Is misoprostol cost-effective in the prevention of nonsteroidal anti-inflammatory drug-induced gastropathy in patients with chronic arthritis? A review of conflicting economic evaluations

Whether misoprostol, a synthetic prostaglandin E1 analogue, should be routinely prescribed along with nonsteroidal anti-inflammatory drugs (NSAIDS) to prevent gastric damage is of great clinical importance and has profound cost implications. No consensus exists on whether misoprostol cotherapy results in a cost-saving, is cost-effective, or is costly. The different conclusions reached by five economic evaluations of misoprostol can be explained solely by the assumed absolute risk reduction of symptomatic ulcer, which was more than seven times greater in the studies that concluded that misoprostol was cost-effective than in a study that concluded misoprostol to be costly. Since no study has directly shown the effectiveness of misoprostol cotherapy in preventing clinically significant ulcer disease (ie, hemorrhage and perforation), it is impossible to judge which assumptions are most appropriate. The absence of firm data on the rate of NSAID-induced gastric ulcers reduced by misoprostol makes it impossible to conclude whether it is cost-effective in patients with chronic arthritis who use NSAIDS.     

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.     

Risk of ulcer and its prophylaxis in therapy with non-steroidal antirheumatic drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed drugs in western countries. The high incidence of adverse gastrointestinal effects which are potentially life-threatening require steps for prevention. The use of NSAIDs should be restricted to patients with inflammatory rheumatic diseases. If NSAIDs are indicated it is important to identify patients who are at high risk to develop serious gastrointestinal side effects. These patients should receive Misoprostol at a dose of 2 to 3 x 200 micrograms per day. Up to date Misoprostol is the only drug with proven efficacy with respect to the prevention of gastroduodenal ulcer and its complications. NSAIDs inhibit the key enzyme of prostaglandin synthesis, the cyclooxygenase. Recently published data show that 2 isoenzymes of the cyclooxygenase exists. Cyclooxygenase-1 is primarily involved in the maintenance of organ function whereas cyclooxygenase-2 is expressed in inflamed tissue. Specific cyclooxygease-2 inhibitors have been developed. Clinical trials have to prove if the concept of a selective cyclooxygenase-2 inhibition with high antiinflammatory potency but lack of gastrointestinal side effects holds true in humans.     

Gastric erosions induced by nonsteroidal anti-inflammatory drugs: clinical significance, pathogenesis, and therapeutic perspectives

The development of ulceration and ulcer complications by nonsteroidal anti-inflammatory drugs (NSAIDs) is now well established. Gastric erosions occur in about 60% of patients receiving long-term NSAID therapy. Many clinicians consider such erosions benign in nature and not requiring therapeutic intervention. Recent evidence, however, indicates that gastric erosions predispose rheumatic patients to frank ulcerations and ulcer complications. This brief overview summarizes the clinical dilemma in the diagnosis and treatment of NSAID-induced gastric erosions. Current data suggest that misoprostol has important therapeutic benefits for the treatment and prevention of gastric erosions in patients receiving long-term NSAID therapy.     

Association of cocaine and methamphetamine use with giant gastroduodenal ulcers

OBJECTIVES: Giant gastric and duodenal ulcers (>2-3 cm in greatest dimension) are reported to have higher rates of complication and mortality and to be associated with increasing age, renal failure, and use of nonsteroidal antiinflammatory drugs (NSAIDs). This study investigated the outcome and associations of gastric and duodenal ulcers >2.5 cm compared to ulcers of lesser size. METHODS: Records from all patients with gastric and duodenal ulcers >0.5 cm diagnosed by upper endoscopy between January 1994 and September 1995 were studied for evidence of concurrent use of aspirin, NSAIDs, methamphetamine, and cocaine, as well as for transfusion requirements, length of hospital stay, mortality, surgery, rebleeding, Helicobacter pylori infection, and malignancy. RESULTS: A logistic regression analysis of the 220 patients identified revealed that recent methamphetamine and/or cocaine use was significantly predictive of giant ulcer formation (p = 0.0002) with an odds ratio of 9.66. Also significant was younger age (p = 0.026) and aspirin or NSAID use (p = 0.046). H. pylori infection was significant only for giant gastric ulcers (p = 0.031). Ulcer size did not predict mortality, rate of rebleeding, requirement for surgery, transfusion requirements, or length of hospital stay. However, giant gastric ulcers were significantly more likely to be malignant (p = 0.002). CONCLUSIONS: Giant gastric and duodenal ulcers were strongly associated with stimulant abuse. They were also associated with younger age and use of aspirin or NSAIDs. Additionally, giant gastric ulcers were associated with malignancy and H. pylori infection. Ulcer size did not predict rate of complications or outcome.     

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.     

Polyamine-enhanced NMDA receptor activity: effect of ethanol

Gastrointestinal symptoms and lesions are often associated with the clinical use of non-steroidal antiinflammatory drugs (NSAIDs). An open-label, single arm multicenter Italian study evaluated if misoprostol, a prostaglandin E1 analogue with gastroduodenal mucosal protective activity, was effective in the prevention and treatment of NSAID-induced gastroduodenal lesions. Patients affected by rheumatoid arthritis (RA) or osteoarthritis (OA), in treatment with NSAIDs and suffering from gastric symptoms or gastroduodenal lesions related to NSAID use, were admitted to the study. Gastrointestinal and arthritic symptoms were assessed before and after 4 weeks co-administration of an NSAID (the most frequent was diclofenac, used in 35% of the RA and in 22% of the OA patients, followed by piroxicam and tenoxicam respectively) + misoprostol (200 mcg two times daily in 58% of the cases, 200 mcg three times daily in 39%, 200 mcg four times daily in 3%). On admission and after 4 weeks of therapy a gastrointestinal endoscopy was performed to evaluate the condition of the gastroduodenal mucosa. Final results showed that: (i) NSAID-related gastric lesions were more frequent than duodenal lesions; (ii) when patients were given misoprostol and NSAIDs, 96% of them did not develop gastric lesions and 97% did not develop duodenal lesions; (iii) even when NSAID therapy was continued, gastric or duodenal lesions induced by NSAIDs healed or in any case did not worsen in 92% and 91% respectively of the cases; (iv) during the period of coadministration of NSAIDs+misoprostol, NSAID-related UGI symptoms disappeared or improved in 77% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

NSAID-induced ulcers--therapy and prevention

There is a lot of epidemiological information to calculate the risk of developing gastroduodenal lesions during NSAID therapy on a reliable base in an individual patient. In treating NSAID ulcers one has to decide whether the antirheumatic treatment can be stopped or whether one has to continue. In the first mentioned condition all antiulcer drugs can be used safely like in chronic recurrent ulcer disease. However, when NSAID therapy has to be continued proton pump inhibitors are necessary in doubled therapeutic dosage. Prophylaxis should not be made in all patients on NSAIDs, but is only indicated with convincing cost-benefit ratio in high-risk patients. Whereas H2-blockers and proton pump inhibitors seem to protect mainly the duodenal mucosa oral prostaglandins (Misoprostol) are effective in the stomach as well.     

Cost effectiveness of misoprostol therapy in prevention of NSAID-induced stomach ulcers

The efficacy of 400 micrograms misoprostol daily in the prevention of NSAID (non-steroidal anti-inflammatory drug)-induced gastric ulcer has been proven. We calculated the cost-effectiveness of a 3-month course of treatment of 200 micrograms twice daily for patients of the sick fund "Wiener Gebietskrankenkasse", based on charges of the year 1993. Since efficacy in preventing NSAID-induced gastric ulcers has not yet been proven for any other drug, we compared misoprostol-treated patients with untreated controls. The model was based on the following assumptions: 70% compliance with respect to misoprostol treatment, 5.6% incidence of gastric ulcer in patients protected with misoprostol, 21.7% incidence among unprotected NSAID users, 20% hospitalisation among patients with gastric ulcer. When using "Kassenpreis" (drug price paid by the sick funds) misoprostol treatment is cost-effective at costs of AS 64,100,--for inpatient care, upwards and at costs of AS 43,361,-upwards when using "Apothekeneinstandspreis" (drug price paid by pharmacies to wholesalers). In Austria costing system of inpatient care is based on a per diem fee. In 1993 the above costs corresponded to an average of 13 and 9 days, respectively, of inpatient care in Vienna. But costs of care increase by almost 25% per year and, hence, this conclusion is only temporarily valid and already in 1994 cost-effectiveness will be reached in less days of inpatient care. Sensitivity analysis shows that cost-effectiveness mainly varies according to the incidence of gastric ulcer among unprotected adults, and the hospitalisation rate of gastric ulcer patients. Efficacy (gastric ulcer rate among misoprostol treated patients) and compliance have a relatively low impact.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug therapy of patients treated in hospitals for duodenal ulcers

Drug therapy in hospitalized patients treated for duodenal ulcer disease was reviewed retrospectively. The information was obtained by the means of a medical audit of patient records indexed by the discharge diagnosis of duodenal ulcers. A total of 485 cases were abstracted. Antacids were found to be the cornerstone of duodenal ulcer drug therapy. Anticholinergic drugs occupied a central role throughout the medical treatment of duodenal ulcers. The investigators identified a need for the dissemination of information concerning the use of anticholinergics in duodenal ulcer patients experiencing the complications of hemorrhage and obstruction.     

Platelet-derived growth factor reverses the effects induced by NSAIDs on ulcer healing

BACKGROUND: It is known that non-steroidal anti-inflammatory drug (NSAID) use delays the healing of peptic ulcers and that growth factors play an important role in the ulcer healing process. AIM: To evaluate the effect of platelet-derived growth factor (PDGF) in healing chronic gastric ulcers in rats treated with NSAIDs. METHODS: Chronic gastric ulcers were induced with acetic acid in male Wistar rats and then treated with either aspirin (100 mg/kg/day), indomethacin (2 mg/kg/day), PDGF-BB (0.1 nM/kg/day) or combinations. Gastric secretion and ulcer size, wound contraction, mucosal regeneration and cell proliferation were assessed in histological specimens. RESULTS: Both aspirin and indomethacin delayed the healing rate of gastric ulcers and reduced ulcer contraction, mucosal regeneration and cell proliferation. All these effects were completely reversed by oral treatment with PDGF-BB without affecting gastric acid secretion. CONCLUSION: Oral administration of PDGF accelerates ulcer healing and reverses the effects induced by NSAIDs on ulcer healing without affecting gastric secretion.     

Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers

BACKGROUND: Helicobacter pylori infection is common in patients with peptic ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs). But the pathogenic role of H pylori in this disease is controversial. We studied the efficacy of eradication of H pylori in the prevention of NSAID-induced peptic ulcers. METHODS: We recruited patients with musculoskeletal pain who required NSAID treatment. None of the patients had previous exposure to NSAID therapy. Patients who had H pylori infection but no pre-existing ulcers on endoscopy were randomly allocated naproxen alone (750 mg daily) for 8 weeks or a 1-week course of triple therapy (bismuth subcitrate 120 mg, tetracycline 500 mg, metronidazole 400 mg, each given orally four times daily) before administration of naproxen (750 mg daily). Endoscopy was repeated after 8 weeks of naproxen treatment or when naproxen treatment was stopped early because of bleeding or intractable dyspepsia. All endoscopic examinations were done by one endoscopist who was unaware of treatment assignment. The primary endpoint was the cumulative rate of gastric and duodenal ulcers. FINDINGS: 202 patients underwent endoscopic screening for enrolment in the trial, and 100 eligible patients were randomly assigned treatment. 92 patients completed the trial (47 in the naproxen group, 45 in the triple-therapy group). At 8 weeks, H pylori had been eradicated from no patients in the naproxen group and 40 (89%) in the triple-therapy group (p < 0.001). 12 (26%) naproxen-group patients developed ulcers: five had ulcer pain and one developed ulcer bleeding. Only three (7%) patients on triple therapy had ulcers, and two of these patients had failure of H pylori eradication (p = 0.01). Thus, 12 (26%) patients with persistent H pylori infection but only one (3%) with successful H pylori eradication developed ulcers with naproxen (p = 0.002). INTERPRETATION: Eradication of H pylori before NSAID therapy reduces the occurrence of NSAID-induced peptic ulcers.     

The relationship between upper gastrointestinal hemorrhage and drug use: a case control study

The relationship between upper gastrointestinal hemorrhage and drug use was studied in 251 Chinese patients (179 men, 72 women) admitted to the Prince of Wales Hospital, Hong Kong, and control subjects matched for age and sex. There was a highly significant difference between the cases and control subjects in the use of NSAIDs (odds ratio 14.0, p < 0.00001), ulcer healing drugs (odds ratio 12.5, p < 0.00001), and Chinese proprietary medicines (odds ratio 16.0, p < 0.00001). There was also a significant difference in the use of analgesics (odds ratio 14.0, p = 0.001), paracetamol (odds ratio 2.5, p = 0.01), antacids (odds ratio 2.7, p < 0.001) and unknown drugs (odds ratio 4.7, p < 0.001). Cases also differed from control subjects regarding the use of tobacco (odds ratio 2.3, p < 0.001) and alcohol (odds ratio 1.7, p = 0.02), and the presence of peptic ulcer symptoms (odds ratio 29.8, p < 0.00001). Significantly more control subjects than cases were receiving aspirin, cardiovascular drugs, bronchodilators, oral hypoglycemic drugs/lipid-lowering drugs, and anticonvulsants/hypnotics, due to the inevitable differences in disease pattern between the 2 groups. NSAID use was a major factor associated with upper gastrointestinal hemorrhage from primarily peptic ulcers. Differences in the use of other drugs may reflect variations in disease patterns between cases and controls, the common practice of self-medication in Hong Kong, and the concomitant use of NSAIDs and ulcer healing drugs/antacids.     

Nonsteroidal anti-inflammatory drug-associated upper gastrointestinal lesions in rheumatoid arthritis patients. Relationships to gastric histology, Helicobacter pylori infection, and other risk factors for peptic ulcer

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are risk factors for peptic ulcer in rheumatoid arthritis (RA) patients, but the contribution of reactive gastritis, concomitant Helicobacter pylori infection, or RA activity to NSAID ulcer pathogenesis is unknown. METHODS: Ninety-six RA patients taking NSAIDs and dyspeptic sex- and age-matched control patients without NSAID use or an RA diagnosis were enrolled in the study. RESULTS: Gastric ulcer (GU) was detected in 29 (30%) RA patients and 3 control patients (P < 0.001). Sixteen RA patients and no control patient had an H. pylori-negative GU. The GUs of the RA patients were mainly located in the prepyloric region (28%) and antrum (62%). Nine of the 29 RA patients (31%) with GU had more than 1 ulcer. Erosive gastropathy was detected in 34 (71% H. pylori-negative) RA patients and in 13 (62% H. pylori-negative) control subjects (P < 0.001). Chronic gastritis was observed in 65 RA patients (48% H. pylori-negative) and in 58 control subjects (43% H. pylori-negative) (NS). whereas reactive gastritis was found in only 2 RA patients and in none of the controls. Corticosteroid use was the only independent risk factor for GU: odds ratio was 6.8 (95% confidence interval, 1.3-36.0). The prevalences of duodenal ulcer or esophagitis were not increased in RA patients. CONCLUSIONS: RA patients using NSAIDs continuously are at a greatly increased risk of developing both H. pylori-negative and -positive GUs, and corticosteroid use is an independent risk factor for ulcer development. Most RA patients have chronic gastritis, whereas reactive gastritis is rarely associated with continuous NSAID use in RA patients.     

Misoprostol and omeprazole in the prevention of chemotherapy-induced acute gastroduodenal mucosal injury. A randomized, placebo-controlled pilot study

BACKGROUND: Chemotherapy (CT) may induce acute mucosal injury to the stomach and duodenum, but its prevention has been scarcely investigated. METHODS: One hundred and eighty-two cancer patients with normal stomach and duodenum or having fewer than 3 erosions, selected to be treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (77 breast carcinoma patients) or 5-fluorouracil (5-FU) (105 colon carcinoma patients), were randomly assigned to prophylactic treatment with misoprostol, 400 micrograms twice a day; omeprazole, 20 mg once a day; or placebo, 1 tablet twice a day. Seven days after the end of the second source of CT, all patients underwent control esophagogastroduodenoscopy. Endoscopic findings were quantified on the basis of an arbitrary score: 0 = normal; 1 = less than 3 erosions; 2 = 3-15 erosions; 3 = more than 15 erosions or ulcer; 4 = giant ulcer (greatest dimension of more than 2 cm) or multiple ulcers with cumulative greatest dimension exceeding 2 cm. RESULTS: Mean score increased significantly in the placebo and misoprostol groups, either after CMF (P < 0.001 and P < 0.05, respectively) or after 5-FU (P < 0.001 for both), whereas it did not in the omeprazole group. Gastric and duodenal ulcers were significantly less frequent in patients receiving omeprazole than in those receiving placebo (P < 0.05 after both CMF and 5-FU). No significant difference was observed between placebo and misoprostol. Omeprazole was significantly more effective than placebo and misoprostol in reducing the frequency and degree of the endoscopic worsening, either after CMF or after 5-FU (P < 0.05 for both CT regimens). Epigastric pain and/or heartburn were significantly less frequent in patients receiving omeprazole than in those receiving placebo (P < 0.01) or misoprostol (P < 0.001). CONCLUSIONS: The strong and prolonged inhibition of gastric acid production induced by omeprazole seems to be effective in preventing chemotherapy-induced gastroduodenal mucosal injury. Further trials are necessary to verify whether such a prevention of endoscopically observed injury can translate into prevention of clinically significant injury.     

Nonsteroidal anti-inflammatory drugs and bone mineral density in older women: the Rancho Bernardo study

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit synthesis of prostaglandins and may help prevent bone loss, but no study has shown the differential association of type or dose of NSAID compound with bone mineral density (BMD). The purpose of this study was to determine the relation of NSAIDs by type and dose to BMD. Participants were 932 Caucasian, community-dwelling women aged 44-98 years from southern California. Data were collected from 1988 to 1991 through the use of standardized medical questionnaires. Medication use was validated by a nurse. BMD at the ultradistal and midshaft radii were measured using single-photon absorptiometry, and at the hip and lumbar spine using dual-energy X-ray absorptiometry. Women (mean age, 72 years) were classified into 818 nonusers and 114 regular daily users of NSAIDs, of which 84 used propionic acid NSAIDs and the remainder used acetic acid NSAIDs. Occasional NSAID users were excluded. Women who used propionic acid NSAIDs, but not acetic acid NSAIDs, had higher BMD at all five sites and significantly higher BMD at the midshaft radius and lumbar spine. These differences remained after controlling for known covariates of osteoporosis. When women with self-reported osteoarthritis were excluded from the model, significantly higher BMD in propionic acid NSAID users was also observed at the femoral neck and total hip. Those who concurrently used estrogen and propionic acid NSAIDs had the highest BMD at all sites, suggesting an additive effect. We conclude that regular daily use of propionic acid NSAIDs, with or without simultaneous use of estrogen, may be helpful in preventing bone loss in older women. However, further research is needed to confirm these results before any clinical practice guidelines can be recommended due to the increased risk of serious complications associated with NSAID use.     

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.     

Gastrointestinal effects of NSAIDs. Difficulties in detection and management

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid are effective analgesic agents, but their use carries a significant potential for gastrointestinal side effects. Because many persons who have serious adverse effects from NSAIDs are asymptomatic, the decision to use these drugs must be tempered by an understanding of the side-effect profile and knowledge of who constitutes the high-risk population. Patients must be vigilantly monitored for signs and symptoms of reactions to the drugs, which should be discontinued when injury is suspected if at all possible. Diagnostic endoscopy should be the mainstay of further evaluation. Treatment of NSAID-induced gastrointestinal disease parallels that of non-NSAID-related reactions. This includes use of histamine2 receptor antagonists or proton pump inhibitors. Although NSAID-induced ulcers can heal while the drugs are continued, only omeprazole (Prilosec) has been shown to speed healing during NSAID use. For persons at highest risk, consideration must be given to prophylaxis against peptic ulcer disease. Misoprostol (Cytotec) has been clearly shown to offer the best protection against gastroduodenal ulceration.     

Ether extract of fetal calf serum protects cultured rat cortical neurons against glutamate cytotoxicity

OBJECTIVE: To elucidate the role of Helicobacter pylori in relapsing disease after partial gastrectomy for peptic ulcer. DESIGN: Retrospective study of gastroscopies between January 1985 and February 1988. SETTING: Department of Surgery, Helsinki University Central Hospital, Finland. PARTICIPANTS: One hundred and fifty-five patients, who had undergone partial gastrectomy for peptic ulcer disease. MAIN OUTCOME MEASURES: Correlation between clinical and laboratory data, macroscopic findings at gastroscopy and histopathology. RESULTS: At gastroscopy 41 patients showed an ulcer at the site of anastomosis or in the gastric stump and two patients had a history of a previous ulcer recurrence. The median time interval between operation and relapse was 4 years. There was no correlation between ulcer recurrence, sex, age, ABO blood group or other diseases. Smokers and patients using non-steroidal anti-inflammatory drugs (NSAIDs) or alcohol had more relapses, but the difference was not significant. The recurrence rate was higher after Billroth II (BII; 34%) than after Roux-en-Y (14%; P = 0.03) or Billroth I (BI) reconstruction (24%). Giemsa staining demonstrated H. pylori in the gastric stump of 37% of the patients. H. pylori expression was related to age but unrelated to sex, ABO blood group, NSAID use, smoking or alcohol consumption. H. pylori positivity was more common (52%) after BI than after BII (28%; P = 0.04) or Roux-en-Y resection (40%). Recurrent ulcer was more often found in gastric remnants with normal mucosa (36%) than in those with H. pylori-positive gastritis (18%; P = 0.03) or H. pylori-negative gastritis (26%). CONCLUSION: It seems that H. pylori infection plays a minor role in the pathogenesis of ulcer recurrence after partial gastrectomy for peptic ulcer disease. Eradication of H. pylori of the remnant stomach is therefore presumably not effective in preventing ulcer recurrence.     

Nephrotoxicities of nonsteroidal anti-inflammatory drugs

While the relative incidence of serious nephrotoxicities in the population consuming nonsteroidal anti-inflammatory drugs (NSAIDs) is very low, the frequency of adverse events in patients at risk has considerably increased due to the rising popularity of the use of the drugs in recent years. Under normal conditions, NSAIDs have relatively little effect on the kidney because of low renal production of prostaglandins. However, in the presence of renal hypoperfusion in which local synthesis of vasodilator prostaglandins is increased to protect the glomerular hemodynamics and to maintain appropriate renal tubular transport of fluid and electrolytes, inhibition of prostaglandin synthesis by NSAIDs can lead to vasoconstrictive acute renal failure as well as fluid and electrolyte disorders such as sodium retention and resistance to diuretics, hyponatremia and hyperkalemia. Conditions that increase the risk for NSAID-induced nephrotoxicities include volume depletion from diuretics and other causes, edematous states such as congestive heart failure and cirrhosis of the liver, old age and underlying renal disease, especially in the presence of renal functional impairment. In addition, renal parenchymal diseases may develop in susceptible patients taking NSAIDs. These include acute tubulointerstitial nephritis, frequently associated with nephrotic syndrome, and chronic progressive renal disease, with or without renal papillary necrosis. Rare cases of vasculitis and glomerulonephritis have also been reported. Finally, NSAIDs may aggravate hypertension by interacting with antihypertensive drugs, especially with diuretics and beta-blockers. Withdrawal of NSAIDs in patients at risk can frequently reverse or improve the nephrotoxicities. It is recommended that physicians be aware of the clinical settings that increase the risk for NSAID-induced nephrotoxicities and take preventive or therapeutic measures accordingly.