Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: Relation to intestinal hypermotility

Background and Aim:  We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes.
Methods:  Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results:  Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE₂ content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE₂ was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE₂ and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions.
Conclusion:  These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

Case of acute urinary retention as a result of non-steroidal anti-inflammatory drugs

Abstract:   A 19-year-old woman presented at our hospital with acute urinary retention in September 2005. She had experienced the same chief complaint twice previously. She had used non-steroidal anti-inflammatory drugs before acute urinary retention. The results of physical examinations were unremarkable, and her neurologic signs were not remarkable. The basic laboratory test values were all normal and a psychiatric assessment indicated that her symptoms were not psychogenic. Magnetic resonance imaging was carried out, but revealed only a slight bulging in the L3/L4/L5 disk. Water cystometry showed acontractile detrusor. We made a diagnosis of acute urinary retention as a result of non-steroidal anti-inflammatory drugs because of her use of such drugs before the development of symptoms on multiple occasions. This patient was regularly followed up as an outpatient, and she could void smoothly in February 2006. This is the first report which acute urinary retention associated with non-steroidal anti-inflammatory drugs in Japan.     

Effect of buffering on pharmacokinetics of ketoprofen enantiomers in man

Aims Concomitant administration of magnesium hydroxide may affect the rate or extent of absorption of non-steroidal anti-inflammatory drugs. In order to find out whether or not buffering modifies the pharmacokinetics of ketoprofen, plasma concentration-time courses resulting from oral administration of unbuffered formulations were compared with those of buffered formulations.
Methods Two groups of 12 healthy and young male subjects were included in two randomized cross-over studies and received single oral doses of ketoprofen 12.5 or 25  mg, respectively, given as tablets which were either unbuffered or buffered with magnesium hydroxide/citrate. Ketoprofen enantiomers in plasma were determined by h.p.l.c. up to 24  h post-dose.
Results Maximum plasma concentrations ( C _max ) of both the (R)- and (S)-enantiomer, observed after administration of the buffered formulations (12.5 and 25  mg), were higher compared with the unbuffered tablets by about 50–80%. The area under concentration-time data (AUC) was unaffected, and, hence, C _max/AUC was increased by buffering. Time to C _max ( t _max ) and mean residence time (MRT) tended to be or was shortened by buffering.
Conclusions It is concluded that buffering of two ketoprofen formulations with magnesium hydroxide/citrate enhanced the concentration maximum by increasing the rate of absorption and leaving AUC unaffected.     

消化性溃疡病因分析

[目的]探讨幽门螺旋杆菌感染和非甾体类消炎药应用与消化性溃疡的关系．[方法]对1062例消化不良患者进行内窥镜检壹、快速尿素酶实验和血清抗幽门螺旋杆菌免疫球蛋白检验，同时记录非甾体类消炎药的应用情况，计算消化不良患者消化性溃疡发病事、幽门螺旋杆菌感染率及非甾体类消炎药应用率．[结果]溃疡发病率为29．3％，幽门螺旋杆菌感染串为37．2％，非甾体类消炎药使用率为10．0％．[结论]幽门螺旋杆菌及非甾体类消炎药相互作用干上消化道黏膜．是引发消化性溃疡的重要病因．     

特异性COX-2抑制剂保护骨关节炎软骨的临床观察

目的探讨特异性COX-2抑制剂对骨关节炎的关节软骨保护作用的临床研究。方法门诊选取膝关节骨关节炎患者80例,随机分为特异性COX-2抑制剂组和维骨力对照组,各40例,单盲给药。应用平均Womac关节炎指数评分和平均OA严重程度指数评定两组用药前后临床症状改善情况及使用血清软骨代谢标志物蛋白聚糖与型胶原和关节MRI进行检测关节软骨结构与功能的改变情况,并作统计学分析。结果经12个月治疗观察,特异性COX-2抑制剂组的平均Womac关节炎指数评分和平均OA严重程度指数在前3个月改善明显优于维骨力对照组(P<0.01),但在治疗12个月后,两组差异不显著(P>0.05);治疗12个月后特异性COX-2抑制剂组的软骨代谢指标蛋白聚糖和型胶原及关节MRI均显示组内变化显著(P<0.01),而与维骨力组对比结果无显著性差异(P>0.05)。结论特异性COX-2抑制剂对骨关节炎的软骨有保护和促进修复作用,兼有抗炎与保护软骨双重疗效,它是一类既能改善关节炎症状又能改善关节软骨结构的药物,值得临床广泛应用。同时本研究为其在临床应用和进一步研究此类药物提供了更好的理论基础和依据。     

Caffeine potentiation of mefenamic acid-induced lesions in the rat renal medulla.

The effect of caffeine given in combination with mefenamic acid on the renal medulla was examined. Sprague-Dawley rats were divided into four groups and gavage fed either vehicle suspension (control), mefenamic acid, mefenamic acid+caffeine or caffeine only for 4 months. Renal tissue taken from the corticomedullary junction was processed for electron microscopy. Ultrathin sections were cut after identification of vasa rectae on survey sections. On subsequent morphometric analysis, percentage interstitial tissue was calculated from the total area of vasa recta less the non-interstitial tissue. The median percentage of interstitial tissue in the mefenamic acid and caffeine group was 41 (range 33-50; n = 15) compared with 34 (20-48; n = 20) in mefenamic acid (P less than 0.01), 29 (15-42; n = 15) in caffeine only (P less than 0.001) and 32 (20-46; n = 18) in vehicle-treated animals (P less than 0.001). There were no significant differences between mefenamic acid alone and vehicle or caffeine-only groups or between caffeine-only and vehicle-treated controls. This suggests that caffeine potentiates the effect of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal medulla, resulting in a quantitative increase in the interstitial tissue between adjacent afferent and efferent vasa recta.     

药物性生理失调的后果-畅销镇痛药罗非昔布另解

Selective cyclo-oxygenase-2(COX-2) inhibitor, VI-OXX(rofecoxib), was voluntarily withdrawn worldwide from drugstores by its maker Merck & Co., Inc. on Sep-tember 30, 2004, for its potential lethal side effects of heart attack or stroke.     

塞来昔布对胃肠毒副反应及用于肿瘤靶向防治的可行性研究

为了研究在化疗期间塞来昔布的胃肠道毒副反应及用于恶性肿瘤靶向预防及治疗的可行性 ,分别采用塞来昔布及双氯芬酸钠对 46例轻中度疼痛的晚期癌症患者进行跟踪治疗 ,并从胃肠道毒副反应、耐受性及安全性等方面加以分析比较。临床结果显示 ,塞来昔布与双氯芬酸钠在抗肿瘤疼痛方面疗效大致相同 ,塞来昔布引起的一过性胃肠不适为 19 4% ,未见症状性溃疡。初步研究结果提示 ,可以充分利用塞来昔布特异性的COX 2抑制特性 ,有效地抑制转移性肿瘤引起的轻中度疼痛 ,它对上消化道毒副反应小、安全性好的优点和潜在的抑制肿瘤发生及发展的作用 ,可以进一步用于恶性肿瘤的靶向预防及治疗。     

药品行政保护品种介绍:消炎镇痛药

双氯芬酸树脂盐口服滴剂 通用名：双氯芬酸树脂盐（diclofenac resinate）。商品名：扶他林（Voharen）。化学名：邻-（2，6-二氯苯胺基）苯乙酸树脂盐。结构式见图1。     

Day-case laparoscopy: a comparison of prophylactic opioid, NSAID or local anesthesia for postoperative analgesia

BACKGROUND: The study was aimed to evaluate the analgesic efficacy, postoperative comfort, recovery characteristics and side effects of three different analgesic agents administered prophylactically. METHODS: Eighty patients undergoing day-case minor operative laparoscopy were randomly allocated into four groups to receive tenoxicam 20 mg i.v. (Group T), fentanyl 100 microg i.v. (Group F), 5 ml of bupivacaine 2.5 mg/ml for infiltration of trocar sites (Group B), 30, 10 and 5 min before incision respectively. Bupivacaine, 35 ml, 2.5 mg/ml was also administered into the pelvic cavity in Group B. Group P received only placebo. Postoperative pain, analgesic requirements, first response to verbal stimulus, first analgesic requirement, ability to walk without help, to drink and to void, blood pressures, SpO2 and respiration rates were recorded in the PACU. Postoperative pain was evaluated by verbal rating scale. Pain scores, analgesic requirements and side effects were evaluated by telephone calls until the 48th postoperative hour. RESULTS: Postoperative pain scores were lower and time to requirement of rescue analgesics was longer in groups F and B compared to Group P. In the PACU, analgesic requirements were lower in Group B, compared to Group P. Nausea and vomiting were increased in Group F. CONCLUSION: Tenoxicam 20 mg i.v. was found to be ineffective whereas bupivacaine was superior to other groups in reducing pain and analgesic requirements. Bupivacaine also increased time to first analgesics and obtained better recovery characteristics, underlining its value in prophylactic pain management compared to the other two agents.