Moberly James B, Xu Jianbo, Desjardins Paul J, Daniels Stephen E, Bandy Donald P, Lawson Janet E, Link Allison J, Truitt Kenneth E
Daiichi Sankyo Pharma Development, Edison, New Jersey 08837, USA.
Clin Ther. 2007 Mar;29(3):399-412. doi: 10.1016/s0149-2918(07)80078-6.
CS-706 is a cyclooxygenase-2 (COX-2)-selective inhibitor with an in vitro selectivity ratio (COX-1:COX-2) similar to that of celecoxib. It has exhibited analgesic, anti-inflammatory, and antitumor properties in animal models.
This study evaluated the tolerability of single doses of CS-706 and compared the analgesic efficacy of CS-706 with that of celecoxib and placebo in the dental pain model.
This was a randomized, double-blind, double-dummy, active- and placebo-controlled study. Healthy male and female subjects with moderate to severe pain intensity (PI) after dental surgery were randomized ( approximately 50 per group) to receive a single oral dose of CS-706 10, 50, 100, or 200 mg; celecoxib 400 mg; or placebo. PI and pain relief (PR) were measured on categorical and visual analog scales through 24 hours after the dose. The primary efficacy variable was the time-weighted sum of PR scores at 4 hours after the dose (TOPAR4). The onset of analgesia was assessed by calculating the pain intensity difference (PID). Perceptible and meaningful pain relief were assessed using a 2-stopwatch method.
The majority of subjects were female (62.0%) and white (59.5%). Subjects' mean (SD) age was 22.6 (3.9) years, and their mean body mass index was 25.3 (5.1) kg/m(2). All doses of CS-706 were associated with significant analgesic efficacy compared with placebo based on the primary end point, TOPAR4 (P<0.001), and on all secondary end points (P<0.05, comparisons of all CS-706 doses vs placebo) with the exception of time to 100% PR for CS-706 10 mg. Single 50-, 100-, and 200-mg doses of CS-706 also were significantly more effective than celecoxib for TOPAR4 (P=0.036, P=0.004, and P=0.006, respectively). The onset of analgesia (PID >or= 1) for all CS-706 doses occurred within 1 hour after dosing (P<0.001 vs placebo). The median duration of analgesia, measured as the time to administration of rescue medication, was significantly greater for all doses of CS-706 compared with placebo (5.7 hours for CS-706 10 mg, >24 hours for CS-706 50, 100, and 200 mg, and 1.7 hours for placebo; P<0.001 for CS-706 50, 100, and 200 mg). These data suggest that once-daily administration of CS-706 may be effective in providing relief of acute pain. The incidence of adverse events was similar among all treatment groups. Adverse events occurring in >or= 5 % of subjects in any treatment group were nausea, vomiting, dry socket, dizziness, headache, and paresthesia.
Single doses of CS-706 had significant analgesic efficacy compared with celecoxib and placebo in the relief of postoperative dental pain in the healthy subjects enrolled in this study.
CS - 706是一种环氧化酶 - 2（COX - 2）选择性抑制剂，其体外选择性比率（COX - 1:COX - 2）与塞来昔布相似。它在动物模型中已表现出镇痛、抗炎和抗肿瘤特性。
本研究评估了单剂量CS - 706的耐受性，并在牙科疼痛模型中比较了CS - 706与塞来昔布及安慰剂的镇痛效果。
这是一项随机、双盲、双模拟、活性药物和安慰剂对照研究。牙科手术后疼痛强度为中度至重度的健康男性和女性受试者被随机分组（每组约50人），分别接受单剂量口服CS - 706 10、50、100或200 mg；塞来昔布400 mg；或安慰剂。在给药后24小时内，通过分类量表和视觉模拟量表测量疼痛强度（PI）和疼痛缓解情况（PR）。主要疗效变量是给药后4小时的PR评分时间加权总和（TOPAR4）。通过计算疼痛强度差值（PID）评估镇痛起效时间。使用双秒表法评估可感知且有意义的疼痛缓解情况。
大多数受试者为女性（62.0%）和白人（59.5%）。受试者的平均（标准差）年龄为22.6（3.9）岁，平均体重指数为25.3（5.1）kg/m²。基于主要终点TOPAR4（P<0.001）以及所有次要终点（所有CS - 706剂量与安慰剂比较，P<0.05），与安慰剂相比，所有剂量的CS - 706均具有显著的镇痛效果，但CS - 706 10 mg达到100%疼痛缓解的时间除外。单剂量50、100和200 mg的CS - 706在TOPAR4方面也显著比塞来昔布更有效（分别为P = 0.036、P = 0.004和P = 0.006）。所有CS - 706剂量的镇痛起效时间（PID≥1）在给药后1小时内出现（与安慰剂相比，P<0.001）。以给予解救药物的时间衡量，所有剂量的CS - 706的镇痛持续时间中位数显著长于安慰剂（CS - 706 10 mg为5.7小时，CS - 706 50、100和200 mg超过24小时，安慰剂为1.7小时；CS - 706 50、100和200 mg，P<0.001）。这些数据表明，CS - 706每日一次给药可能有效缓解急性疼痛。所有治疗组的不良事件发生率相似。任何治疗组中≥5%的受试者出现的不良事件有恶心、呕吐、干槽症、头晕、头痛和感觉异常。
在本研究纳入的健康受试者中，单剂量CS - 706在缓解术后牙科疼痛方面与塞来昔布和安慰剂相比具有显著的镇痛效果。
