Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.     

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.

OBJECTIVES: To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with, and after cessation of, non-steroidal anti-inflammatory drugs. DESIGN: Cohort study with a prospectively constructed, population based, record linkage database containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses. SETTING: The population of Tayside, Scotland. SUBJECTS: 52,293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73,792 subjects who did not receive one during the same period (controls). MAIN OUTCOME MEASURES: Admission to hospital for upper gastrointestinal bleeding and perforation, and admission for other upper gastrointestinal diagnoses. RESULTS: About 2% of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4% of controls. The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure. The results were similar for admissions for all upper gastrointestinal events. CONCLUSION: This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure. There seems to be carryover toxicity after the end of prescribing. These findings have implications for the management of patients requiring non-steroidal anti-inflammatory drugs.     

The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage

NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.     

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.     

Parathion Poisoning—A New Antidote!

Two thousand five hundred forty-five cases of upper gastrointestinal tract hemorrhage were studied especially with a view to determining the indications for urgent surgical treatment.Decisions as to whether and when to operate were as follows:Immediate operation for patients over 50 years with a good history of ulcer and a severe initial bleed.Operation after the first repetition of bleeding in patients (1) over 50 with a good history and a mild initial bleed, (2) over 50 with inconclusive history but severe initial bleed, (3) under 50 with a good history and a severe initial bleed.In all other cases, operation was used only if conservative treatment failed.Absolute indications for operation were (a) association with perforation, (b) association with stenosis, (c) persistence of severe ulcer pain after hemorrhage, (d) continuous bleeding.Since operation is to be avoided if possible in cases of esophagitis, erosive gastritis and small acute or subacute ulcers, emergency gastroscopy has valuable uses.Where operation is deemed necessary and no obvious lesion found at laparotomy, blind gastrectomy^* appears to be the most satisfactory procedure.The mortality rate associated with upper gastrointestinal tract bleeding in patients less than 60 years of age was low (2.5 per cent). Even in cases in which operation was required, it was 6.2 per cent. Over 60 years the mortality rises steeply with increasing age, and in cases of operation the rise is even steeper.By using the methods of selection the overall mortality rate was appreciably reduced.     

Balancing the gastrointestinal benefits and risks of nonselective NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of medications to treat pain and inflammation. However, gastrointestinal complications associated with NSAIDs are prevalent, largely due to the frequent use of these agents. Adverse events associated with NSAIDs include minor side effects, such as dyspepsia, as well as serious complications, such as bleeding and perforation. Although the probability that any given individual user of an NSAID will suffer a serious gastrointestinal complication is fairly low, widespread patient exposure can translate into a major national health burden. The increasing use of aspirin in the prevention of cardiovascular events and the availability of select over-the-counter NSAIDs represent additional challenges to clinicians in their efforts to make the most appropriate therapeutic decisions while minimizing the potential gastrointestinal risks associated with the use of these agents. Side effects such as dyspepsia do not provide adequate warning of gastrointestinal complications, because most complications occur without the presence of antecedent symptoms. Therefore, accurate risk assessment and the management of controllable risk factors are crucial to the safe administration of NSAIDs. This review focuses on the gastrointestinal effects of aspirin, acetaminophen, and other nonselective NSAIDs, and discusses those factors that are associated with increased risk for adverse gastrointestinal events in certain individuals.     

Role of nitric oxide in the gastrointestinal tract

Worldwide osteoarthritis (OA) affects more than 9.6% of men and 18% of women older that 60 years. Treatment for OA often requires chronic use of selective or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which have been associated with gastrointestinal and cardiovascular complications. An increased risk for upper gastrointestinal bleeding with NSAIDs alone and when combined with low-dose aspirin has been described in numerous studies. Although cyclo-oxygenase-2 inhibitors have been shown to carry a lower risk for gastrointestinal injury than nonselective NSAIDs, research continues to identify new treatments that not only are effective but also provide an improved benefit/risk profile, including better gastrointestinal tolerability. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract. In preclinical studies NO was shown to help maintain gastric mucosal integrity, to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Recent studies have shown that cyclo-oxygenase inhibiting NO-donating drugs (CINODs), in which a NO molecule is chemically linked to an NSAID, are effective anti-inflammatory agents and may result in less gastrointestinal damage than is associated with NSAID use. Therefore, these agents provide a potential therapeutic option for patients with arthritis who require long-term NSAID therapy.     

The Interplay Between NSAIDs and Candida albicans on the Gastrointestinal Tract of Guinea Pigs

Recent studies suggest that Candida albicans colonization is associated with several gastrointestinal inflammatory disorders and is also responsible for the delay in ulcer healing. No data are reported about the effects of C. albicans on the nonsteroidal anti-inflammatory drugs (NSAIDs)-induced necroinflammatory lesions. On the other hand, beneficial effects of NSAIDs regarding the colonization potential with C. albicans have been reported. Our aim was to investigate whether the association between NSAIDs and C. albicans could potentially induce necroinflammatory lesions in the guinea pigs gastric and enteral mucosa. Three interventional groups of 11 guinea pigs each were investigated after 5 days of receiving indomethacin, C. albicans or the association of both. C. albicans and necroinflammatory lesions were graded based on histological examinations. Statistical analysis used Mann–Whitney nonparametric test. NSAIDs did not significantly decrease C. albicans colonization grades on gastrointestinal mucosa. Administration of indomethacin subsequent to C. albicans determined significantly more severe necroinflammatory lesions compared to group that only received C. albicans. The association of NSAIDs and C. albicans did not cause significantly more severe degenerative or inflammatory lesions compared to the administration of only NSAIDs in this experimental model. Associations between NSAIDs and C. albicans caused significantly more severe necroinflammatory injuries than the lesions produced by C. albicans, without enhancing the mucosal injury or inflammation caused by NSAIDs.     

Stigmata of recent haemorrhage in diagnosis and prognosis of upper gastrointestinal bleeding

In 277 consecutive episodes of suspected upper gastrointestinal bleeding, lesions bearing stigmata of recent haemorrhage (stigmata) were found by endoscopy in 110 (47%) out of 233 patients who were judged to have bled; 78 (33%) had lesions without stigmata, and in 45 (19%) no lesion was seen. Results in 176 entirely unselected admissions for upper gastrointestinal bleeding were similar.Forty-eight chronic duodenal and 41 chronic gastric ulcers were identified by endoscopy. Stigmata were found in 27 (56%) and 33 (80%) of these cases respectively. Sixteen patients had multiple lesions, and in 12 (75%) the presence of stigmata permitted diagnosis of the source of the haemorrhage. Stigmata were more likely to be seen in cases of duodenal ulcer, Mallory-Weiss lesions, and oesophageal varices when endoscopy was performed within 12 hours of bleeding, but were as common in cases of gastric ulcer after longer intervals.In the absence of stigmata one out of 21 patients with duodenal ulcer had further haemorrhage and one other needed emergency surgery; no patient with gastric ulcer had further haemorrhage or needed emergency surgery. In contrast, when stigmata were present 15 of the 27 patients with duodenal ulcer (56%) had further haemorrhage and 17 (63%) needed emergency surgery; of the 33 patients with gastric ulcer, 10 (30%) had further haemorrhage and 15 (45%) required emergency surgery. Superficial mucosal lesions may have been the source of haemorrhage when an ulcer unmarked by stigmata was seen at endoscopy. Stigmata were superior to any other single factor or combination of factors in predicting rebleeding and the need for emergency surgery.     

Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam

Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.     

The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents

Most anti-inflammatory drugs have been associated with an increased risk of serious upper gastrointestinal complications. Epidemiological studies have estimated the magnitude of the risk for specific anti-inflammatory drugs. The risk of upper gastrointestinal tract bleeding or perforation increases around twofold with use of oral steroids or low dose aspirin, and increases around fourfold with use of nonaspirin nonsteroidal anti-inflammatory drugs. Acetaminophen at daily doses of 2000 mg and higher has also been associated with an increased risk. Overall, the risk is dose dependent and is greater with more than one anti-inflammatory drug taken simultaneously. Hence, whenever possible, anti-inflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of serious upper gastrointestinal complications.     

Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study

Background

Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding.

Methods

We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day).

Results

581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants.

Conclusions

The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.     

Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.     

Upper gastrointestinal haemorrhage in patients over 80 years-old

Objectives

To evaluate the patient characteristics, outcome, and prognosis of upper gastrointestinal haemorrhage in the elderly.

Material and methods

A prospective study was conducted on 103 patients aged 80 years and over, admitted to a Gastrointestinal Bleeding Unit after an episode of upper gastrointestinal bleeding. We analysed the personal history, the characteristics of the bleeding event, and whether an urgent diagnostic or therapeutic endoscopy was performed, in order to identify clinical data and endoscopic findings that may have an influence on the outcome of the haemorrhage.

Results

The major cause of the haemorrhage was peptic ulcer in 65.1%, and 60.2% of patients were on chronic treatment with non-steroidal anti-inflammatory drugs. An urgent diagnostic endoscopy was performed in all of them, identifying the source of bleeding in 94.2%, and treatment was carried out on 28.2%. The likelihood of rebleeding was 8%, and 4.9% of patients underwent emergency surgery, with an overall mortality rate of 5.8%.

Conclusions

The performance of urgent endoscopy and the application of endoscopic haemostasis are safe and effective in stopping upper gastrointestinal bleeding in the elderly. This has significantly reduced the need for emergency surgery, improving the survival of the bleeding elderly patient and preventing recurrent bleeding.     

One hundred years ago: Presents from patient

ObjectiveTo compare rates of upper gastrointestinal haemorrhage among elderly patients given selective cyclo-oxygenase-2 (COX 2) inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs).DesignObservational cohort study.SettingAdministrative data from Ontario, Canada, used from 17 April 2000 to 31 March 2001 to identify population based, NSAID-naive cohorts of patients.PatientsSubjects aged ⩾66 years who started taking non-selective NSAIDs (n=5391), diclofenac plus misoprostol (n=5087), rofecoxib (n=14 583), or celecoxib (n=18 908) and a randomly selected control cohort not exposed to NSAIDs (n=100 000).ResultsRelative to controls, the multivariate model revealed an increased short term risk of upper gastrointestinal haemorrhage for users of non-selective NSAIDs (adjusted rate ratio 4.0 (95% confidence intervals 2.3 to 6.9)), diclofenac plus misoprostol (3.0 (1.7 to 5.6)), and rofecoxib (1.9 (1.3 to 2.8)) but not celecoxib (1.0 (0.7 to 1.6)). Relative to celecoxib, significantly higher risks of upper gastrointestinal haemorrhage were observed for non-selective NSAIDs (4.4 (2.3 to 8.5)), diclofenac plus misoprostol (3.2 (1.6 to 6.5)), and rofecoxib (1.9 (1.2 to 2.8)). Relative to rofecoxib, non-selective NSAID users were at significantly higher risk of upper gastrointestinal haemorrhage (1.9 (1.0 to 3.5)).ConclusionsThis population based observational study found a lower short term risk of upper gastrointestinal haemorrhage for selective COX-2 inhibitors compared with non-selective NSAIDs.

What is already known on this topic

Long term NSAID use is associated with the development of peptic and duodenal ulcersSelective COX 2 inhibitors are claimed to cause fewer gastrointestinal problems than conventional, non-selective NSAIDsIt is unclear to what degree COX 2 inhibitors increase gastrointestinal risk relative to not using NSAIDs, and the relative gastrointestinal safety of the different COX 2 inhibitors is uncertain

What this study adds

The risk of upper gastrointestinal haemorrhage with the COX 2 inhibitors rofecoxib and celecoxib was significantly lower than with conventional NSAIDs, but the risk with rofecoxib was significantly higher than that with celecoxibThe risk of gastrointestinal haemorrhage with celecoxib was similar to that in controls not using NSAIDs     

Gastrointestinal complications of renal transplantation. 1. The upper gastrointestinal tract.

In 95 consecutive cases of cavaderic renal transplantation followed up for 1 to 83 months (mean 23.1 months) 17 complications developed in the upper gastrointestinal tract of 15 patients; these included duodenal ulcer in 12 and gastric ulcer, esophagitis, hemorrhagic gastritis, small-bowel obstruction and small-bowel perforation in 1 each. The occurrence of a complication was not related to the patient''s age, sex, blood group or use of cigarettes or alcohol, the duration of hemodialysis before transplantation, the tissue match or the number of infusions of immunosuppressive medication. One patient died of the complication. The peptic ulcers that developed after transplantation were successfully managed conservatively in 69% of cases. Since surgical treatment in patients whose immune response has been suppressed is associated with an increased frequency of complications such as disruption of suture lines, it is preferable to reserve it for those in whom complications develop that are unresponsive to conservative measures.     

Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study

ObjectivesTo determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding.DesignRetrospective cohort study from population based databases.SettingOntario, Canada.Participants317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended.ResultsOverall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85).ConclusionsAfter age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding.

What is already known on this topic

A case-control study found that the risk of upper gastrointestinal bleeding increases with intake of antidepressants that extensively inhibit serotonin reuptakeThe study''s validity was questioned because antidepressants were not specifically classified by the extent that they inhibit serotonin reuptake, and absolute differences in bleeding rates between antidepressants were unavailable

What this study adds

The risk of upper gastrointestinal bleeding in elderly and depressed patients increases with antidepressants having the greatest extent of inhibition of serotonin reuptakeThis increased risk of bleeding is clinically important for patients with a high risk of bleeding—namely, octogenarians and those with previous upper gastrointestinal bleedingThe extent that an antidepressant inhibits serotonin reuptake should be considered when drugs are required for depression in high risk patients     

Host-guest complexation of oxicam NSAIDs with beta-cyclodextrin

Spectroscopic and molecular modeling techniques have been employed to study the interaction of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs) with a polysaccharide such as beta-cyclodextrin (beta-cd). beta-cd is a good drug delivery system and is known to reduce harmful side effects of these drugs in the gastrointestinal tract and to increase their clinical efficacy. A detailed understanding of such host-guest interaction helps in designing a better drug delivery system coupled with increased therapeutic potential. However, there exists a controversy as to which prototropic form of piroxicam, a drug belonging to the oxicam group, becomes encapsulated in the host and also the stoichiometry of binding. In this study, we have revisited that controversy using steady state fluorescence, absorption, fluorescence anisotropy measurements, and molecular modeling techniques. In addition, we have for the first time studied the interactions of two other oxicam drugs, viz. tenoxicam and meloxicam, with beta-cd in aqueous solution. In all cases the neutral forms of these drugs were incorporated in the beta-cd cavity with a binding stoichiometry of 1:1 host : guest. The values of the binding constants for piroxicam, meloxicam, and tenoxicam with beta-cyclodextrin are 134 +/- 21, 114 +/- 15, and 115 +/- 13 M(-1), respectively. Molecular modeling studies show that the minimum energy configuration gives favorable interaction energy between the host and the guest in the complex with 1:1 stoichiometry when the conjugated rings of the drugs are inside the hydrophobic bucket-like cavity of beta-cd and the third ring is exposed to the solvent.     

Therapy and prevention of gastric ulcer.

After establishing the benign nature of a gastric ulcer, the treatment is primarily medical. This medical therapy is aimed to alleviate symptoms, to heal the ulcer and to prevent relapses. Based on the history of non-steroidal anti-inflammatory drugs (NSAIDs) and the Helicobacter pylori-status, gastric ulcer patients can be divided into four categories (1) H. pylori positive plus NSAID-use, (2) H. pylori positive without NSAID use, (3) NSAID use with negative H. pylori-status, (4) Negative H. pylori-status and no NSAID use. Patients taking NSAIDs should stop this therapy if possible. Patients with gastric H. pylori infection should be treated by a regimen of a proton pump inhibitor with at least two appropriate antibiotics. This treatment will result in early alleviation of symptoms, rapid healing of the ulcer and prophylaxis of ulcer relapse. In patients with gastric ulcer who cannot stop NSAIDs, maintenance therapy with prostaglandins or potent antisecretory drugs should be considered. The few patients with gastric ulcer who do not take NSAIDs and do not have gastric H. pylori infection should be treated by antisecretory drugs, and they should be carefully followed endoscopically to exclude malignant (carcinoma, lymphoma) or non-peptic (Crohn''s disease) disease. All patients with gastric ulcer should be re-endoscoped to verify complete ulcer healing. Surgery may be considered in gastric ulcer patients with complications, in those with severe dysplasia of the gastric mucosa, and in those who are not able or willing to take the medication.