临床药理学 消化系统精.ppt

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1、临床药理学 消化系统第1页，本讲稿共75页消化性溃疡（消化性溃疡（peptic ulcer）为消化系）为消化系统最常见疾病，发病率约统最常见疾病，发病率约8%10%。为。为一种慢性疾病，可反复发作，病情持续一种慢性疾病，可反复发作，病情持续数年至数十年，可发生于消化道任何部数年至数十年，可发生于消化道任何部位，最多见于胃和十二指肠溃疡。胃溃位，最多见于胃和十二指肠溃疡。胃溃疡多位于胃小弯近幽门处，十二指肠溃疡多位于胃小弯近幽门处，十二指肠溃疡一般位于球部。疡一般位于球部。消化性溃疡消化性溃疡第2页，本讲稿共75页一、病因及发病机制一、病因及发病机制 溃疡病的发病机制过去过于强调胃酸和胃蛋白酶的

2、攻击作用，后来开始重视粘膜屏障、细胞保护因子、局部血液循环等抗溃疡因素。正常情况下两者处于平衡状态，当致溃疡因素作用超过抗溃疡因素，两者不平衡时就易发生溃疡。第3页，本讲稿共75页攻击因子（致溃疡因素）1.胃酸过多：各种刺激引起胃酸和胃蛋白酶分泌，产生自身消化作用。有“无酸不成溃疡”的说法。2.幽门螺杆菌（Helicobacter pylori,Hp）：寄生在胃粘液层之下，破坏粘液层，减弱其保护作用。是溃疡病长期不愈，反复发作的重要因素。3.药物：阿斯匹林及非甾体类抗炎药 4.胆汁和十二指肠液的反流：可破坏胃粘膜，刺激G细胞分泌胃泌素促胃酸分泌。第4页，本讲稿共75页防御因子（抗溃疡因素）1.

3、粘膜屏障：粘液-碳酸氢盐屏障（胃腔中pH常/=3 mm in size with depth,that can involve the stomach(gastric ulcer)or duodenum(duodenal ulcer).The most important contributing factors are Helicobacter pylori,nonsteroidal anti-inflammatory drugs(NSAIDs),acid,and pepsin.第16页，本讲稿共75页Although peptic ulcers produce a variety of s

4、ymptoms,none is specific for the disease.Severe pain or a rapid increase in pain suggests an ulcer complication or another diagnosis;associated dyspepsia symptoms include nausea,bloating,heartburn,and belching.Indeed,peptic ulcers are the most common cause of acute upper GI bleeding第17页，本讲稿共75页H pyl

5、ori eradication and/or antisecretory therapies are the mainstay of todays treatment strategies.第18页，本讲稿共75页四、治疗溃疡病药物分类四、治疗溃疡病药物分类（一）治疗溃疡病药物的评价治疗溃疡病主要有4个有目的：（1）控制症状；（2）促进溃疡愈合；（3）防止并发症发生；（4）防止溃疡复发。现今的所有抗溃疡药物均能达到（1）和（2）的目的，有的还可减少并发症，如出血，穿孔等。但现有的抗溃疡药物都不能彻底根治溃疡病，而杀灭幽门螺旋杆菌的药物能大大降低复发率。第19页，本讲稿共75页抗酸剂：氢氧化铝，

6、三硅酸镁，碳酸钙等，起中和胃酸作用，现已很少用。抑制胃酸分泌：H2受体阻断剂：西咪替西，雷尼替丁，法莫替丁H+-K+-ATP酶抑制剂（质子泵抑制剂）：奥美拉唑，兰索拉唑其他还有M受体阻断剂和胃泌素受体阻断剂胃粘膜保护剂：前列腺素E，枸橼酸铋钾，硫糖铝杀灭幽门螺杆菌：三联疗法：枸橼酸铋、甲硝唑、羟氨苄青霉素二联疗法：奥美拉唑、甲红霉素，或加羟氨苄青霉素三联疗法第20页，本讲稿共75页Acid Peptic Diseases Pharmacological Approach to Treatmenthttp:/ Modulating Gastric Acid抗酸药物的发展Beginning wit

7、h antacids,histamine type-2 receptor antagonists(H2RAs),and sucralfate,there has been a steady development of effective therapies for these conditions,culminating with the proton-pump inhibitors(PPIs)第22页，本讲稿共75页Antacids现已用得越来越少了，大多被H2RAs和PPIs取代。特点：They are inexpensive,readily available,and safe in

8、most populations.Antacids work nearly instantaneously and find utility for rapid relief of mild or sporadic symptoms.The effective time for antacids to reduce stomach acidity is relatively short on an empty stomach.calcium carbonate,sodium bicarbonate,magnesium hydroxide and aluminum hydroxide.hydro

9、talcite铝碳酸镁第23页，本讲稿共75页H2-receptor AntagonistsThe H2RAs are reversible structural analogs of histamine that cause a decrease in the tonic activation rate of the receptor,thus,these agents act as inverse agonists with a functional antagonism of histamine activity.Cimetidine,ranitidine,famotidine and

10、nizatidine.（西咪替丁为肝药酶抑制剂，有抗雄激素作用）第24页，本讲稿共75页特点：H2RAs mainly inhibit basal rate of acid release during nonfeeding periods.This is of particular importance during the nocturnal periods of fasting,which is the rational for the use of H2RA dosing at bedtime.The H2RAs are often administered once a day pr

11、ior to bedtime to maximally impact nocturnal basal acid secretion.All agents have linear pharmacokinetics and are eliminated primarily by renal mechanisms.Dose adjustments are needed for patients with renal impairment.第25页，本讲稿共75页H2RAs are superior to placebo,but inferior to PPIs for the treatment o

12、f esophageal reflux disease.Histamine receptor antagonists have modest efficacy in nonulcer dyspepsia,however,they are not as effective as PPIs.第26页，本讲稿共75页Proton Pump InhibitorsPPIs are weak bases that act as prodrugs and need an acidic environment in order to inhibit the H+K+-ATPase.PPIs accumulat

13、e in the secretory canaliculus of the parietal cell.The PPI becomes protonated and converted into the active sulfenamide species,which forms disulfide bonds with cysteine residues in the-subunit of the H+K+-ATPase.第27页，本讲稿共75页By contrast,with H2RAs,PPIs also decrease pepsin secretion,which serves to

14、 reduce mucosal damage.Morning dosing of PPIs is associated with significantly improved acid suppression.PPIs should be administered before breakfast.The effects of the PPIs increase with repeated administration and,generally by the third day.第28页，本讲稿共75页PPIs undergo metabolism via hepatic CYP2C19.O

15、f the PPIs,rabeprazole is unique as only 15-20%of its metabolism involves the CYP system.There is differential metabolism between individuals due to pharmacogenetic variation.Possible associations with hip fractures,renal complications and community-acquired pneumonia have also been demonstrated.The

16、 long-term safety of the class include prolonged hypergastrinemia,the possible association of PPIs with gastric atrophy and chronic hypochlorhydria.第29页，本讲稿共75页PPIs should not be administered concomitantly with H2-antagonists,prostaglandins or other antisecretory agents owing to the marked reduction

17、 in their acid inhibitory effects when administered simultaneously.第30页，本讲稿共75页Mucosal Protective AgentsSucralfate It is a nonabsorbable medication that binds to gastric mucosa and ulcerated tissue.These properties favor healing and provide cytoprotective effects.Sucralfate has similar efficacy in h

18、ealing of duodenal ulcer and gastric ulcers when compared with H2RAs.The primary utility is in the prophylaxis of stress ulceration in critically ill patients.sucralfate is best avoided in patients with kidney failure第31页，本讲稿共75页PPIs抗泌酸作用强，并可用于上消化道出血等PPI infusion and high-dose oral therapy in the se

19、tting of bleeding PUD have been common practices for the last several years.The use of intravenous formulations of PPIs prior to endoscopy in patients with bleeding PUD.第32页，本讲稿共75页PPI抑制夜间泌酸改善症状After 1.4 months of pantoprazole(40 mg daily)therapy,any sleep disturbances had improved in more than 75%o

20、f patients,with resolution of nighttime heartburn and nighttime regurgitation in 73%and 84%of patients,respectively.第33页，本讲稿共75页PPI新剂型增强药效AGN,the enteric-coated novel PPI,was shown to provide faster and more profound acid suppression than esomeprazole on day 1 and also at day 5,the time point that b

21、oth medications should have reached steady state.Both medications were well tolerated and no adverse events were reported.Nocturnal acid suppression was also greater by 2 pH units after 5 days 第34页，本讲稿共75页长期使用长期使用PPIs的不良反就应的不良反就应Adverse Effects of Proton Pump Inhibitor Drugs:Clues and Conclusions ht

22、tp:/ for Treating Peptic Ulcer Disease Helicobacter pylori infection be eradicated and antisecretory therapy,preferably with a proton pump inhibitor(PPI),be given for 4 weeks;patients with persistent symptoms should undergo endoscopy.第37页，本讲稿共75页根除Hp有助于病愈及防止复发To facilitate healing and to decrease th

23、e risk for recurrence of gastric and duodenal ulcers,H pylori should be eradicated in patients with peptic ulcer disease.第38页，本讲稿共75页PPIs抗酸效果较其它药好PPIs offer suppression of acid secretion,healing,and symptom relief in patients with peptic ulcers that are superior to those associated with other antise

24、cretory therapies 第39页，本讲稿共75页溃疡出血应用PPIsPatients with bleeding peptic ulcers should be treated with a PPI to decrease the need for transfusions or surgery and to reduce the duration of hospital stay.Those with bleeding peptic ulcers and positive H pylori testing should have eradication therapy presc

25、ribed 第40页，本讲稿共75页穿孔性溃疡也应根除HpPatients with perforated ulcers should undergo eradication of coexisting H pylori infection.Successful eradication should reduce the need for long-term antisecretory therapy and additional surgery 第41页，本讲稿共75页Patients with peptic ulcers who are older than 55 years,have a

26、larm symptoms,or have ulcers that fail to respond to treatment should promptly undergo upper endoscopy注意恶变注意恶变第42页，本讲稿共75页肠易激综合征肠易激综合征Irritable Bowel Syndrome是一组包括腹痛、腹胀、排便习惯改变和大便性状异常、粘液便等表现的临床综合征，持续存在或反复发作，经检查排除可以引起这些症状的器质性疾病。本病是最常见的一种功能性肠道疾病。第43页，本讲稿共75页临床表现临床表现最主要的临床表现是腹痛与排便习惯和粪便性状的改变。腹痛腹痛 几乎所有IBS

27、患者都有不同程度的腹痛。部位不定，以下腹和左下腹多见。腹泻腹泻 一般每日35次左右，少数严重发作期可达十数次。大便多呈稀糊状，也可为成形软便或稀水样。部分患者腹泻与便秘交替发生。便秘便秘 排便困难，粪便干结、量少，呈羊粪状，表面可附黏液。其他消化道症状 多伴腹胀或腹胀感，可有排便不尽感、排便窘迫感。全身症状 相当部分患者可有失眠、焦虑、抑郁、头昏、头痛等精神症状。体征 无明显体征，可在相应部分有轻压痛，部分患者可触及腊肠样肠管，直肠指检可感到肛门痉挛、张力较高，可有触痛。第44页，本讲稿共75页肠易激综合征类型肠易激综合征类型 便秘型：伴有周期性便秘与较频繁的正常大便交替，大便经常有白色黏液，

28、疼痛呈绞榨样，阵发性发作，或持续性隐痛，排便后可缓解。进食常会促发症状，也可以出现腹胀、恶心、消化不良和烧心等症状。腹泻型：特别是在进食刚开始，或结束时出现突发性腹泻。夜间腹泻很少，常有疼痛、腹胀和直肠紧迫感，也可出现大便失禁等情况。第45页，本讲稿共75页治治 疗疗一般治疗建立良好的生活习惯。饮食上避免诱发症状的食物，因人而异，一般而言宜避免产气的食物如乳制品、大豆等。高纤维食物有助改善便秘。对失眠、焦虑者可适当给予镇静药。药物治疗胃肠解痉药：抗胆碱药物，胃动力药，5-HT3拮抗剂 止泻药：洛哌丁胺，思密达、药用炭等泻药：对便秘型患者酌情使用泻药，但不宜长期使用。半纤维素或亲水胶体，在肠腔内

29、吸水膨胀增加肠内容物水分及容积，起到促进肠蠕动、软化大便的作用，被认为是治疗IBS便秘比较理想的药物。第46页，本讲稿共75页http:/ Pump Inhibitors,Irritable Bowel Syndrome,and Small Intestinal Bacterial Overgrowththe role of antibiotics vs.conventional pharmacotherapy in treating symptoms of irritable bowel syndrome.Aliment Pharmacol Ther 25,12711281;2007第47页

30、，本讲稿共75页慢性胃炎慢性胃炎病因病机：病因病机：80%以上的成年人具有不同程度的浅表性胃炎。浅表性胃炎和糜烂性胃炎主要由烟、洒、刺激性食物和药物，胆汁反流和幽门螺杆菌等引起。萎缩性胃炎则还与自身免疫反应，胃粘膜反复受损，胃腺萎缩有关。第48页，本讲稿共75页主要临床表现：主要临床表现：上腹不适、胃痛、食欲不振、嗳气及腹胀等。一般无明显体征。第49页，本讲稿共75页分 型：浅表性胃炎：胃镜下见散在胃粘膜水肿、斑点状出血、糜烂，显示红白相间。腺体与粘膜厚度多数正常，肠上皮化生很少。糜烂性胃炎：病变范围深于浅表性胃炎。粘膜上有多个5-10mm大小的疣或丘疹样隆起，中央糜烂，病变多见于胃窦部。萎缩

31、性胃炎：胃镜下粘膜色泽红白相间，而以白相为主。粘膜萎缩变薄，腺体萎缩，胃酸低下，腺上皮化生多，可能出现恶性贫血 pernicious anemia或癌变。第50页，本讲稿共75页诊断依据：依靠胃镜检查和胃粘膜病检。治 疗：保护胃粘膜和对症治疗。幽门螺杆菌感染者杀菌。第51页，本讲稿共75页Chronic gastritis associated with Helicobacter pyloriinfection 第52页，本讲稿共75页 Left:An antral gland of the stomach with a large colony of Helicobacter pylori

32、in the lumen(arrow).Right:A transverse section of the gastric lamina propria is shown.In the lower part,an antral gland of the stomach is present with some Helicobacter pylori in the lumen(red-blue arrow),while in the upper part a mast cell(yellow arrow)is present.第53页，本讲稿共75页幽门螺杆菌幽门螺杆菌胃腺萎缩胃腺萎缩萎缩性胃炎

33、萎缩性胃炎肠肠上皮化生上皮化生 胃胃癌癌幽门螺杆菌幽门螺杆菌胃窦炎、十二指肠炎胃窦炎、十二指肠炎十二指肠溃疡、胃十二指肠溃疡、胃溃疡溃疡第54页，本讲稿共75页对幽门螺杆菌若干问题共识意见对幽门螺杆菌若干问题共识意见（安徽桐城会议（安徽桐城会议2003）Hp感染及其相关疾病感染及其相关疾病流行病学调查证实Hp在有些国家或地区的人群中，感染率仍很高.胃是Hp在人体内定植的主要部位，我国不同地区、不同民族人群胃内Hp检出率在30-80%之间，有很大差别。1 Hp是慢性胃炎和消化性溃疡(PU)的重要致病因子。第55页，本讲稿共75页2 Hp与胃癌的发生有关:(1)Hp可增加胃癌发生的危险性.(2)H

34、p根除后可阻断或延缓萎缩性胃炎和肠化的进一步发展，但是否能使两种病变逆转尚需进一步研究.(3)Hp根除后可降低早期胃癌术后的复发率.(4)在亚太地区如日本、韩国和中国，绝大多数Hp菌株均为cagA阳性菌株,其在消化性溃疡、胃癌和慢性胃炎中的阳性率无显著差异。(5)胃癌的发生是一个多步骤过程，从慢性胃炎经过萎缩、肠化生和不典型增生，最后到胃癌.胃癌的发生是Hp感染、宿主因素和环境因素共同作用的结果.cytotoxin-associated gene(cag)第56页，本讲稿共75页3 Hp是胃黏膜相关淋巴组织(MALT)淋巴瘤重要的致病因素，Hp感染是MALT淋巴瘤产生的原因，胃MALT淋巴瘤在

35、Hp高发区常见、多发.根除Hp可以治愈早期胃MALT淋巴瘤，染色体分析提示胃MALT淋巴瘤的发生可能具有遗传性.4 Hp与非甾体类抗炎药(NSAID)是消化性溃疡发生的两个重要独立危险因素，单纯根除Hp不足以预防NSAID溃疡，初次使用NSAID前根除Hp可降低NSAID溃疡的发生率，使用NSAID过程中根除Hp不能加速NSAID溃疡的愈合.5 Hp与胃食管反流性疾病(GERD)的关系尚无肯定结论.6 Hp感染和功能性消化不良(FD)的关系仍未明确.第57页，本讲稿共75页Hp感染的治疗感染的治疗一线方案一线方案:(1)PPI/RBC(标准剂量标准剂量)+A(1.0)+C(0.5)，Bid7

36、d;(2)PPI/RBC(标准剂量标准剂量)+M(0.4)+C(0.5)，Bid7 d;(3)PPI/RBC(标准剂量标准剂量)+A(1.0)+F(0.1)/M(0.4)，Bid7d;第58页，本讲稿共75页(4)B(标准剂量标准剂量)+F(0.1)/M(0.4)+C(0.5)，Bid7 d;(5)B(标准剂量标准剂量)+M(0.4)+T(0.75-1.0)，Bid14 d;(6)B(标准剂量标准剂量)+M(0.4)+A(0.5)Bid14 d.代号说明代号说明:PPI(质子泵抑制剂质子泵抑制剂):目前有埃索米拉唑目前有埃索米拉唑(E)、雷贝拉唑、雷贝拉唑(R)、兰索拉唑、兰索拉唑(L)、奥美

37、拉唑、奥美拉唑(O);RBC(枸椽酸铋雷尼替丁枸椽酸铋雷尼替丁);A阿莫西林阿莫西林;C克拉霉素克拉霉素;M甲硝唑甲硝唑;T四环素四环素;B 铋剂铋剂(枸椽酸铋钾、果胶铋等枸椽酸铋钾、果胶铋等);F呋呋喃唑酮喃唑酮.也可以也可以H2受体阻断剂受体阻断剂(H2RA)替代替代PPI(如如:西西米替丁、雷尼替丁、法莫替丁米替丁、雷尼替丁、法莫替丁).但根除率可能会有所但根除率可能会有所降低降低.第59页，本讲稿共75页二线方案二线方案:(1)PPI(标准剂量标准剂量)+B(标准标准剂量剂量)+M(0.4 Tid)+T(0.75-1.0)，Bid7-14 d;(2)PPI(标准剂量标准剂量)+B(标准

38、剂量标准剂量)+F(0.1)+T(0.75-1.0)，Bid7-14 d.第60页，本讲稿共75页Hp阳性的下列疾病阳性的下列疾病必须必须支持支持不明确不明确消化性溃疡消化性溃疡1v早期胃癌术后早期胃癌术后v胃胃MALT淋巴瘤淋巴瘤v明显异常的慢性胃炎明显异常的慢性胃炎2v计划使用计划使用NSAIDsv部分部分FD3vGERD3v胃癌家族史胃癌家族史v个人强烈要求治疗者个人强烈要求治疗者v胃肠道外疾病胃肠道外疾病v1PU:无论活动或非活动，无论有无并发症无论活动或非活动，无论有无并发症.2明显异常明显异常:指合并糜烂，中指合并糜烂，中-重度重度萎缩，中萎缩，中-重度肠化生，轻重度肠化生，轻-中

39、度不典型增生中度不典型增生.重度不典型增生应考虑癌重度不典型增生应考虑癌变变.3FD和和GERD应根除应根除Hp的理由如前所述的理由如前所述.表表2 Hp感染治疗适应证感染治疗适应证第61页，本讲稿共75页幽门螺杆菌感染和环氧化酶幽门螺杆菌感染和环氧化酶-2表达在胃癌表达在胃癌发生中的作用发生中的作用1 Hp感染与胃癌及癌前病变感染与胃癌及癌前病变流行病学资料提示长期Hp感染可导致胃黏膜的萎缩、肠上皮化生及异型增生，最终形成胃癌。因此，1994年世界卫生组织国际癌症研究机构已正式将Hp列为第一类生物致癌因子。近年来动物实验研究、胃黏膜上皮细胞培养和Hp根除干预实验等均证实了Hp感染致胃癌的危险

40、性。Hp细胞毒素相关基因A(cagA)阳性菌株具有更强的毒力和危险性，cagA+菌株感染后胃黏膜上皮细胞损害明显并影响壁细胞的分泌功能，导致胃酸分泌减少，胃内细菌过度生长，促使硝酸盐降解为亚硝酸盐和亚硝胺等致癌物。第62页，本讲稿共75页2 Hp感染诱导感染诱导COX-2的表达的表达 Hp感染和COX-2表达在胃癌的发生、发展中均起重要作用，Hp作为促癌因子诱导COX-2表达，Hp感染者胃黏膜中COX-2表达明显增加。Hp感染相关的急、慢性胃窦炎的胃上皮细胞和单核细胞中COX-2蛋白表达增加.虽然根除Hp减少胃黏膜COX-2表达，但不能逆转肠上皮化生。第63页，本讲稿共75页3 COX-2在胃

41、癌和癌前病变中表达增加在胃癌和癌前病变中表达增加 COX-2与细胞增生和肿瘤发生密切相关，正常情况下COX-2几乎不表达或表达甚少，而在炎症因子、生长因子、内毒素和促癌剂等刺激下，COX-2表达迅速增加，并参与炎症过程和肿瘤的发生、发展16.众多研究显示，COX-2在胃癌和结直肠癌中表达增加。癌组织中COX-2 mRNA显著高于癌周正常组织。第64页，本讲稿共75页4 COX-2的致癌和促癌机制的致癌和促癌机制 尽管COX-2与胃癌的发生发展密切相关，但COX-2表达在肿瘤发生、发展中的作用机制尚不明确。COX-2可能经多种途径促进细胞增生、抑制细胞凋亡、调节肿瘤新生血管形成和增加癌细胞的侵袭

42、性等而发生致癌和促癌作用。COX-2表达增加PGE2合成，PGE2可诱导细胞增生并刺激Bcl-2蛋白表达，后者可抑制细胞凋亡。COX-2促进VEGF相关的肿瘤血管生成，可能是其在致癌和促癌中发挥作用的另一重要途径.第65页，本讲稿共75页5 Hp感染诱导感染诱导COX-2表达的机制表达的机制 目前，Hp感染诱导胃黏膜COX-2表达的机制尚待阐明，可能是Hp感染引起胃黏膜损伤刺激COX-2表达，也可能是Hp感染及其毒素直接诱导COX-2表达。国内外研究表明，Hp细菌悬液、超声提取物甚至Hp细菌培养液均可诱导培养细胞的COX-2表达.Hp感染可能通过炎症细胞释放细胞因子的间接作用，亦可能是直接诱导

43、胃黏膜炎症细胞表达COX-2，再通过旁分泌机制和信号传导引起上皮细胞表达COX-2。第66页，本讲稿共75页有关Hp感染的新进展Helicobacter pylori Infection and Current Clinical Areas of Contentionhttp:/ NSAID以预防溃疡的复发。对现患胃溃疡或既往有胃溃疡病史且正应用NSAID者，应用铋剂为中心的根除Hp的治疗方案较以PPI为中心的根除方案在NSAID相关性胃溃疡的治疗和预防中有更好的疗效。第68页，本讲稿共75页对Hp阳性的有胃肠症状的阿司匹林应用者，如果需要继续应用阿司匹林，根除Hp会减少患者溃疡出血的危险性;

44、如果无消化不良症状或无溃疡病史，则没有必要检测Hp或根除Hp治疗.如果患者即将应用NSAID，检测并根除Hp将肯定会减少溃疡的危险性.应用选择性COX-2 NSAID的患者，有关Hp根除的建议与未应用NSAID者相同.在长期应用NSAID者，根除Hp和随后的PPI预防疗法将肯定减少溃疡的发生和复发，促进溃疡的愈合.第69页，本讲稿共75页Withdrawal of Vioxx Casts a Shadow Over COX-2 Inhibitorsthe COX-2 inhibitor Vioxx,off the market after an alarming pattern surface

45、d halfway through a 3-year colon polyp prevention study.Heart attacks and strokes had occurred at a much higher rate among the roughly 1300 volunteers on Vioxx(3.5%)than among the 1300 taking a placebo(1.9%).http:/www.sciencemag.org/cgi/content/full/306/5695/384第70页，本讲稿共75页Vioxxs propensity to trigg

46、er heart attacks and strokes isnt fully understood.But some experts believe that its valued mechanism-specifically,its ability to suppress a narrow set of molecules that mediate inflammation-may have been its downfall.Anti-inflammatory drugs like naproxen suppress both prostacyclin,which plays a rol

47、e in inflammation,and thromboxane.But COX-2 inhibitors block only prostacyclin;this may tilt the balance in favor of thromboxane and,potentially,blood clotting.So far the thrombosis theory has been supported only by animal studies.第71页，本讲稿共75页A study showed that rofecoxib(Vioxx),compared here to naproxen,could cause cardiovascular problems.ADAPTED FROM D.MUKHERJEE ET AL.,JAMA 286,8(2001)第72页，本讲稿共75页第73页，本讲稿共75页第74页，本讲稿共75页第75页，本讲稿共75页