钙调蛋白抑制剂的Neoformans抗药性菌株相比。 AIM 1。产生来自I阶段的6种早期铅化合物的紧密相关的类似物。目标2。在体外表征化合物以进行进步。根据需要进行迭代库。 AIM 3。表征化合物在体内的药代动力学和功效。