USING LIPID LINKED AZT DRUGS TO IMPROVE HIV THERAPY

通过将药物连接到酰基链来保持极性脂质头基身份 增加药物靶向性将是一项重大成就。 将材料导向特定位置的能力减少了以下需求： 使所有药物隔室饱和，以达到治疗水平， 一个. 第一阶段的研究建议将确定的可行性， 递送与极性脂质连接的药剂， 特定的头群完整。 这些研究应该提供统计数据 令人信服的实验数据支持AE 6C（3 '-叠氮基- 2 '，3'，双脱氧胸苷[AZT]连接到神经酰胺），很容易穿过 血脑屏障并表现出上级的脑和CNS积累， 抗病毒活性和较低的细胞和骨髓毒性相比， AZT AZT在大脑和中枢神经系统的累积增加可能非常 在防治艾滋病相关痴呆症方面很重要。 使用体外 我们将确定AE 6C是否能够建立一个有效的 细胞贮库能够提供恒定的药物供应。 在 患者，该储库将降低剂量频率和剂量。 治疗所需的药物，从而减轻压力，增加患者的 合规 第二种药物利用AZT连接到磷脂酰甘油， AE 6PG具有很好的结构特性， 并对其药理学和抗病毒特性进行评估。 拟议的商业应用：将药物连接到极性脂质酰基链 代表了一个机会，以改善药物作用， 在需要的地方保留药物。 极性脂质AZT-1的研制 一种被提议的关联药物可能在对抗艾滋病毒的战斗中发挥重要作用 和其他病毒感染。 将AZT和其他药物 通过血脑屏障，同时减少所需的剂量 以及随之而来的毒性和患者不适是重要的， 令人向往 同样，其他脂质和药物可用于引导材料 优先考虑器官和位置，也许有助于解决 阻力问题。 重要的是，它提供了一种平台技术， 适用于目前正在使用的其他药物。 这种药物的开发 交付方法将是重要和及时的，因为它解决和 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.