Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers
Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers
复制标题
DOI：
10.1128/aac.47.12.3907-3916.2003
复制
发表时间：
2003-12-01
影响因子：
4.9
通讯作者：
Zalman, LS
中科院分区：
文献类型：
--
作者：
Hayden, FG;Turner, RB;Zalman, LS
人鼻病毒（HRV）感染通常是自限性的，但可能与严重后果有关，特别是那些患有哮喘和慢性呼吸道疾病的人。预防和治疗HRV疾病需要有效的抗病毒药物。Ruprintrivir （Agouron Pharmaceuticals, Inc., San Diego, california）选择性抑制HRV 3C蛋白酶，并在体外显示出有效的广谱抗HRV活性。我们在202名健康志愿者中进行了3项双盲、安慰剂对照的临床试验，以评估ruprintrivir在实验性HRV感染中的活性。受试者在感染前6小时开始接受鼻用鲁普特里韦（8mg）或安慰剂喷雾剂作为预防（每天2或5次[2 x/天或5 x/天]，持续5天），或在感染后24小时开始接受治疗（5 x/天，持续4天）。Ruprintrivir预防降低了病毒培养阳性受试者的比例（5次/天剂量组，Ruprintrivir治疗组为44%，安慰剂治疗组为70% [P = 0.03]； 2次/天剂量组，Ruprintrivir组为60%，安慰剂组为92% [P = 0.004]）和病毒滴度，但没有降低感冒的频率。Ruprintrivir治疗使平均每日总症状评分（Ruprintrivir治疗组为2.2分，安慰剂治疗组为3.3分[P = 0.014]）降低33%。次要终点，包括病毒滴度、个体症状评分和鼻分泌物重量，也被ruprintrivir治疗降低。总体而言，ruprintrivir耐受性良好；带血黏液和鼻腔刺激是最常见的不良反应。血浆和鼻腔ruprintrivir浓度的药代动力学分析显示，药物在鼻腔内停留，全身吸收最小。这些实验性鼻病毒感染研究的结果支持在自然HRV感染的情况下继续研究鼻用鲁普特里韦。
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 [2 x/day or 5 x/day] for 5 days) starting 6 h before infection or as treatment (5 x /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.