NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: HOW DO THEY DAMAGE THE GUT?

NSAIDs are widely prescribed for the treatment of musculoskeletaldisorders. The gastrointestinal tract, predominantly the stomach,bears the brunt of their side-effects. The basis of this toxicityis certainly multifactorial, with a wide range of local effectsand mucosal defences being implicated. This review will highlight:(1) the epidemiology of NSAID-induced gastrointestinal toxicity;(2) their effects on prostaglandins, and the phenomenon of cytoprotection;(3) effects on neutrophil function; (4) effects on mucosal bloodflow; (5) responses of the mucosa to damage (restitution, adaptation,and regenerative repair); (6) the relevance of growth factors;(7) interactions with Helicobacter pylori in ulcerogenesis,and finally (8) the effects of NSAIDs on the small intestineand colon. KEY WORDS: Non-steroidal anti-inflammatory drugs, Gastrointestinal tract, Toxicity, Gastropathy, Repair, Adaptation, Healing, Cytoprotection, Blood flow, Neutrophil, Helicobacter pylori, Growth factors     

A GASTROSCOPIC STUDY OF THE PREDICTIVE VALUE OF RISK FACTORS FOR NON-STEROIDAL ANTI-INFLAMMATORY DRUG-ASSOCIATED ULCER DISEASE IN RHEUMATOID ARTHRITIS PATIENTS

Peptic ulcer disease (PUD) in RA patients is associated withNSAID use. This study aimed to validate the predictive valueof presumed risk factors for NSAID-associated PUD in a prospectivegastroscopic study in RA patients. Eighty-one NSAID using RApatients were prospectively divided into four presumed riskgroups according to Helicobacter pylori status and history ofPUD. As additional risk factors the following were analysed:upper gastrointestinal GI complaints; disability; daily doseof NSAID and antral gastritis. The presence of PUD in the fourrisk groups did not differ. Additionally it was found that ahistory of PUD was predictive for current PUD [odds ratio (OR)3.9; 95% CI 1.1–14]. H. pylori status was not predictive.Transformation from one ulcer type to another was rare. NSAIDdose was not a risk factor, while disability was of borderlineimportance (OR 2.1; 95% CI 1–4.8). Current upper GI complaintswere bad predictors. PUD only occurred with a concomitant antralgastritis. A history of PUD, disability and antral gastritiswere the most important predictors for current PUD. When anulcer relapsed it was of the same ulcer type as had been presentearlier. This may have practical implications for prophylaxisenabling stratification by previous ulcer type. KEY WORDS: Non-steroidal anti-inflammatory drugs, Peptic ulcer disease, H. pylori, Gastritis     

NON-STEROIDAL ANTI-INFLAMMATORY DRUG USAGE AND REQUIREMENT IN ELDERLY ACUTE HOSPITAL ADMISSIONS

There is a strong feeling that despite the increasing awarenessof their adverse effects, non-steroidal anti-inflammatory drugs(NSAIDs) are not always used appropriately. To examine thisproblem amongst elderly patients who may be at particular risk,500 acute admissions to Health Care of the Elderly wards werestudied prospectively. Sixty-five patients were currently receivingNSAIDs; 56 had medical conditions possibly caused by, or aggravatedby NSAIDs. Indications for NSAIDs were often no longer apparent,and these drugs were successfully discontinued in 56; in 22no alternative therapy was required. Importantly, followingdischarge the majority of patients remained off NSAIDs. Thesedata support the need for continual review of NSAID requirementsand regular monitoring for adverse effects, particularly inthis high risk group. KEY WORDS: Audit     

GASTRO-DUODENAL DAMAGE DUE TO NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN CHILDREN

Thirteen juvenile chronic arthritis patients with abdominalsymptoms related to non-steroidal anti-inflammatory drug therapywere endoscoped before and after a 6-week course of either misoprostolor ranitidine therapy. Major presenting symptoms were generalizedabdominal pain and nausea. Symptoms did not correlate well withendoscopic findings which revealed no evidence of ulcerationand minimal erosive damage. Five patients had mild erythemaor gastritis. Bleeding lesions were confined to small numbersof petechiae. Following treatment with either misoprostol orranitidine, patients improved symptomatically without a correspondingimprovement on endoscopic and histological examination of stomachand duodenum. Both treatments were well tolerated. KEY WORDS: JCA, Non-steroidal anti-inflammatory agents, Gastroscopy, Duodenoscopy     

THE GASTRODUODENAL SAFETY AND EFFICACY OF THE FIXED COMBINATION OF DICLOFENAC AND MISOPROSTOL IN THE TREATMENT OF OSTEOARTHRITIS

A double-blind, randomized, parallel group study was conductedto compare the gastroduodenal safety and antiarthritic efficacyof a fixed combination of diclofenac 50 mg and misoprostol 200tg with that of a combination of diclofenac 50 mg and placeboin patients with osteoarthritis. Three hundred and sixty-onepatients with no significant gastroduodenal lesions were enrolledand received study medication two or three times daily for 4weeks. Post-treatment endoscopic examination of the gastroduodenalmucosa revealed ulcers in 4% of patients in the diclofenac/placebogroup compared with none in the diclofenacimisoprostol group(P=0.015). There were no clinically or statistically significantdifferences between the two treatment groups in formal assessmentsof osteoarthritis after either 2 or 4 weeks. It was concludedthat diclofenadmisoprostol was associated with significantlyless gastroduodenal damage than diclofenac, whilst being aseffec tive as diclofenac alone in the treatment of osteoarthritis. KEY WORDS: Gastroduodenal safety, Diclofenac, Misoprostol, NSAIDs, Osteoarthritis, Ulcers     

幽门螺杆菌破坏胃粘膜屏障的研究

为了解幽门螺杆菌（Ｈｐ）对胃粘膜屏障的损伤作用，对５０例Ｈｐ感染的胃炎及５０例非Ｈｐ感染胃炎者测定其胃窦粘膜的磷脂和氮基已糖值，并与病理改变相比较。结果示Ｈｐ感染组胃窦粘膜的磷脂平均值低于非Ｈｐ感染组（Ｐ＜０．０５）。Ｈｐ感染组的胃窦粘膜氨基己糖值明显低于非Ｈｐ感染组（Ｐ＜０．００５）。而Ｈｐ感染组的活动性胃炎明显高于非感染组。结果表明，Ｈｐ可通过破坏胃粘膜屏障而导致胃粘膜炎症性改变。     

THE USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN PAEDIATRIC RHEUMATIC DISEASES

The use of NSAIDs for arthritis differs in children from adultsin their indications, uses and pharmacokinetics, and fewer areavailable. Children with arthritis are assessed differently,as they complain less of pain. Salicylates, indomethacin andibuprofen are used for the fever of systemic JCA. For controlof joint symptoms, diclofenac, ibuprofen, tolmetin and naproxenare equal in their efficacy and tolerance: salicylates and indomethacinare no more effective but more toxic. Children tolerate NSAIDswell. Gastrointestinal symptoms appear to be less common thanin adults, but the evidence regarding endoscopic changes isconflicting. Renal toxicity is rare. Tolmetin can cause pseudoproteinuriaand naproxen pseudoporphyria. The liver in systemic JCA is vulnerableto drug toxicity. A therapeutic trial of an NSAID should continuefor 8 weeks. Interactions with methotrexate and carbonic anhydraseinhibitors for glaucoma complicating iridocyclitis may occur. KEY WORDS: Children, JCA, Juvenile rheumatoid arthritis, Drug therapy, Side effects     

NON-STEROIDAL ANTI-INFLAMMATORY INDUCED DIAPHRAGM DISEASE OF THE SMALL INTESTINE: COMPLEXITIES OF DIAGNOSIS AND MANAGEMENT

A 52-yr-old lady with RA on long term NSAIDs developed an iron-deficiencyanaemia and subsequently presented with subacute intestinalobstruction. After intensive investigation, a diagnosis of diaphragmdisease of the small intestine was made at laparotomy. The featuresof diaphragm disease and the difficulties with diagnosis andmanagement of the condition are discussed. KEY WORDS: Diaphragm disease, Non-steroidal anti-inflammatory drugs, Intestine, Arthritis, Diagnosis     

NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSAID) USAGE AND HYPERTENSION IN THE ELDERLY

Aims: To determine the prevalence of usage of NSAIDs and whether these drugs contribute to the high prevalence of hypertension in this age group. Method: Data obtained from participants in a cardiac screening program for the non-institutionalised elderly were submitted to a cross-sectional analysis. Results: 529 elderly ambulatory subjects were screened. Twenty eight percent of all participants (females > males) were consuming NSAIDs. A significantly higher prevalence of usage of NSAIDs was found in hypertensive females (60–64 years) and in hypertensive males (65–69 years) compared to those with a normal cardiovascular state in the same sex and age groups. Conclusions: NSAID usage may be excessive in the elderly and an association between NSAID usage and hypertension in some elderly patients is postulated although further studies are required to adequately evaluate this potential interaction.     

CHARACTERISTICS OF ULCERS OF THE SMALL BOWEL INDUCED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN THE RAT: IMPLICATIONS FOR CLINICAL PRACTICE

Small bowel ulcers were created in the rat after the oral administrationof non-steroidal anti-inflammatory drugs (NSAIDs). Of the sixNSAIDs tested, indomethacin and diclofenac alone were associatedwith such damage which did not occur in a simple dose-relatedfashion. Bacteria were observed by electron microscopy in anactive state of division in the base of the ulcers. When grownaerobically these were shown to be strains of Escherichia coliand Proteus mirabilis. Anatomically, NSAID-induced ulcers werefound throughout the length of the bowel although more abundantin the proximal half. In vivo and in vitro sensitivity to antibioticssuggested that in addition to the bacteria identified, anaerobicß-lactamase-producing organisms also have an importantrole in ulcer production in this model. This rat model of NSAID-inducedgut toxicity is discussed in relation to the human situation,particularly for patients who take NSAIDs and who have an iron-deficiencyanaemia and blood in their faeces, but no lesions in eitherthe upper or lower bowel. KEY WORDS: Small bowel, Ulcers, Bacteria, Antibiotics     

THE EFFECT OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON FAECAL FLORA AND BACTERIAL ANTIBODY LEVELS IN RHEUMATOID ARTHRITIS

The faecal flora and bacterial antibody levels of 22 patientswith active rheumatoid arthritis (RA) were compared with thoseof 26 patients with osteoarthritis (OA) undergoing comparabletreatment with non-steroidal anti-inflammatory drugs (NSAIDs),and a further 22 patients with OA who were not receiving NSAIDs.Faecal counts of Clostridium perfringens were significantlyhigher in the RA patient group and in those OA patients receivingNSAIDs, compared with those OA patients not taking NSAIDs (P=0.032,P=0.0004 respectively). Total aerobic and anaerobic counts were,however, identical in all three groups. Levels of serum IgA antibody to the alpha toxin of Cl. perfringenswere higher in the RA group and in the OA group taking NSAIDsthan in OA patients not taking NSAIDs (P=0.011, P=0.055). SerumIgG antibody to alpha toxin was higher in the RA group thanin OA patients both on and off NSAIDs (P=0.019, P=0.0072) andalso a group of normal controls (P=0.032). These results suggest that the increased faecal counts of Cl.perfringens together with the associated increased antibodylevels seen in this and previous studies are more likely toresult from NSAID therapy used to treat the disease than froma disease specific changk in bowel flora. KEY WORDS: Rheumatoid arthritis, Cl. perfringens, NSAIDs     

THE COMPARATIVE ANALGESIC EFFICACY OF TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION AND A NON-STEROIDAL ANTI-INFLAMMATORY DRUG FOR PAINFUL OSTEOARTHRITIS

Thirty-six non-hospitalized subjects with chronic pain fromOA of the knee participated in an evaluation of transcutaneouselectrical nerve stimulation (TENS) and naproxen, an NSAID.All pre-experiment treatment was withdrawn. Each subject experiencedin some order three 3-week treatment phases: NSAID plus placeboTENS; TENS plus placebo drug; and double placebo. A broad rangeof pain measures was used, including daily diary ratings, andfourtimes-per-day ratings entered into a small electronic datalogger (the PIPER) worn by the subject. A substantial placeboresponse occurred across all conditions, which may have maskedtreatment differences. Broad comparisons across subjects, combiningthe four main measures of pain, found no significant differencesamong the three experimental treatments. Analysis of diary andPIPER data for individuals suggested that, in a small minorityof subjects, the NSAID plus placebo TENS combination may bemore effective than double placebo. The PIPER ratings seemedto tap aspects of the pain experience different from those capturedby conventional measures, suggesting the value of very frequentpain assessments, such as those entered by a subject into thePIPER, in the study of chronic pain. KEY WORDS: Osteoarthritis, Chronic pain, Transcutaneous electrical nerve stimulation, Non-steroidal anti-inflammatory drug, Aged, Clinical trial     

A TWO-YEAR, PLACEBO-CONTROLLED TRIAL OF NON-STEROIDAL ANTI-INFLAMMATORY THERAPY IN OSTEOARTHRITIS OF THE KNEE JOINT

Eighty-nine patients with established OA of the knee joint,already on regular NSAIDs for joint pain, were randomly allocatedto receive lOOmg/day of slow release diclofenac (45 patients)or matching placebo (44), in place of their NS AID, for 2 years. Thirty-eight patients withdrew or dropped out of the study.The major causes for withdrawal were lack of efficacy (threeactive, 12 placebo, P<0.01) or side effects (six active,five placebo), and most withdrawals occurred within the first6 months. Long term follow up of these patients was not possible. Fifty-one patients completed the study (31 active, 20 placebo),35 of whom reported that they were the same or better at theend of the 2-year period than at the beginning. Most of therecorded clinical parameters showed little or no change over2 years in these 51 subjects, and in 70% there was no detectablechange in the radiographs. We conclude that long term placebo-controlled trials are bothfeasible and ethical in knee OA, but that conventional clinicaland radiographic techniques detect very little change in jointstructure or function over a 2-year time period. This may reflectthe insensitivity of the methods used to assess progressionrather than absence of change. The fact that 20 of 44 patientschanged from an NSAID to placebo completed the 2-year studywithout any symptomatic penalty indicates that not all patientsentered needed or responded to NSAIDs. KEY WORDS: Osteoarthritis, Knee joint, NSAID, Controlled trial, Radiology      

EFFECT OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON NEUTROPHIL CHEMOTAXIS--AN IN VITRO AND IN VIVO STUDY

We have studied the effects of the two non-steroidal anti-inflammatorydrugs (NSAIDs), nabumetone and indomethacin, on neutrophil chemotaxisin vitro and in vivo. When used in therapeutic concentrationsin vitro, neither agent had any effect on the chemotactic responseof neutrophils isolated from healthy volunteers. This was truefor the three chemotactic agents studied: FMLP, zymosan activatedserum and purulent sputum. Nabumetone and indomethacin decreasedneutrophil chemotaxis over a period of 2 weeks in 12 normalsubjects in vivo. The average chemotactic response to 10^–8mol/1 FMLP for all 12 during the control period was 42.1 ±6.1 cells per high power field and this fell to 26.1 ±4.9 (P>0.025) after 7 days and to 15.6 ± 2.5 (P>0.005)after 14 days. The results were similar for both drugs analysedindependently. The results suggest that NSAIDs have no effect on the chemotacticresponse of mature cells in vitro, but suppress chemotaxis progressivelywhen given in vivo. This may be explained by an effect of NSAIDson maturing cells prior to release into the circulation KEY WORDS: Polymorphonuclear cells, Chemotaxis, Nabumetone, Indomethacin     

EVENING PRIMROSE OIL IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SIDE-EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Forty patients with rheumatoid arthritis and upper gastrointestinallesions due to non-steroidal anti-inflammatory drugs entereda prospective 6-month double-blind placebo controlled studyof dietary supplementation with gamma-linolenic acid 540 mg/day.Nineteen patients received active therapy (as evening primroseoil 6g/day) and 21 received placebo (olive oil 6g/day). No patientstopped non-steroidal anti-inflammatory therapy but three patientsin each group reduced their dose. Other results showed a significantreduction in morning stiffness with gamma-linolenic acid at3 months and reduction in pain and articular index at 6 monthswith olive oil. Whilst gamma-linolenic acid may produce mildimprovement in rheumatoid arthritis, olive oil may itself havehitherto unrecognized benefits. KEY WORDS: Rheumatoid arthritis, Inflammation, Evening primrose oil, NSAIDs, Peptic ulcer, Gastritis     

TWELVE CASES OF ACUTE ESOPHAGEAL MUCOSAL LESION

Background and Aims: The incidence of erosive esophagitis in emergent endoscopy for upper gastrointestinal bleeding is not rare but the clinical and endoscopic findings have not been fully investigated. The aim of the present study was to clarify features of acute esophagitis cases showing acute onset and severe endoscopic findings. Methods: We defined severe esophagitis that endoscopically showed circumferential diffuse mucosal lesion involving at least the entire lower third of the esophagus as acute esophageal mucosal lesion and investigated the clinical and endoscopic characteristics. Results: We experienced six cases of black or dark esophagitis and six cases of non‐black esophagitis. Both groups showed common clinical features. Patients were predominantly males older than middle age. The presenting symptoms were upper gastrointestinal bleeding such as coffee‐ground‐like vomit, hematemesis or tarry stool. Seven cases had a history of taking non‐steroidal anti‐inflammatory drugs. Endoscopically, both types of case showed diffuse circumferential erosion in the lower esophagus, which continuously extended, and worsened towards the esophagogastric junction. All had esophageal sliding hernia and five cases had duodenal mucosal lesion. All cases rapidly improved with a proton pump inhibitor except one case. Conclusion: Black and non‐black esophagitis was considered to belong to the same disease entity, acute esophageal mucosal lesion, which should be recognized as a differential diagnosis on emergency endoscopy for upper gastrointestinal bleeding.     

EFFECT OF A NON-STEROIDAL ANTI-INFLAMMATORY DRUG, NAPROXEN, ON FAECAL MICROBIAL FLORA

Faecal Clostridium perfringens counts have been observed tobe elevated in RA patients. The use of NSAIDs has been suggestedas being responsible for this increase. To clarify the potentialof NSAIDs to change faecal flora, 10 male volunteers were givennaproxen 500 mg twice daily for 2 weeks in a randomized, placebo-controlledand double-blind study, and 10 other volunteers were given aplacebo in tablets of identical appearance. Stool samples were collected and subjected to direct stool samplegas—liquid chromatography of bacterial fatty acids. Themethod has proved to be practical and sensitive in detectingoverall changes in faecal flora. The samples were also culturedfor Cl. perfringens. No significant change of faecal flora wasobserved by either method. The results show that naproxen given in doses and over a periodin excess of the levels reported to increase intestinal permeability,does not change intestinal flora. KEY WORDS: Clostridium perfringens, Faecal flora, Fatty acids, Gas chromatography, Naproxen, Non-steroidal anti-inflammatory drugs     

大鼠急性坏死性胰腺炎合并肾损害及前列环素的保护作用

制作大鼠急性坏死性胰腺炎（ＡＮＰ）模型，观察肾组织学、肾功能的变化及前列环素（ＰＧＩ２）的影响。结果发现，ＡＮＰ模型制作后４８小时，肾组织出现严重的损害，肾功能明显下降，肾静脉血６－酮－ｐＧＦ１α／ＴＸＢ２比值、肾血流量及肾组织灌流量均明显下降。给予外源性ｐＧＩ２能明显增加６－酮－ｐＧＦ１α／ＶＴＸＢ２比值，增加肾血流量及肾组织灌流量，减轻肾组织学改变，改善肾功能。