AN APPLICATION OF THE C-ASTERISK CONCEPT IN PREDICTING THE TOPICAL EFFICACY OF FINITE DOSE ACYCLOVIR IN THE TREATMENT OF CUTANEOUS HSV-1 INFECTIONS IN HAIRLESS MICE
AN APPLICATION OF THE C-ASTERISK CONCEPT IN PREDICTING THE TOPICAL EFFICACY OF FINITE DOSE ACYCLOVIR IN THE TREATMENT OF CUTANEOUS HSV-1 INFECTIONS IN HAIRLESS MICE
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DOI：
10.1016/0378-5173(93)90172-c
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发表时间：
1993-05-31
影响因子：
5.8
通讯作者：
HIGUCHI, WI
中科院分区：
文献类型：
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作者：
LEE, PH;SU, MH;HIGUCHI, WI
本研究检查了C*（及其时间模式）作为一个参数，用于预测局部抗病毒疗效的阿昔洛韦（ACV）制剂在最近开发的无毛小鼠模型治疗HSV-1皮肤感染。此处所指的C* 是靶部位的游离药物浓度，该靶部位被认为是表皮的基底细胞层。两种不同的局部ACV制剂，一种市售（Zovirax 5%软膏），另一种在我们的实验室制备（3% ACV混悬液），以有限剂量多次给药方案（每天两次应用）进行研究，以模拟临床情况。根据体外通量数据和从先前基线研究获得的信息计算C*。体外ACV通量测定涉及体内-体外实验设计，据信该设计非常接近实际的体内抗病毒治疗方案。对于体内抗病毒效力研究，实施了延迟1天（病毒接种后）的4天处理方案，并且动物穿着Velcro夹克以保护制剂在药物施用期间不被移除。Zovirax 5%软膏每12小时给予3 mg，我们的结果显示0%的局部疗效，与C* 预测一致。在实验室制备的3% ACV混悬液的情况下，每12小时给予2穆尔的剂量，我们的结果显示了适度的局部有效性水平（33-44%），这略高于从C* 考虑的预测值（0-25%）。此外，在实验室制备制剂的有效性研究（但不是体外通量研究）中，在实验结束时（第5天）观察到严重皮肤刺激/损伤的情况（20-33%）。考虑到这一点，建议这些研究代表了基于体外数据的预测（C*）与体内抗病毒疗效之间的良好相关性，并验证了这种方法的预测价值。
This study has examined C* (and its temporal pattern) as a parameter for predicting topical antiviral efficacy of acyclovir (ACV) formulations in a recently developed hairless mouse model for the treatment of HSV-1 cutaneous infections. C* referred to here is the free drug concentration at the target site, which is believed to be the basal cell layer of the epidermis. Two different topical ACV formulations, one available commercially (Zovirax 5% ointment) and the other prepared in our laboratories (3% ACV suspension) were investigated in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. C* was calculated from in vitro flux data and information obtained from previous baseline studies. In vitro ACV flux determinations involved an in vivo-in vitro experimental design that was believed to approximate closely the actual in vivo antiviral treatment protocol. For the in vivo antiviral efficacy studies, a 1-day delayed (after virus inoculation) 4-day treatment protocol was implemented and the animals wore a Velcro jacket to protect the formulations from being removed during the drug application period. With Zovirax 5% ointment given 3 mg every 12 h, our results showed a 0% topical efficacy which was consistent with the C* predictions. In the case of the laboratory prepared 3% ACV suspension, a dose of 2 mul was given every 12 h and our results showed a modest level (33-44%) of topical effectiveness, which was somewhat higher than predicted (0-25%) from C* considerations. Also, in the efficacy studies (but not in the in vitro flux studies) with the laboratory prepared formulation, there were instances (20-33%) of severe skin irritation/damage noted at the end (day 5) of the experiments. Taking this into consideration, it is suggested that these studies represent a good correlation between predictions (C*) based on the in vitro data and the in vivo antiviral efficacy and validate the predictive value of this approach.