USING LIPID LINKED AZT DRUGS TO IMPROVE HIV THERAPY

通过将药物连接到酰链来保持极性脂类头基的同一性 增加药物靶向将是一项重大成就。 将材料定向到特定位置的能力减少了以下需求 饱和所有药理隔间，以达到治疗水平 一。拟议的第一阶段研究将确定 给与极性脂类连接的药物制剂 特定的头部群完好无损。这些研究应该提供统计数据 令人信服的实验数据支持AE6C(3‘-叠氮基- 2‘，3’，连接到神经酰胺的双脱氧胸苷[AZT])，很容易与 血脑屏障，并表现出优越的脑和中枢神经系统积聚， 抗病毒活性，细胞和骨髓毒性低于 AZT。AZT增强大脑和中枢神经系统的蓄积可能非常 在抗击艾滋病相关痴呆症方面很重要。在体外利用一种 方法，我们将确定AE6C是否能建立有效的 能够提供恒定药物供应的蜂窝储存库。在……里面 患者，该储存库将降低剂量频率和剂量 治疗所需的药物，从而减轻压力，增加患者 合规性。第二种药物利用AZT连接到磷脂酰甘油， 将合成具有良好结构特征的AE6PG 并对其药理和抗病毒性能进行了评价。 拟议的商业应用：将药物连接到极性脂酰链 代表着一个改善毒品行动的机会，通过指导和 把药物留在需要的地方。极性脂类AZT-的研究进展 相关药物的提出可能在抗击艾滋病毒的战斗中发挥重要作用 以及其他病毒感染。递送AZT和其他药物的能力 穿过血脑屏障，同时减少所需的剂量 随之而来的毒性和病人的不适是很重要的 令人向往。同样，其他脂类和药物也可以用来引导材料 优先用于器官和位置，并可能有助于解决 阻力问题。值得注意的是，它提供了一种平台技术 适用于目前正在使用的其他药物。该药的研制 交付方法将是重要和及时的，因为它解决了 克服了目前可用的抗病毒药物的许多主要缺点。

Retaining polar lipid head group identity by linking drugs to acyl chains to increase drug targeting would represent a significant accomplishment. The ability to direct material to specific locations reduces the need to saturate all pharmacological compartments to achieve therapeutic levels in one. The Phase I research proposed will determine the feasibility of delivering pharmaceutical agents linked to polar lipids with their specific head groups intact. These studies should provide statistically compelling experimental data supporting the hypothesis that AE6C(3'-Azido- 2',3',dideoxythymidine [AZT] linked to ceramide), readily crosses the blood brain barrier and exhibits superior brain and CNS accumulation, antiviral activity, and lower cellular and marrow toxicity compared to AZT. Enhanced brain and CNS accumulation of AZT is likely to be very important in combating AIDS-related dementia. Utilizing an in vitro approach, we will determine whether AE6C can establish an effective cellular reservoir capable of providing a constant drug supply. In patients, this reservoir would decrease dosage frequency and the amount of drug required for therapy, thereby reducing stress and increasing patient compliance. A second drug utilizing AZT linked to phosphotidylglycerol, AE6PG, exhibits promising structural characteristics, will be synthesized and it's pharmacological and antiviral properties evaluated. PROPOSED COMMERCIAL APPLICATION: Linking drugs to polar lipid acyl chains represents an opportunity to improve drug action by directing and retaining drug where it is needed. Development of the polar lipid AZT- linked drugs proposed is likely to be important in the battle against HIV and other virus infections. The ability to deliver AZT and other drugs across the blood brain barrier, while decreasing both the dose required and attendant toxicities and patient discomfort is important and desirable. Likewise other lipids and drugs can be used to direct material preferentially to organs and locations and maybe of help in addressing the resistance problem. Significantly, it provides a platform technology applicable to other drugs presently in use. Development of this drug delivery approach will be significant and timely, as it addresses and overcomes many major shortcomings of currently available antiviral drugs.