In Vivo Efficacy Studies of Clofazimine against CDAD in Hamster Model

氯法齐明在仓鼠模型中抗 CDAD 的体内药效研究

• 批准号: 9047460
• 负责人: Sharanjit KS VedBrat
• 金额: $ 24.06万
• 依托单位: KAMTEK, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-14 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047460
• 关键词: Acids; Address; Affect; Animal Disease Models; Animal Diseases; Animal Model; Animals; Antibiotics; Autoimmune Diseases; Autoimmune Process; Bacteria; Bioavailable; Biological Availability; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clindamycin; Clinical Trials; Clostridium difficile; Colon; Combined Modality Therapy; Control Groups; Crohn' s disease; Data; Development; Diarrhea; Disease; Disease model; Dose; Drug Controls; Drug Formulations; Drug Kinetics; Drug vehicle; Elderly; Epidemic; Equipment and supply inventories; Exhibits; Exposure to; Formulation; Funding; Generic Drugs; Goals; Growth; Half-Life; Hamsters; Hospitals; Human; Immunization; Incentives; Incidence; Individual; Infection; Inflammatory; Ingestion; Intestines; Investments; Lead; Left; Length; Lepromatous Leprosy; Leprosy; Measures; Mesocricetus auratus; Metronidazole; Microbe; Modeling; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; National Institute of Allergy and Infectious Disease; Oral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phase II Clinical Trials; Probiotics; Property; Pseudomembranous Colitis; Public Health; Recording of previous events; Recurrence; Regimen; Reporting; Reproduction spores; Resistance; Rosa; Safety; Small Business Innovation Research Grant; Span 40; Staging; Survival Rate; Symptoms; Systemic infection; Testing; Therapeutic; Therapeutic Agents; Time; Toxic Megacolon; Toxin; Tuberculosis; United States National Institutes of Health; Vancomycin; Virulent; Work; antimicrobial drug; bactericide; base; cost; fecal transplantation; human data; in vitro activity; in vivo; killings; mortality; mutant; new growth; pharmacokinetic model; phase 2 study; prevent; prophylactic; public health relevance; resistant strain; tuberculosis drugs; tuberculosis treatment

 DESCRIPTION (provided by applicant CDC identified in a 2013 report, C. difficile (CD) associated disease (CDAD) as "urgent public health threat" responsible for at least 14,000 deaths annually. A primary factor for origin of CDAD is exposure to broad spectrum antibiotics causing a disruption of normal intestinal bacterial flora, unchecked growth of CD and its toxins causing serious inflammatory damage to colon wall. Recent emergence and spread of a more virulent strain of CD (NAP1/027/B1) is accompanied by a decrease in efficacy of current drug regimens of metronidazole (MET) and vancomycin leading at times, to fatal conditions. Recent RFI from NIAID (# HHS-NIH-NIAID-BAA-15-037) shows an urgent need for a therapeutic agent that can overcome the re-occurrence problems arising from either emergence of resistant strains of CD and/or from ingestion and growth of new spores in a hospital setting. It is both, incentive and cost prohibitive for major pharmaceuticals to invest in discovery and development of new antimicrobial agents with low return on investment, leaving repurposing of generics as a favorite choice. Based on over 20 yrs of work on tuberculosis (TB) with clofazimine (CFM) antibiotic, the PI tested in detail and found its activity to be excellent against many strains of D including NAP1/027/B1 in culture and not so for a majority of normal flora of the gut. This data led us to examine the properties of CFM to treat CDAD and found to be worth exploring. These are: 1) CFM has over forty years' history of safe use in lepromatous leprosy and multidrug- resistant TB treatment; 2) It has also been used against Crohn's disease, an inflammatory condition of the intestine, as well as other autoimmune conditions; 3) Its bactericidal activity appears to preclude the emergence of resistant mutants of targeted bacteria; 4) It has exhibited promising pharmacological and toxicological data for human use; 5) Half-life of 8-10 days even after a single dose, and upto 70 days after a course of treatment could protect against reinfection with new spores in a hospital. These properties make CFM great candidate to explore its efficacy in a CDAD animal model. To this end, we need non-dilutive SBIR phase I funding to do: 1) Pharmacokinetic study to identify drug formulation and lowest delivery dose that would optimize bioavailability of CFM in the gut lumen; 2) establish conditions of animal model for CDAD in our hands especially to determine minimal amount of CD NAP1/027/B1 spores to kill all clindamycin treated animals; followed by 3) testing 3 pre-selected doses of preselected formulation of CFM on CDAD animals to show improvement in survival. Acceptable data would lead to SBIR phase II study to Optimize Dose, time to treat before or after CD challenge to achieve 100% survival for over 27 days in animal model, a goal to do initial clinical trials during this Phase II period.

 描述（由申请人提供 CDC 在 2013 年的一份报告中将艰难梭菌 (CD) 相关疾病 (CDAD) 确定为“紧急公共卫生威胁”，每年导致至少 14,000 人死亡。CDAD 起源的一个主要因素是接触广谱抗生素，导致正常肠道细菌菌群遭到破坏，CD 及其毒素不受控制的生长，对结肠壁造成严重炎症损伤。最近出现和传播了一种毒性更强的菌株 CD (NAP1/027/B1) 的发生伴随着当前甲硝唑 (MET) 和万古霉素药物治疗方案疗效的下降，有时会导致致命的情况。 NIAID 最近的 RFI (# HHS-NIH-NIAID-BAA-15-037) 显示迫切需要一种治疗剂，可以克服因耐药菌株出现而引起的复发问题 CD 和/或在医院环境中摄入和生长新孢子。对于主要制药公司来说，投资发现和开发投资回报率较低的新型抗菌药物既具有激励作用，又成本高昂，因此仿制药的重新利用成为最受欢迎的选择。基于 20 多年使用氯法齐明 (CFM) 抗生素治疗结核病 (TB) 的工作，PI 进行了详细测试并 发现其对培养物中的许多 D 菌株（包括 NAP1/027/B1）具有优异的活性，但对大多数肠道正常菌群则不然。这些数据促使我们检查 CFM 治疗 CDAD 的特性，并发现值得探索。它们是： 1) CFM 在麻风病和多重耐药结核病治疗中具有四十多年的安全使用历史； 2) 它还被用于治疗克罗恩病、肠道炎症以及其他自身免疫性疾病； 3) 其杀菌活性似乎可以排除目标细菌耐药突变体的出现； 4) 已展现出有前景的供人类使用的药理和毒理数据； 5) 单剂量后的半衰期为 8-10 天，一个疗程后的半衰期长达 70 天，可以防止在医院被新孢子再次感染。这些特性使 CFM 成为探索其在 CDAD 动物模型中功效的绝佳候选者。为此，我们需要非稀释性 SBIR 一期资金来完成：1）药代动力学研究，以确定药物配方和最低输送剂量，以优化 CFM 在肠腔中的生物利用度； 2)建立我们手中的CDAD动物模型条件，特别是确定杀死所有克林霉素治疗动物的CD NAP1/027/B1孢子的最低量；随后3)在CDAD动物上测试3个预选剂量的CFM预选制剂以显示存活率的改善。可接受的数据将导致 SBIR II 期研究优化剂量、CD 攻击之前或之后的治疗时间，以在动物模型中实现超过 27 天的 100% 存活率，这是该 II 期期间进行初步临床试验的目标。