CRL-1072 FOR TREATMENT OF MYCOBACTERIUM

I期研究表明，CRL 1072对急性 鸟分枝杆菌（MAI）感染与 克拉霉素、利福必利和克林霉素。 第二阶段的目标是 推荐特定剂型的特定药物组合， 将有效治疗耐药微生物，减少 耐药微生物，并最大限度地减少与多种 MAI感染的药物治疗。 第一个目标是优化 使用CRL 1072与克拉霉素、利福布雷定联合的方案 和克林霉素的完全清除，复发， 感染和出现耐药性。 标准化米色小鼠模型 是为了解决这些问题而开发的。 下一个目标是使用 这些方法来研究CRL 1072与几个 抗生素对一系列克拉霉素耐药临床分离株的作用 使用U937巨噬细胞模型，然后在米色小鼠中进行研究。 第二 共聚物，CRL 1605，已被证明是通过不同的机制，从 CRL 1072，并与之产生协同作用。将在 努力进一步减少药物治疗的剂量和毒性。 下一个是 将进行实验以开发用于口服给药的方案， 使用来自亲本研究的最有效组合的药物。 最后，我们将研究CRL 1072对已知限制的影响。 一线和二线抗分枝杆菌药物的毒性。 拟议的商业应用：治疗MAI感染的新型药物 由于耐药性和耐药问题， 毒性 CRL-1072的研制 活性和降低毒性将填补一个重要的需求，因此具有 商业应用。

Studies in Phase I demonstrated that CRL 1072 is effective against acute infection with Mycobacterium Avium (MAI) in combination with clarithromycin, rifabutin and clindamycin. The goal of Phase II is to recommend a specific combination of drugs in specific dosage forms that will effectively treat drug resistant organisms, reduce the emergence of drug resistant organisms, and minimize toxicity associated with multiple drug therapy of infections with MAI. The first aim is to optimize protocols for using CRL 1072 in combination with clarithromycin, rifabutin and clindamycin in terms of completeness of clearance, recrudescence of infection and emergence of resistance. A standardized beige mouse model has been developed to address these questions. The next aim is to use these methods to investigate the effects of CRL 1072 with several antibiotics on a series of clarithromycin resistant clinical isolates using a U937 macrophage model followed by studies in beige mice. A second copolymer, CRL 1605, has been shown to act via different mechanisms from CRL 1072 and to produce synergy with it. It will be evaluated in an effort to further reduce the dose and toxicity of drug therapy. Next, experiments will be done o develop protocols for oral administration of drugs using the most effective combinations from parental studies. Finally, we will investigate effects of CRL 1072 on the known limiting toxicities of first and second line antimycobacterial drugs. PROPOSED COMMERCIAL APPLICATION: Novel agents for treating MAI infections in HIV patients are needed because of problems in drug resistance and drug toxicity. The development of CRL-1072 s a novel agent to increase drug activity and reduce toxicity will fill in an important need and thus have commercial applications.