Van Damme L, Wright A, Depraetere K, Rosenstein I, Vandersmissen V, Poulter L, McKinlay M, Van Dyck E, Weber J, Profy A, Laga M, Kitchen V
Institute of Tropical Medicine, Antwerp, Belgium.
Sex Transm Infect. 2000 Apr;76(2):126-30. doi: 10.1136/sti.76.2.126.
Although the male condom provides a reliable means of preventing HIV transmission, a broader choice of methods is required particularly in circumstances where the negotiation of condom use is difficult. Development of new products that may be effective as topical vaginal microbicides is the focus of a great deal of research activity currently. The novel agent PRO 2000, a naphthalene sulphonate derivative with in vitro activity against HIV and other sexually transmissible pathogens, is one such compound. We have studied the local and systemic safety and tolerance of a vaginal gel formulation of this agent at two concentrations (0.5% and 4%) over a 2 week period of daily exposure in two cohorts of healthy sexually abstinent women (one in London, UK, and the other in Antwerp, Belgium).
This was a randomised, placebo controlled, double blind, three arm clinical trial conducted on two sites. Macroscopic evidence of genital epithelial changes was sought using colposcopy and evidence of microscopic inflammation was acquired using high vaginal biopsy from predetermined sites (UK cohort only). Blood levels of PRO 2000 were measured and laboratory safety tests, including coagulation screens, were performed. The impact on vaginal ecology was also assessed.
73 women were enrolled across both sites (36 UK, 37 Belgium); 24, 24, 25 in the 4%, 0.5%, and placebo groups respectively. Of these, 70 completed 2 weeks' exposure to the study gel. Three (all in the 4% group) withdrew owing to adverse events which were possibly or probably gel related. Cervicovaginal abrasion was seen colposcopically in three subjects after 14 days of gel use (two in the 4% group and one in the placebo group). Genital ulceration was not seen during gel use in any of the subjects who completed the study. Histological evaluation of vaginal biopsy samples (36 women only) showed evidence of increased inflammatory signs in one participant of the 4.0% group. One volunteer in the placebo group had moderate inflammation at screening and at follow up. Severe inflammation was not seen among any of the subjects tested. Plasma levels of PRO 2000 and laboratory safety tests showed no evidence of systemic absorption. No impact was seen on normal vaginal ecology in the UK cohort where samples were taken 12 hours after the last gel application.
In this phase I study PRO 2000 gel was found to be generally well tolerated with promising local and systemic safety profiles. The 0.5% gel was better tolerated than the 4% gel as fewer genital epithelial adverse events were seen in the former. Phase II studies are about to begin in sexually active women.
尽管男用避孕套是预防艾滋病毒传播的可靠手段，但仍需要更多样化的方法，尤其是在难以协商使用避孕套的情况下。开发可能作为局部阴道杀微生物剂有效的新产品是目前大量研究活动的重点。新型药物PRO 2000是一种萘磺酸盐衍生物，在体外对艾滋病毒和其他性传播病原体具有活性，就是这样一种化合物。我们在两组健康的性禁欲女性（一组在英国伦敦，另一组在比利时安特卫普）中，对该药物两种浓度（0.5%和4%）的阴道凝胶制剂进行了为期2周的每日暴露研究，观察其局部和全身安全性及耐受性。
这是一项在两个地点进行的随机、安慰剂对照、双盲、三臂临床试验。通过阴道镜检查寻找生殖器上皮变化的宏观证据，并通过从预定部位进行高阴道活检（仅英国队列）获取微观炎症证据。检测PRO 2000的血药浓度，并进行包括凝血筛查在内的实验室安全性测试。还评估了对阴道生态的影响。
两个地点共招募了73名女性（英国36名，比利时37名）；4%、0.5%和安慰剂组分别有24名、24名和25名。其中，70名完成了2周的研究凝胶暴露。3名（均在4%组）因可能或很可能与凝胶相关的不良事件退出。在使用凝胶14天后，通过阴道镜检查发现3名受试者有宫颈阴道擦伤（4%组2名，安慰剂组1名）。在完成研究的任何受试者中，使用凝胶期间均未出现生殖器溃疡。对阴道活检样本的组织学评估（仅36名女性）显示，4.0%组的一名参与者有炎症迹象增加的证据。安慰剂组的一名志愿者在筛查和随访时均有中度炎症。在所有测试的受试者中均未发现严重炎症。PRO 2000的血浆水平和实验室安全性测试未显示全身吸收的证据。在英国队列中，在最后一次使用凝胶12小时后采集样本，未发现对正常阴道生态有影响。
在这项I期研究中，发现PRO 2000凝胶总体耐受性良好，局部和全身安全性良好。0.5%凝胶的耐受性优于4%凝胶，因为前者出现的生殖器上皮不良事件较少。II期研究即将在性活跃女性中开展。
