Adverse drug reactions: Can consumers provide early warning?

In order to investigate the potential value of a drug monitoring system based on consumer reports we asked community pharmacists to distribute previously validated event report forms to users of two popular non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and diclofenac, in the Hunter Region of New South Wales, Australia. Although response rates were low, comparisons of replies from NSAID users and drug-free subjects in the community identified a range of established symptomatic reactions from NSAIDs affecting the gastrointestinal tract, central nervous system and lower urinary tract. In comparison, analysis of adverse reaction reports from health professionals revealed a tendency to report more severe but rarer reactions affecting the upper gastrointestinal tract, liver, skin and haematological system. It is likely that a system based on consumer reports could augment current sources of information on adverse drug effects by revealing reactions which are important to consumers and yet often evade detection during pre-marketing clinical trials. Such a system might also have a capacity to generate very early signals of previously unsuspected symptomatic reactions with new drugs.     

非甾体抗炎药的临床研究新进展

非甾体抗炎药(NSAIDs)是临床上广泛应用的一类具有解热镇痛,大部分还有抗炎、抗风湿作用的药物.非甾体抗炎药的不良反应如消化道损害,肝肾损害发生率较高,针对这些不良发应开发了许多新的药物,如非甾体缓(控)释剂、非甾体和胃肠道保护剂的复方制剂、NO型非甾体药物等.近期研究还发现,非甾体抗炎药除了传统的治疗作用外,对阿尔茨海默病、早产、癌症等疾病均有预防或治疗作用,其临床应用不断扩展.本文就非甾体抗炎药的临床研究新进展作一综述.     

Strategy for development of NSAIDs with lower risk for side effects

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.     

Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in the world, primarily for symptoms associated with osteoarthritis and other chronic musculoskeletal conditions. However, adverse effects caused by oral administration, such as local or systemic disturbance in the gastrointestinal tract, have limited the clinical applications of these drugs. In the present study we have assessed the ability of polyamidoamine (PAMAM) dendrimers to facilitate transdermal delivery of NSAIDs, using Ketoprofen and Diflunisal as model drugs. In vitro permeation studies with excised rat skins indicated that PAMAM dendrimers significantly enhanced the accumulative permeated amount of both drugs after 24 h, as compared to drug suspensions without PAMAM dendrimers. Similarly, anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic profile for the NSAIDs-PAMAM dendrimer complex after transdermal administration. In addition, blood drug level studies revealed that the bioavailability was 2.73 times higher for the Ketoprofen-PAMAM dendrimer complex and 2.48 times higher for the Diflunisal-PAMAM dendrimer complex, respectively, than the pure drug suspensions. These results demonstrated that PAMAM dendrimers can effectively facilitate skin penetration of NSAIDs and may have the potential applications for the development of new transdermal formulations.     

Assessment and prevention of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory and, in the case of aspirin, for anti-thrombotic actions. The serious gastrointestinal side-effects associated with these drugs are of concern and pose a significant obstacle to their use. This review discusses the pathogenic mechanisms by which the conventional acidic NSAIDs induce gastrointestinal toxicity, with particular emphasis on non-prostaglandin effects. Methods of assessment of NSAID-induced enteropathy are reviewed, with particular emphasis on the use of functional measurement of NSAID-induced changes in the gastrointestinal tract. The advances in our knowledge of the pathogenesis of these effects have resulted in the development of a range of novel NSAIDs. Where functional assessment of the effects of NSAIDs has been employed, it appears to be more useful as an indicator of early-stage changes rather than a predictor of the effects of long-term NSAID exposure. Successful pharmaceutical strategies now offer considerable promise for reducing the severity of NSAID damage to the gastrointestinal tract. The utility of intestinal permeability measurements for selection and assessment of these strategies is discussed.     

癌性疼痛药物不良反应的防治

治疗癌性疼痛最常用的的药物是阿片类药物和非甾体消炎药。阿片类药物常见的不良反应包括便秘、恶心、呕吐、呼吸抑制和尿潴留等。非甾体消炎药常见的不良反应包括胃肠道损伤、肝肾损伤、血液系统损害等。治疗时以预防不良反应为主,包括避免用于高危人群、控制剂量与时间、同时使用治疗不良反应的药物等。出现不良反应时应及时采取相应的治疗措施。     

Protection from nsaid-induced gastrointestinal damage

Increased understanding of the damaging and protecting factors in the gastrointestinal tract opens up possibilities of safer use of NSAIDs or the development of safer NSAIDs in preventing gastrointestinal tract damage. Highly effective gastric acid suppression can successfully prevent both duodenal and gastric lesions associated with NSAIDs. The development of synthetic prostaglandin analogues and drugs with a selective prostaglandin effect has been shown to be successful, although the side-effects of current prostaglandin analogues limits their use. Selective prostaglandin drugs such as etodolac have been shown in prospective endoscopic studies significantly to reduce damage, and this is associated with less suppression of gastrointestinal prostaglandins than conventional NSAIDs.     

Gastrointestinal sparing anti-inflammatory drugs--effects on ulcerogenic and healing responses

The use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a wide array of alterations in gastrointestinal integrity and function. Various approaches have been taken to developing NSAIDs with reduced gastrointestinal toxicity, and few have been successfully reduced the incidence of adverse reactions. These include cyclooxygenase-2 (COX-2) selective inhibitors and nitric oxide (NO)-releasing NSAIDs. Especially, much has been written about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for the majority of prostaglandin synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived prostaglandins play a role in the maintenance of gastrointestinal mucosal integrity, particularly when the mucosa is injured, and the delineation of COX-1 and COX-2 might not be quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that the NO released from the derivatives will exert beneficial effects on the gastrointestinal mucosa. This approach has been successfully demonstrated to lessen the incidence of gastrointestinal damage and to promote the healing of gastric ulcers. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances, and the effects of gastrointestinal sparing NSAIDs, mainly COX-2 selective inhibitors and NO-releasing derivatives of NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa of experimental animals.     

Tolfenamic Acid: Clinical Experience in Rheumatic Diseases

Abstract Tolfenamic acid (TA) is an interesting drug for the treatment of rheumatic diseases because of its capacity to inhibit the synthesis of leukotrienes. It may have fewer upper gastrointestinal side effects than other NSAIDs which inhibit only the synthesis of prostaglandins. Several controlled and non-controlled studies on the clinical efficacy and side effects of TA have been carried out since the early seventies. These studies include about 900 patients suffering from different rheumatic diseases. The clinical efficacy of TA has proved to be at least as good as that of control drugs in all double-blind trials. We have compared the analgesic effect of ten NSAIDs in patients with rheumatoid arthritis, using a single-blind method by asking the patients which one of two drugs was the better. The study gave a rank order to the drugs favoured by the patients and the results showed that TA was among the four best drugs together with naproxen, indomethacin, and diclofenac. The side effect profile of TA is different from that of other NSAIDs. The number of upper gastrointestinal side effects during TA treatment was less than half the number during treatment with control NSAIDs in eight double-blind studies. On the other hand, dysuria was found only during TA treatment. In 1989 the official side effect registers of Denmark and Finland included a total of 462 side effect reports. The frequency of side effects per treatment day was about the same as for other NSAIDs according to these reports. Allergic skin reactions represented 40% of all reported side effects, dysuria 19%, diarrhoea 10%. and upper gastrointestinal symptoms (dyspepsia, nausea, vomiting, gastric pain, and ulcer) only 6%. TA is an effective NSAID with a short half-life, and probably has fewer upper gastrointestinal side effects than NSAIDs with no effect on the leukotriene synthesis.     

Gastrointestinal effects of selective and non-selective non-steroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed group of drugs. Patients receiving NSAIDs often experience abdominal discomfort, and some of them develop serious gastrointestinal complications, such as ulceration, bleeding, perforation, or obstruction. Gastrointestinal side effects of NSAIDs are mostly attributed to cyclooxygenase (COX) inhibition resulting in reduction of prostaglandin in gastric mucosa. Topical irritant effects are also contributed to their systemic effect of prostaglandin inhibition. Anti-inflammatory effects of NSAIDs are mediated by COX-2 inhibition, while COX-1 inhibition is responsible for gastric prostaglandin inhibition. Management of gastrointestinal complications of NSAIDs is costly. In order to prevent or treat the gastrointestinal complications of NSAIDs, anti-ulcer drugs can be used concomitantly. Other alternative is the application or substitution of COX-2 selective inhibitors, which spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Application of COX-2 selective inhibitors as a first line treatment for arthritic disorders may not be cost-effective, if patients do not have any risk factors including advanced age, history of complicating peptic ulcer, concomitant anticoagulant and corticosteroid medication. Patients with risk factors or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors if necessary.     

Dual COX-inhibitors: the answer is NO?

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.     

Hydrogen sulfide-based therapies: focus on H2S releasing NSAIDs

Nonsteroidal anti-inflammatory pain medications, commonly referred to as NSAIDs, are effective treatment for pain, fever and inflammation. However their use associates with a 4-6 fold increase in the risk of gastrointestinal bleeding. The basic mode of action of NSAIDs lies in the inhibition of cyclooxygenases (COXs), a family of enzymes involved in the generation of prostaglandins (PGs). The COX exists at least in two isoforms, COX-1 and COX-2, with PGs mediating inflammation at site of injury generated by the COX-2, while COX-1 produces PGs that are essential in maintaining integrity in the gastrointestinal tract. Selective inhibitors of COX-2, the coxibs, spare the gastrointestinal tract while exerting anti-inflammatory and analgesic effects. However, their use has been linked to an increased risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H(2)S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. In the last decade hybrid molecules that release NO or H(2)S have been coupled with non-selective NSAIDs to generate new classes of anti-inflammatory and analgesic agents with the potential to spare the gastrointestinal and cardiovascular system. These agents, the NO-releasing NSAIDs, or CINOD, and the H(2)S-releasing NSAIDs are currently investigated as a potential alternative to NSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD extensively investigated in clinical trials. Despite its promising profile, the approval of this drug was recently rejected by the Food and Drug Administration because the lack of long-term controlled studies. NSAIDs that release H(2)S as a mechanism to support an enhanced gastrointestinal and cardiovascular safety are being investigated in preclinical studies. Either naproxen or diclofenac coupled to an H(2)S releasing moiety has been reported to cause less gastrointestinal and cardiovascular injury than parent NSAIDs in preclinical models.     

Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.     

Nitric oxide-releasing NSAIDs: GI-safe antithrombotics

Aspirin is increasingly being used for long-term prophylaxis of myocardial infarction and stroke, but its use is limited by toxicity in the gastrointestinal tract. Even very low doses of aspirin can markedly increase the risk of gastrointestinal bleeding and ulceration. While proven effective in prophylaxis of stroke and myocardial infarction, the efficacy of aspirin is limited. Addition of a nitric oxide-releasing moiety to several non-steroidal anti-inflammatory drugs results in a profound reduction in their toxicity in the gastrointestinal tract and kidney. A similar derivatization of aspirin has recently been shown to result in a more potent, gastrointestinal-sparing antithrombotic drug. Two such compounds (NCX-4215 and NCX-4016; NicOx SA) have undergone detailed evaluation thus far. In each case, the NO-aspirin has shown improved anti-aggregatory activity while not inducing detectable gastric damage. The compounds have also been shown to exert protective effects in the gastrointestinal tract exposed to other injurious agents. The NO-aspirin derivatives significantly inhibit leukocyte adherence to the vascular endothelium, which may contribute to their anti-thrombotic activity. NO-releasing derivatives of aspirin and naproxen also exhibit beneficial effects in experimental hypertension, which would also contribute to improved anti-thrombotic activity. NO-releasing derivatives of NSAIDs offer great potential as gastrointestinal-sparing anti-thrombotic drugs.     

NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes

In this review, we have discussed our current understanding of the barrier properties that are in place to protect the upper gastrointestinal mucosa from luminal acid, and the pathogenic mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce injury to the gastrointestinal tract. The changes in our view of the importance of NSAID-induced cyclo-oxygenase (COX) inhibition on the pathogenesis and prevention of NSAID-induced gastrointestinal injury is presented. The focus of this paper has been placed on the effects of NSAIDs on the mucosal surface, and specifically the effect of these powerful drugs in inducing changes in the hydrophobicity, fluidity, biomechanical and permeability properties of extracellular and membrane phospholipids. Lastly, recent evidence is presented that salicylic acid and related NSAIDs may alter the stability of membranes, inducing the formation of unstable pores that may lead to back-diffusion of luminal acid and membrane rupture. This understanding of the interaction of NSAIDs with membrane phospholipids may prove valuable in the design of novel NSAID formulations with reduced gastrointestinal side-effects.     

Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in pregnancy to treat fever, pain and inflammation. Indications for chronic use of these agents during pregnancy are inflammatory bowel or chronic rheumatic diseases. Since the seventies, NSAIDs have been used as effective tocolytic agents: indomethacin has been the reference drug, delaying delivery for at least 48 hours and up to 7-10 days. Additionally, self-medication with NSAIDs is practiced by pregnant women. NSAIDs given to pregnant women cross the placenta and may cause embryo-fetal and neonatal adverse effects, depending on the type of agent, the dose and duration of therapy, the period of gestation, and the time elapsed between maternal NSAID administration and delivery. These effects derive from the action mechanisms of NSAIDs (mainly inhibition of prostanoid activity) and from the physiological changes in drug pharmacokinetics occurring during pregnancy. Increased risks of miscarriage and malformations are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks' gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Fetal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been reported after prenatal exposure to NSAIDs. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for the shortest duration possible. This article discusses in detail the placental transfer and metabolism of NSAIDs, and the adverse impact of prenatal NSAID exposure on the offspring.     

Section Review: Pulmonary-Allergy,Dermatological, Gastrointestinal & Arthritis: Development of NSAIDs with reduced gastrointestinal and renal toxicity

While nonsteroidal anti-inflammatory drugs remain among the most widely used medications, their use continues to be associated with significant toxicity, particularly in the gastrointestinal tract and kidney. As more is learned about the pathogenesis of these adverse effects, several strategies have been taken to develop NSAIDs that are less toxic. Many such strategies have failed to have significant impact on the frequency and/or severity of NSAID-related adverse effects. However, recently, two new approaches have been taken which show great promise. Selective inhibitors of the inducible isoform of prostaglandin synthase are reported to spare the gastrointestinal tract. As we know little about the possible physiological role of this isoform of prostaglandin synthase, there are some concerns about the true potential for these compounds. A second approach is the linking of standard NSAIDs to a nitric oxide-releasing moiety. Studies in experimental models are extremely encouraging, demonstrating that these compounds retain the desired effects of the NSAID, but do not produce injury in the gastrointestinal tract or kidney.     

非甾体抗炎药的胃肠损害及其预防

非甾体抗炎药（NSAIDs）在临床上广泛用于风湿性疾病及心血管疾病的治疗。NSAIDs的常见不良反应为胃肠道不适、恶心，严重不良反应有消化性溃疡、胃肠道出血或穿孔。胃肠损伤发生的原因是由于NSAIDs抑制了环氧酶（COX）系统而阻断了前列腺素的合成，因此干扰了正常黏膜保护机制导致局部受损。NSAIDs致胃肠道损伤的危险因素为高龄、有消化性溃疡或出血史。预防NSAIDs所致胃肠损伤的措施有：应用预防溃疡的药物，选择新一代高选择性COX-2抑制剂，根据患者情况应用抗幽门螺杆菌疗法，依据患者相关的危险因素采用不同的治疗方案。     

Current problems with non-specific COX inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective treatments for pain and inflammation. They have a substantial toxicity profile with side effects mainly affecting the gastrointestinal tract, heart and kidneys. Although they comprise a chemically diverse group of drugs, NSAIDs are unified by a common mode of action the ability to inhibit the enzyme cyclo-oxygenase (COX). This also accounts for much of their toxicity. The enzyme exists in at least 2 isoforms. COX-1 generates prostaglandins with physiological functions, COX-2 is induced by inflammation and its physiologic functions are unclear at present. Conventional NSAIDs, like diclofenac, ibuprofen, and naproxen, are non-selective COX inhibitors, blocking the production of both physiologic and inflammatory prostaglandins. In this chapter, we describe the main predictable gastrointestinal, cardiac and renal toxicities that can be explained by such blockade and review the supporting clinical and epidemiological evidence. In the gastrointestinal tract, the side effects associated with conventional NSAIDs are both local and systemic, and include ulceration, bleeding, perforation, and obstruction. The upper gastrointestinal tract is more commonly affected than the lower. The cardiac and renal side effects are most likely to occur in patients with existing heart or kidney disease, where prostaglandins play an essential role in maintaining the vasoconstrictor/dilator balance necessary for homeostasis. The patients at highest risk of toxicity are the elderly, those with a prior history of ulceration or bleeding, and those with a history of cardiac disease. Among such patients, the decision to prescribe NSAIDs requires careful consideration of the potential benefits and harms.