Prichard M N, Prichard L E, Shipman C
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor 48109.
Antimicrob Agents Chemother. 1993 Mar;37(3):540-5. doi: 10.1128/AAC.37.3.540.
The development of new drugs effective against human viral diseases has proven to be both difficult and time-consuming. Indeed, there are but 10 drugs licensed for such applications in the United States today. An attractive solution to this problem may be to optimize the efficacy and selectivity of existing antiviral drugs by combining them with agents that strategically block carefully selected metabolic pathways. This approach was used in the rational design of a three-drug combination to increase the apparent potency of acyclovir against herpes simplex virus. Recent advances in analytical techniques have made the evaluation of this complex drug strategy both possible and practical. A modified version of a previously described analytical method was used to identify optimal drug concentrations and to quantitate statistically significant synergy. Concentrations of 0.25 microM 5-fluorodeoxyuridine, 3.6 microM 2-acetylpyridine thiosemicarbazone, and 0.3 microM acyclovir were determined to be optimal in terms of antiviral activity. The volume of synergy produced was nearly 2,000 microM3% at a 95% level of confidence (corresponding to a 186-fold decrease in the apparent 50% inhibitory concentration of acyclovir with the addition of 0.25 microM 5-fluorodeoxyuridine and 3.6 microM 2-acetylpyridine thiosemicarbazone). We anticipate that this strategic approach and the supporting three-dimensional analytical method will prove valuable in designing and understanding multidrug therapies.
事实证明，研发有效对抗人类病毒性疾病的新药既困难又耗时。的确，如今在美国仅有10种药物获许可用于此类用途。解决这一问题的一个有吸引力的办法可能是，将现有抗病毒药物与能策略性阻断精心挑选的代谢途径的药物相结合，从而优化其疗效和选择性。这种方法被用于合理设计一种三联药物组合，以提高阿昔洛韦对单纯疱疹病毒的表观效力。分析技术的最新进展使得评估这种复杂的药物策略成为可能且切实可行。采用了一种先前描述的分析方法的改进版本来确定最佳药物浓度，并对具有统计学意义的协同作用进行定量分析。就抗病毒活性而言，已确定0.25微摩尔/升的5-氟脱氧尿苷、3.6微摩尔/升的2-乙酰吡啶硫代半卡巴腙和0.3微摩尔/升的阿昔洛韦浓度为最佳。在95%的置信水平下产生的协同作用量接近2000微摩尔³%（相当于在添加0.25微摩尔/升的5-氟脱氧尿苷和3.6微摩尔/升的2-乙酰吡啶硫代半卡巴腙后，阿昔洛韦的表观50%抑制浓度降低了186倍）。我们预计，这种策略性方法以及配套的三维分析方法在设计和理解多药疗法方面将被证明是有价值的。
