The epidemiology of the gastroduodenal damage induced by aspirin and other nonsteroidal anti-inflammatory drugs

A substantial body of studies (controlled, cohort and case-control studies) now confirm the long established impression that there is an increased prevalence of gastric and duodenal ulcer and of associated complications in subjects treated with aspirin (ASA) or with non-steroidal anti-inflammatory drugs (NSAIDs). The overall percentage of ulcers/erosions in patients treated with ASA ranges from 10 to 50% with a relative risk of bleeding ranging from 1.8 to 15%. The overall relative risk of ulcers/erosions in NSAIDs-treated subjects is around 3%, with complications detectable in 2.4% of cases. The risk of lesions and complications associated with ASA/NSAIDs is more marked in patients aged over 65, in those with a previous history of ulcer (both symptomatic and silent), in those treated with substantial doses or with combinations of NSAIDs and in those concomitantly using anticoagulants and/or steroids. The epidemiological data highlight the importance of implementing ASA/NSAIDs therapy only when strictly necessary as well as the advisability of adopting as broad a range of measures as possible to reduce the tissue-damaging effects of these pharmacological agents.     

Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance

OBJECTIVE: To review the mechanisms and clinical significance of adverse interactions between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) and discuss how these interactions can be avoided. DATA SOURCES: Previous studies of interactions between warfarin and NSAIDs or reports of adverse interactions were identified from a MEDLINE search (1976 to present) and from the reference lists of pertinent articles. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for inclusion in the review. Pertinent information was selected for discussion. DATA SYNTHESIS: All NSAIDs can prolong bleeding time by inhibiting platelet function. High-dose aspirin has a direct hypoprothrombinemic effect. Phenylbutazone and its analogs enhance the hypoprothrombinemic effect of warfarin through a pharmacokinetic interaction by inhibiting the hepatic metabolism of warfarin. Mefenamic acid also enhances the anticoagulant effect of warfarin, but the mechanism is not known. The clinical relevance of protein binding displacement in the interaction between warfarin and NSAIDs has been overstated, although a significant one may be more likely in the presence of high concentrations of NSAIDs in patients with slow elimination of warfarin (e.g., those with severe heart failure or impaired liver function). NSAIDs can induce gastrointestinal bleeding, which is likely to be more severe if warfarin is also given. CONCLUSIONS: The combined use of warfarin and NSAIDs is generally discouraged because of the increased risk of bleeding in these patients. In patients receiving warfarin who also require NSAIDs, phenylbutazone and its analogs, high-dose aspirin, mefenamic acid, excessive use of topical methyl salicylate, and NSAIDs that are associated with a higher risk of bleeding peptic ulcers should be avoided. Patients should be closely monitored for anticoagulant control and bleeding complications during the combined use of warfarin and NSAIDs.     

Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer

We have studied the feasibility of detecting tumor-associated aberrant p16 methylation in the circulation of patients with hepatocellular carcinoma (HCC). We extracted DNA from the tumor tissues and peripheral blood plasma or serum of 22 HCC patients. p16 methylation was found in 73% (16 of 22) of HCC tissues using methylation-specific PCR. Among the 16 cases with aberrant methylation in the tumor tissues, similar changes were also detected in the plasma/serum samples of 81% (13 of 16) of the cases. No methylated p16 sequences were detected in the peripheral plasma/serum of the six HCC cases without these changes in the tumor, in 38 patients with chronic hepatitis/cirrhosis, or in 10 healthy control subjects. These results suggest that circulating liver tumor DNA may be detected using tumor-associated DNA methylation changes. Because methylation abnormalities have been found in many other genes and tumor types, this approach may have implications for the noninvasive detection of a wide variety of cancers.     

Omeprazole. A review of its use in Helicobacter pylori infection, gastro-oesophageal reflux disease and peptic ulcers induced by nonsteroidal anti-inflammatory drugs

Omeprazole is a well studied proton pump inhibitor that reduces gastric acid secretion. This review examines its use in Helicobacter pylori infection, gastro-oesophageal reflux disease (GORD) with or without oesophagitis and gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs). Optimal omeprazole regimens for anti-H. pylori therapy are those that administer the drug at a dosage of 40 mg/day (in 1 or 2 divided doses) for 7, 10 or 14 days in combination with 2 antibacterial agents. As a component of 3-drug regimens in direct comparative studies, omeprazole was at least as effective as lansoprazole, pantoprazole, bismuth compounds and ranitidine. However, a meta-analysis suggests that triple therapies with omeprazole are more effective than comparable regimens containing ranitidine, lansoprazole or bismuth. Omeprazole also appears to be successful in triple therapy regimens used in children with H. pylori infection. In patients with acute GORD with oesophagitis, omeprazole is at least as effective as lansoprazole or pantoprazole in promoting healing, and superior to ranitidine, cimetidine or cisapride in oesophagitis healing and symptom relief. Omeprazole was similar to lansoprazole and superior to ranitidine in preventing oesophagitis relapse in patients with all grades of oesophagitis, but may be superior to lansoprazole or pantoprazole in patients with more severe disease. More patients with symptomatic GORD without oesophagitis experienced symptom relief after short term treatment with omeprazole than with ranitidine, cisapride or placebo, and symptoms were more readily prevented by omeprazole than by cimetidine or placebo. Omeprazole was effective in healing and relieving symptoms of reflux oesophagitis in children with oesophagitis refractory to histamine H2 receptor antagonists. Omeprazole is superior to placebo in preventing NSAID-induced gastrointestinal damage in patients who must continue to take NSAIDs. It is also similar to misoprostol and superior to ranitidine in its ability to heal NSAID-induced peptic ulcers and erosions, and superior to misoprostol, ranitidine or placebo in its ability to prevent relapse. In long and short term studies, omeprazole was well tolerated, with diarrhoea, headache, dizziness, flatulence, abdominal pain and constipation being the most commonly reported adverse events. Usual omeprazole dosages, alone or combined with other agents, are 10 to 40 mg/day for adults and 10 to 20 mg/day for children. CONCLUSIONS: Omeprazole is a well studied and well tolerated agent effective in adults or children as a component in regimens aimed at eradicating H. pylori infections or as monotherapy in the treatment and prophylaxis of GORD with or without oesophagitis or NSAID-induced gastrointestinal damage.     

Gastric erosions: radiological and endoscopic aspects

Varioliform gastric erosion is a common lesion which can be reliably diagnosed radiologically. The diagnosis was established in 27 (1.7%) of 1,600 detailed radiological examinations made in 1975. There was a good correlation with gastroscopic findings.     

Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs

PURPOSE: The authors determined the effect of photocoagulation of drusen on visual acuity and progression to subretinal neovascular membranes (SRNV). METHODS: One of paired eyes was randomized to photocoagulation with other eye to control in 27 patients having symmetrical maculopathy and visual acuities, aged 46 to 81 years (mean, 69.7 years); follow-up 1 to 6 years (mean, 3.2 years). RESULTS: Final visual acuity was improved in treated eye or decreased in control eye in 12 patients, equal in 13 patients, and decreased in treated eye in 2 patients (P < 0.006). Progression to SRNV was less with treatment. CONCLUSION: Laser photocoagulation of confluent soft macular drusen may improve long-term visual prognosis.     

Pathomorphology of kidney lesions induced by non-steroidal anti-inflammatory drugs

Pathomorphological findings on nephrobiopsies from two groups of patients with NSAID-induced kidney lesions are provided. In the first group (9 patients) the disease developed in patients of different age after short-term use of NSAID and was clinically manifested by acute renal failure with extrarenal allergic symptoms (skin, rash, eosinophilia). Morphological features were acute tubulo-interstitial nephritis without glomerular lesions. In the second group (23 patients) the disease developed after longterm use of NSAID in older patients with a compromised renal blood circulation presenting clinically with nephrotic syndrome, and morphologically by acute tubulo-interstitial nephritis with minimal change (lipoid nephrosis).     

Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1

We recently cloned and characterized the rat kidney-specific organic anion transporter, OAT-K1, which was suggested to mediate renal tubular transport of methotrexate. In this study, we investigated the interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) with OAT-K1 by evaluating the effects of these drugs on renal distribution of methotrexate in vivo, and on methotrexate accumulation in the stably transfected LLC-PK1 cells expressing OAT-K1 (LLC-OAT-K1). NSAIDs such as indomethacin and ketoprofen had significant inhibitory effects on renal accumulation of methotrexate in rats after coadministration. Indomethacin and ketoprofen inhibited methotrexate accumulation by LLC-OAT-K1 cells in a competitive manner with the apparent inhibition constant values of 1. 0 mM and 1.9 mM, respectively. Other NSAIDs including ibuprofen, flufenamate and phenylbutazone also showed potent inhibitory effects on methotrexate accumulation. However, indomethacin was not transported via OAT-K1. These results indicate that NSAIDs have potent inhibitory effects against the OAT-K1-mediated methotrexate transport, which suggests that the OAT-K1 may be one of interaction sites for methotrexate and NSAIDs in the kidney.     

Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application

Nonsteroidal anti-inflammatory drugs (NSAIDs) are being administered increasingly by transdermal drug delivery for the treatment of local muscle inflammation. The human epidermal permeabilities of different NSAIDs (salicylic acid, diethylamine salicylate, indomethacin, naproxen, diclofenac and piroxicam) from aqueous solutions is dependent on the drug's lipophilicity. A parabolic relationship was observed when the logarithms of NSAID permeability coefficients were plotted against the logarithms of NSAID octanol-water partition coefficients (log P), the optimum log P being around 3. The local tissue concentrations of these drugs after dermal application in aqueous solutions were then determined in a rat model. The extent of local, as distinct from systemic delivery, for each NSAID was assessed by comparing the tissue concentrations obtained below a treated site to those in contralateral tissues. Local direct penetration was evident for all NSAIDs up to a depth of about 3 to 4 mm below the applied site, with distribution to deeper tissues being mainly through the systemic blood supply. A comparison of the predicted tissue concentrations of each NSAID after its application to human epidermis was then made by a convolution of the epidermal and underlying tissue concentration-time profiles. The estimated tissue concentrations after epidermal application of NSAIDs could be related to their maximal fluxes across epidermis from an applied vehicle.     

Laxative-like effects of nonsteroidal anti-inflammatory drugs on intestinal fluid movement and membrane integrity

Certain nonsteroidal anti-inflammatory drugs (NSAID) of the fenamate chemical class are known to cause diarrhea in clinical use. Paradoxically, this action is shared by prostaglandins, against whose syntheses are inhibited by NSAID. This study was done to investigate the laxative potential of 5 NSAID (meclofenamate, flufenamate, mefenamate, indomethacin and aspirin). The ability to produce a laxative response was assessed by determining effects on fluid absorption in vitro in hamster everted sacs and by the enteropooling assay in hamster small intestine. In addition, the lytic action of these drugs on the erythrocyte membrane was determined to arrive at a possible mechanism of action. All of the NSAID, except aspirin, produced dose-related inhibition of fluid transport, similar to prostaglandin E1 and E2. The order of inhibition was flufenamate greater than meclofenamate greater than mefenamate greater than indomethacin. Like results were obtained when enteropooling was measured in vivo. Flufenamate and meclofenamate produced lumenal fluid accumulation comparable to two laxatives, dioctyl sodium sulfosuccinate and ricinoleic acid. Finally, the effects of these NSAID on fluid movement paralleled their lytic action on the erythrocyte membrane model, suggesting that NSAID may produce diarrhea in a manner similar to certain laxatives, by increasing mucosal permeability through membrane damage.     

Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diagnosis, and clinical significance

Oral hairy leukoplakia (OHL) is a lesion frequently, although not exclusively, observed in patients infected by human immunodeficiency viruses (HIV). OHL is clinically characterized by bilateral, often elevated, white patches of the lateral borders and dorsum of the tongue. Histologically, there is profound acanthosis, sometimes with koilocytic changes, and a lack of a notable inflammatory infiltrate. The koilocytic changes are due to intense replication of Epstein-Barr virus (EBV), while epithelial hyperplasia and acanthosis are likely to result from the combined action of the EBV-encoded proteins, latent membrane protein-1, and antiapoptotic BHRF1. How OHL is initiated and whether it develops after EBV reactivation from latency or superinfection remain unresolved; nevertheless, definitive diagnosis requires the demonstration of EBV replicating vegetatively in histological or cytological specimens. In patients with HIV infection, the development of OHL may herald severe HIV disease and the rapid onset of AIDS, but despite its title, OHL is not regarded as premalignant and is unlikely to give rise to oral squamous cell carcinoma.     

Neutrophils, Helicobacter pylori, and nonsteroidal anti-inflammatory drug ulcers

BACKGROUND & AIMS: Gastric injury by nonsteroidal anti-inflammatory drugs (NSAIDs) is minimal in neutropenic animals. This study examined peptic ulcer development in the presence or absence of gastric neutrophils in patients requiring long-term use of NSAIDs. METHODS: Gastric histology, neutrophils, and Helicobacter pylori were assessed in 120 patients randomized to receive placebo or 20 or 40 mg famotidine twice daily as prophylaxis against NSAID-related ulcers and who underwent endoscopy at 0, 4, 12, and 24 weeks. RESULTS: In 43 patients without gastric neutrophils, ulcers developed in 1 of 14 (7.7%) taking placebo, 2 of 16 (12.5%) taking 20 mg famotidine, and none of 13 taking 40 mg famotidine. However, in 77 patients with neutrophils, ulcers developed in 13 of 28 (47. 4%) taking placebo (P < 0.001), 3 of 26 (12.6%) taking 20 mg famotidine, and 3 of 23 (13%) taking 40 mg famotidine. Eight of 46 patients (17%) without H. pylori had neutrophils compared with 69 of 74 (93%) with both H. pylori and neutrophils (P < 0.001). CONCLUSIONS: Gastric neutrophils increase the incidence of ulceration in long-term NSAID users. Because neutrophils exist with H. pylori, eradicating this infection might prevent NSAID-related peptic ulcers.     

Gastric motor dysfunction in diabetic patients: pathogenesis, clinical manifestations, diagnosis and treatment

Recent reports provide evidence, that the disordered gastric motoric function in diabetic patients depends on glycaemia and that it can influence metabolic control. The etiopathogenesis of disordered gastric motoric function is poorly understood and is mainly hypothetical. The diagnosis of this dysfunction is difficult. It is recommended to evaluate of gastric motility, especially by scintigraphy, manometry and electrogastrography. In the treatment, it is important to remember about the good metabolic control of diabetes and use the gastrokinetic drugs in the combination or alternating therapy. In especially severe cases, surgical therapy is indicated. Lack of effective method of gastric motoric dysfunction treatment in diabetic patients suggest the necessity of further studies on new drugs, which would normalise the motoric abnormality and eliminate the symptoms.     

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.     

Effect of systemic versus topical nonsteroidal anti-inflammatory drugs on postexercise jaw-muscle soreness: a placebo-controlled study

Certain types of jaw-muscle pain may be managed with pharmacologic treatment. This study evaluated the effect of topical and systemic nonsteroidal anti-inflammatory drugs on acute postexercise jaw-muscle soreness. Ten men without temporomandibular disorders performed six 5-minute bouts of submaximal eccentric jaw exercise. The outcome variables were pressure pain thresholds and pain tolerance thresholds at the masseter muscles, and maximum voluntary occlusal force. Surface electromyography from the masseter muscles was used to assess the development of muscle fatigue during the exercise period. Three treatment modalities were tested in a placebo-controlled, double-blind approach: (A) placebo gel and placebo tablets; (B) nonsteroidal anti-inflammatory drug gel (2 g, 5% ibuprofen) and placebo tablets; and (C) placebo gel and nonsteroidal anti-inflammatory drug tablets (400 mg ibuprofen). The subjects used their medication 3 times a day for 3 days in the postexercise period. In the exercise period, the mean power frequency of the electromyography signal, pressure pain threshold, pain tolerance threshold, and maximum voluntary occlusal force decreased significantly (analysis of variance, P < .01). In the postexercise period, the effect of treatment on pressure pain thresholds was significant (F[2,9] = 4.41, P = .02). On day 3, treatment with topical nonsteroidal anti-inflammatory drugs was associated with significantly higher pressure pain thresholds as compared to treatment with systemic nonsteroidal anti-inflammatory drugs (P < .05) and placebo (P < .05). Treatment effects on pain tolerance thresholds and on maximum voluntary occlusal force were nonsignificant. The results demonstrated that repeated eccentric jaw exercise caused muscle fatigue and low levels of postexercise pain and soreness. Topical nonsteroidal anti-inflammatory drugs seem to have some advantages over systemic nonsteroidal anti-inflammatory drugs for management of exercise-induced jaw-muscle pain.