Hayden Frederick G, Turner Ronald B, Gwaltney Jack M, Chi-Burris Kathy, Gersten Merril, Hsyu Poe, Patick Amy K, Smith George J, Zalman Leora S
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
Antimicrob Agents Chemother. 2003 Dec;47(12):3907-16. doi: 10.1128/AAC.47.12.3907-3916.2003.
Human rhinovirus (HRV) infections are usually self-limited but may be associated with serious consequences, particularly in those with asthma and chronic respiratory disease. Effective antiviral agents are needed for preventing and treating HRV illnesses. Ruprintrivir (Agouron Pharmaceuticals, Inc., San Diego, Calif.) selectively inhibits HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro. We conducted three double-blind, placebo-controlled clinical trials in 202 healthy volunteers to assess the activity of ruprintrivir in experimental HRV infection. Subjects were randomized to receive intranasal ruprintrivir (8 mg) or placebo sprays as prophylaxis (two or five times daily [2x/day or 5x/day] for 5 days) starting 6 h before infection or as treatment (5x/day for 4 days) starting 24 h after infection. Ruprintrivir prophylaxis reduced the proportion of subjects with positive viral cultures (for 5x/day dosing groups, 44% for ruprintrivir treatment group versus 70% for placebo treatment group [P=0.03]; for 2x/day dosing groups, 60% for ruprintrivir group versus 92% for placebo group [P=0.004]) and viral titers but did not decrease the frequency of colds. Ruprintrivir treatment reduced the mean total daily symptom score (2.2 for ruprintrivir treatment group and 3.3 for the placebo treatment group [P=0.014]) by 33%. Secondary endpoints, including viral titers, individual symptom scores, and nasal discharge weights, were also reduced by ruprintrivir treatment. Overall, ruprintrivir was well tolerated; blood-tinged mucus and nasal passage irritation were the most common adverse effects reported. Pharmacokinetic analysis of plasma and nasal ruprintrivir concentrations revealed intranasal drug residence with minimal systemic absorption. Results from these studies in experimental rhinoviral infection support continued investigation of intranasal ruprintrivir in the setting of natural HRV infection.
人鼻病毒（HRV）感染通常为自限性，但可能会导致严重后果，尤其是在哮喘和慢性呼吸道疾病患者中。预防和治疗HRV疾病需要有效的抗病毒药物。鲁普立韦（Agouron制药公司，加利福尼亚州圣地亚哥）选择性抑制HRV 3C蛋白酶，并在体外显示出强大的广谱抗HRV活性。我们在202名健康志愿者中进行了三项双盲、安慰剂对照临床试验，以评估鲁普立韦在实验性HRV感染中的活性。受试者被随机分组，在感染前6小时开始接受鼻内鲁普立韦（8毫克）或安慰剂喷雾作为预防措施（每天两次或五次[2次/天或5次/天]，共5天），或在感染后24小时开始接受治疗（每天5次，共4天）。鲁普立韦预防措施降低了病毒培养阳性受试者的比例（对于每天5次给药组，鲁普立韦治疗组为44%，安慰剂治疗组为70%[P = 0.03]；对于每天2次给药组，鲁普立韦组为60%，安慰剂组为92%[P = 0.004]）以及病毒滴度，但并未降低感冒频率。鲁普立韦治疗使平均每日总症状评分降低了33%（鲁普立韦治疗组为2.2，安慰剂治疗组为3.3[P = 0.014]）。包括病毒滴度、个体症状评分和鼻分泌物重量在内的次要终点指标也因鲁普立韦治疗而降低。总体而言，鲁普立韦耐受性良好；血性黏液和鼻道刺激是报告的最常见不良反应。血浆和鼻内鲁普立韦浓度的药代动力学分析显示鼻内药物滞留且全身吸收极少。这些实验性鼻病毒感染研究的结果支持在自然HRV感染情况下继续研究鼻内鲁普立韦。
