Ponticello G S, Sugrue M F, Plazonnet B, Durand-Cavagna G
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Pharm Biotechnol. 1998;11:555-74.
Dorzolamide, on the basis of its pharmacological profile and lack of undesirable side effects in safety assessment studies together with the fact that it could be formulated in solution at 2%, underwent extensive clinical studies. Early clinical studies in the development of dorzolamide have been described elsewhere (Maren, 1995; Serle and Podos, 1995). In a 1-year study in which a comparison was undertaken in patients for intraocular pressure lowering effects between 2% dorzolamide administered three times daily, 0.5% betaxolol twice daily, and 0.5% timolol twice daily, the peak reductions in intraocular pressure were 23, 21, and 25%, respectively. Tachyphylaxis did not develop to dorzolamide nor were electrolyte and/or systemic side effects encountered (Strahlman et al., 1995). The latter is consistent with results of a pharmacokinetic study in humans in which plasma levels of dorzolamide were lower than the limit of detection (5 ng/ml) at a time when the red blood cell content of dorzolamide had reached steady state which was appreciably less than the red blood cell content of the enzyme (Biollaz et al., 1995). Patients taking 0.5% timolol twice daily received either 2% dorzolamide twice daily or 2% pilocarpine four times daily for 6 months and the additional reductions in intraocular pressure elicited by dorzolamide and pilocarpine were very similar. However, pilocarpine usage resulted in a higher discontinuation rate (Strahlman et al., 1996). In a separate study in which dorzolamide and pilocarpine were compared at these dosage schedules, patients preferred dorzolamide to pilocarpine by a ratio of over 7 to 1 in terms of quality of life (Laibovitz et al., 1995). In summary, the quest for a topical, ocular hypotensive, CA inhibitor, though time-consuming, was a successful one with the introduction of dorzolamide into general clinical practice.
基于其药理特性以及安全性评估研究中未出现不良副作用，再加上它可以配制成2%的溶液，多佐胺进行了广泛的临床研究。多佐胺研发过程中的早期临床研究已在其他地方有所描述（马伦，1995年；塞尔和波多斯，1995年）。在一项为期1年的研究中，对每日三次给予2%多佐胺、每日两次给予0.5%倍他洛尔和每日两次给予0.5%噻吗洛尔的患者降低眼压效果进行了比较，眼压的最大降幅分别为23%、21%和25%。多佐胺未出现快速耐受现象，也未出现电解质和/或全身性副作用（斯特拉尔曼等人，1995年）。后者与一项人体药代动力学研究结果一致，在该研究中，当多佐胺的红细胞含量达到稳态时，其血浆水平低于检测限（5纳克/毫升），且该稳态明显低于该酶的红细胞含量（比奥拉兹等人，1995年）。每日两次服用0.5%噻吗洛尔的患者，改为每日两次服用2%多佐胺或每日四次服用2%毛果芸香碱，持续6个月，多佐胺和毛果芸香碱引起的眼压额外降幅非常相似。然而，毛果芸香碱的使用导致停药率更高（斯特拉尔曼等人，1996年）。在另一项按照这些给药方案比较多佐胺和毛果芸香碱的研究中，就生活质量而言，患者对多佐胺的偏好超过毛果芸香碱，比例超过7比1（莱博维茨等人，1995年）。总之，寻找一种局部用的降眼压碳酸酐酶抑制剂虽然耗时，但随着多佐胺引入一般临床实践，这一探索取得了成功。
