Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials

Risedronate sodium is a pyridinyl bisphosphonate effective for treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis. Some bisphosphonates have been associated with upper gastrointestinal (GI) tract adverse effects. The objective of this study was to determine the frequency of upper GI tract adverse events associated with risedronate, especially among high-risk patients. The GI tract adverse events reported during 9 multicenter, randomized, double-blind, placebo-controlled studies of risedronate conducted from November 1993 to April 1998 were pooled and evaluated. The evaluation included 10,068 men and women who received placebo (n=5048) or 5 mg of risedronate sodium (n=5020) for up to 3 years (intent-to-treat population). Studies incorporated a comprehensive, prospective evaluation of GI tract adverse events. Adverse event information was collected every 3 months. The treatment groups were similar with respect to baseline GI tract disease and use of concomitant treatments during the studies. At study entry, 61.0% of patients had a history of GI tract disease and 38.7% had active GI tract disease; 20.5% used antisecretory drugs during the studies. Sixty-three percent used aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the studies. Upper GI tract adverse events were reported by 29.6% of patients in the placebo group compared with 29.8% in the risedronate group. The risk of experiencing such an event in the risedronate group was 1.01 (95% confidence interval, 0.94-1.09) relative to the placebo group (P=.77). The rate of upper GI tract adverse events per 100 patient-years was 19.2 in the placebo group compared with 20.0 in the risedronate group (P=.30). Risedronate-treated patients with active heartburn, esophagitis, other esophageal disorders, or peptic ulcer disease at study entry did not experience worsening of their underlying conditions or an increased frequency of upper GI tract adverse events overall. Concomitant use of NSAIDs, requirement for gastric antisecretory drugs, or the presence of active GI tract disease did not result in a higher frequency of upper GI tract adverse events in the risedronate-treated patients compared with controls. Endoscopy, performed in 349 patients, demonstrated no statistically significant differences across treatment groups. The results of this extensive evaluation indicate that daily treatment with 5 mg of risedronate sodium is not associated with an increased frequency of adverse GI tract effects, even among patients at high risk for these events.     

Epidemiology and role of nonsteroidal antiinflammatory drugs in causing gastrointestinal bleeding

This article outlines the epidemiology and role of nonsteroidal antiinflammatory drugs (NSAIDs) in causing gastrointestinal (GI) bleeding. The morbidity and mortality associated with NSAID-induced GI bleeding are discussed, and the mechanisms of NSAID-related GI injury, the potency of various NSAIDs, new NSAIDs associated with a decrease in GI pathology, dual-acting antiinflammatory drugs, hydrogen sulfide-releasing NSAIDs, lipoxygenase/cyclooxygenase, phospholipid NSAIDs, and the comprehensive effects of NSAIDs on the GI tract are described.     

Gastrointestinal safety and tolerability of oral non-aspirin over-the-counter analgesics

Over-the-counter (OTC) analgesics are routinely used worldwide for self-management of various painful conditions. Despite this, there has been little in-depth review of the safety of non-aspirin analgesics at OTC doses. This paper reviews the available literature on the gastrointestinal (GI) and hepatic safety of non-aspirin OTC analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, ketoprofen, diclofenac, and naproxen) and acetaminophen; safety in overdose is also reviewed. Each non-aspirin OTC analgesic has a distinct adverse event (AE) profile, with GI AE rates for OTC dosing in one study ranging from 37% for diclofenac to 7.2% for ibuprofen and 7.6% for acetaminophen; GI effects accounted for 75% of total AEs in the study. Across all studies reviewed here, the risk of serious GI toxicity, including upper GI bleeding and peptic ulcers, was low at OTC doses. By contrast, while both NSAIDs and acetaminophen may be associated with hepatotoxicity and acute liver failure (ALF), the risks associated with acetaminophen are somewhat higher and better documented. Reports of NSAID-associated hepatotoxicity rarely make distinctions by dose, making the risk at OTC doses difficult to assess. Liver injury due to acetaminophen, however, can occur at doses < 4000 mg. Case reports of NSAID-associated overdose are rare, while acetaminophen-containing drugs are a leading cause of overdose and are implicated in up to 97% of ALFs leading to transplant involving overdose. OTC analgesics are effective for self-management of pain; however, they are associated with a low but important rate of GI and hepatic events, as well as a risk of intentional and non-intentional overdose. Given the widespread use of this class of drugs, it is important for healthcare professionals to be mindful of their patients’ use of OTC analgesics.     

Non-steroidal anti-inflammatory drug-induced enteropathy

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs in the world. NSAID-induced lower gastrointestinal (GI) complications are increasing while upper GI complications are decreasing. Lower GI events accounted for 40% of all serious GI events in patients on NSAIDs. Capsule endoscopy and device assisted enteroscopy are available for detection of small intestinal lesions. Capsule endoscopy studies have demonstrated that NSAIDs use in healthy volunteers raised the incidence (55% to 75%) of intestinal damage. It appears that selective cyclooxygenase-2 inhibitors (coxibs) improved upper and lower GI safety based on results of clinical trials. Selective coxibs are still capable of triggering GI adverse events and cardiovascular toxicity issues were the main focus of concerns. Unfortunately, definite strategies are not available to prevent or heal NSAID-induced intestinal injuries. Thus, there is still a strong clinical need for effective drugs with improved safety profiles than the existing NSAIDs.     

Gastrointestinal safety and tolerability of nonselective nonsteroidal anti-inflammatory agents and cyclooxygenase-2-selective inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used of all drugs and are the most common medications used by persons aged 65 years or more. NSAIDs have a number of side effects, of which the most prevalent and serious is gastrointestinal (GI) toxicity. GI side effects of NSAIDs range from dyspepsia and gastroduodenal ulcers to serious, potentially fatal GI complications including bleeding and perforation. Serious GI complications often lack warning signs; knowledge of risk factors for NSAID-related gastropathy can identify patients at high risk, allowing for initiation of the appropriate therapeutic intervention. Risk factors include advanced age, NSAID dose, prior GI complications, infection with Helicobacter pylori, and use of corticosteroids and anticoagulants. There are few well-established strategies to prevent GI complications in NSAID users. Risk assessment and cotherapy with acid suppressors (H2-receptor antagonists and proton pump inhibitors) or prostaglandin replacement (misoprostol) and H pylori eradication are beneficial. Cyclooxygenase-1 (COX-1) is a key enzyme in gastroprotective mucosal defenses, and the best way to prevent GI toxicity is to avoid drugs that inhibit COX-1. Clinical studies of the COX-2-selective inhibitors rofecoxib and celecoxib have demonstrated efficacy equivalent to nonselective NSAIDs with lower rates of GI side effects (for example, incidence of endoscopic ulcers equivalent to placebo). Selective COX-2 inhibitors (coxibs) provide effective treatment of pain and inflammation while reducing risk of gastropathy.     

The present state and problem of gastric ulcer caused by low-dose aspirin

Upper gastrointestinal (GI) injuries induced by non-steroidal anti-inflammatory drugs (NSAID) and low-dose aspirin (LDA) have been increasing, because the number of patients who need to use NSAID, LDA, other anti-platelet drugs and anti-coagulants have been increasing. The aging is one of the most important risk factors of upper GI injuries induced by LDA, such as gastric ulcer. Since atypical symptoms often lead to a delay in diagnosis and treatment in the elderly patients, endoscopic examination should be considered especially in the elderly patients to detect upper GI lesions before using LDA.     

Prospective evaluation of the impact of amoxicillin, clarithromycin and their combination on human gastrointestinal colonization by Candida species

BACKGROUND: Amoxicillin and clarithromycin have been used extensively for the eradication of Helicobacter pylori. However, no study has examined the impact of their combination on the Candida albicans concentration of the gastrointestinal (GI) tract. This is the first study examining and comparing directly the effect of amoxicillin, clarithromycin and their combination on the C. albicans concentration of the human GI tract. METHODS: Thirty-three adult patients (11 in each antibiotic group) were studied prospectively. Quantitative stool cultures for Candida were conducted at the beginning, the end and 1 week after the discontinuation of antibiotic treatment. RESULTS: All three regimens increased the GI colonization in patients by Candida. The combination of amoxicillin with clarithromycin caused the highest increase; however, this was not statistically significant. CONCLUSION: Amoxicillin and clarithromycin used either alone or in combination cause a small to moderate increase in GI colonization by Candida. Hence, these drugs could be safely used in patients at risk for candidiasis originating from the GI tract.     

Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding

The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. However, a drug-drug interaction with warfarin was evident only for co-trimoxazole and fluconazole.     

Repetitive doses of activated charcoal in the treatment of poisoning

Activated charcoal has found a renewed role in the management of overdosed patients. Routinely administered to reduce the gastrointestinal (GI) absorption of many drugs, growing evidence indicates that repeated doses of charcoal also may enhance drug elimination. Some drugs are excreted into the bile or gastric fluids (phencyclidine, digoxin) and are reabsorbed. Other drugs (theophylline, phenobarbital) can diffuse from the plasma into the lumen of the GI tract. Activated charcoal is administered at regular intervals to sequester these toxins in the GI tract, eventually causing their excretion in feces. This article reviews the evidence for the safety and efficacy of repetitive charcoal therapy. While supportive management remains the mainstay of therapy in poisoned patients, activated charcoal is inexpensive, effective, simple to administer, and may obviate the need for more invasive methods of toxin removal.     

Prevalence and incidence of NSAID-induced gastrointestinal ulcers and bleeding

Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAID) have been accepted as major causes of upper gastrointestinal (GI) ulcers and bleeding. As patients with Helicobacter pylori infection have decreased, upper GI disorders related to NSAID have been relatively increasing. Among patients taking low-dose aspirin, the prevalence of upper GI ulcers is 10-40% and aspirin increases the risk of upper GI bleeding up to 2-fold. Among patients taking nonaspirin NSAID, the prevalence of upper GI ulcers is around 20% and nonaspirin NSAID increases the risk of upper GI bleeding up to 4- to 6-fold. Since the prevalence of GI disorders related to NSAID is very high, endoscopic examination might be considered to monitor GI lesions for patients taking NSAID.     

Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial

Bowel obstruction may be an inoperable complication in patients with end-stage cancer. Scopolamine butylbromide (SB) and octreotide (OCT) have been successfully used with the aim of reducing gastrointestinal (GI) secretions to avoid placement of a nasogastric tube (NGT); however, there have been no comparative studies concerning the efficacy of these drugs. Furthermore, there is little information about the role played by parenteral hydration in symptom control of these patients. In a prospective trial that involved all 17 inoperable bowel-obstructed patients presenting to our services with a decompressive NGT, patients were randomized to OCT 0.3 mg/day or SB 60 mg/day for 3 days through a continuous subcutaneous infusion. Clinical data, survival time, and the time interval from the first diagnosis of cancer to the onset of inoperable bowel obstruction were noted. The intensity of pain, nausea, dry mouth, thirst, dyspnea, feeling of abdominal distension, and drowsiness were assessed by means of a verbal scale before starting treatment with the drugs under study (T0) and then daily for 3 days (T1, T2, T3). Moreover, daily information was collected regarding the quantity of GI secretions through the NGT, the oral intake of fluids, the quantity of parenteral hydration, and the analgesic therapy used. The NGT could be removed in all 10 home care and in 3 hospitalized patients without changing the dosage of the drugs. OCT significantly reduced the amount of GI secretions at T2 (P = 0.016) and T3 (P = 0.020). Compared to the home care patients, the hospitalized patients received significantly more parenteral hydration (P = 0.0005) and drank more fluids (P = 0.025). There was no difference in the daily thirst and dry mouth intensity in relation to the amount of parenteral hydration or the treatment provided (OCT or SB). Independent of antisecretory treatment, the patients receiving less parenteral hydration presented significantly more nausea (T0 P = 0.002; T1 P = 0.001; T2 P = 0.003; T3 P = 0.001) and drowsiness at T3 (P < 0.5). Pain relief was obtained in all 17 patients and only two patients required an increase in morphine dose at T1. All patients with inoperable malignant bowel obstruction should undergo treatment with antisecretory drugs so as to evaluate the possibility of removing the NGT. When a more rapid reduction in GI secretions is desired, OCT should be considered as the first choice drug. Parenteral hydration over 500 ml/day may reduce nausea and drowsiness.     

Risk factors and comorbidities for NSAID associated ulcer

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to increase the risk of upper gastrointestinal tract bleeding. To reduce the morbidity associated with NSAID, it will be necessary to establish specific estimates individual drugs and different risk profile. Advanced age has been identified as one of the primary risk factors for adverse GI events in NSAID users. This may be due to the increased use of these drugs by the elderly population or to pathophysiological mechanisms such as age-related changes in drug pharmacokinetics or reductions in gastroduodenal defensive mechanisms. Many studies have also identified the following risk factor: sexuality; history of previous GI problems; higher NSAID doses; concomitant anticoagulant use. Corticosteroids, bisphosphonates and selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeding. The combined use of these drug and NSAID strongly increases the risk of gastrointestinal bleeding. Adverse GI events in NSAID users can be affected by the following comorbidities: rheumatoid arthritis; liver cirrhosis; renal failure; diabetes; arteriosclerosis.     

Predicting the risk for gastrointestinal toxicity in patients taking NSAIDs: The Gastrointestinal Toxicity Survey

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the world, but their use is often associated with adverse gastrointestinal (GI) events that may be life threatening in some patients. Development of simple questionnaires for predicting GI events in individuals taking NSAIDs may help to prevent use of these drugs in high-risk patients. The present study was undertaken to test a new questionnaire designed to identify patients at high risk for NSAID-associated GI events—the Gastrointestinal Toxicity Survey (NSAID Induced) (GITS [NI]). In this study, results for GITS (NI) were compared with those for an established questionnaire, the Stanford Calculator of Risk for Events (SCORE), in a small cohort of 400 patients. Feasible generalized least squares (FGLS) and multinomial logistic (MNL) regression were used to perform the comparison. The overall correlation between results for GITS (NI) responses and the total score for the SCORE questionnaire was 0.962 (P<.0001). The agreement between the 2 instruments with respect to their ability to predict the same risk for NSAID-induced GI events was similar for both FGLS and MNL. For 4 levels of risk, the agreement was approximately 80% between the 2 instruments. For 3 levels of risk, the agreement was approximately 90%. This study showed that results obtained with GITS (NI) are highly correlated with those from SCORE and that GITS (NI) may provide physicians with information that will help them avoid administering NSAIDs to patients who are at high risk for adverse GI reactions.     

The relationship of absorption characteristics and gastrointestinal side effects of oral antimicrobial agents

Normal bowel flora play an important role in preserving gastrointestinal (GI) function. They inhibit colonization by pathogenic bacteria, help in the metabolism of by-products of drugs and endogenous substances, aid in the synthesis of vitamins, and stimulate nonspecific host immune systems that protect against potential pathogens. Antimicrobial agents that are poorly absorbed from the GI tract can substantially alter the bowel flora. Narrow-spectrum antimicrobial agents are less likely to disrupt the bowel flora than broad-spectrum agents. Drugs that undergo extensive enterohepatic circulation can also disrupt normal flora. Knowledge of the extent of GI absorption, bile excretion, and spectrum of activity allows prediction of the likelihood of GI side effects. For example, clindamycin, which is relatively poorly absorbed and has significant bile secretion, is associated with a high incidence of diarrhea. The use of an antibiotic with a relatively narrow spectrum, excellent GI absorption, and minimal bile excretion should reduce the incidence of GI side effects.     

Management principles of gastrointestinal bleeding

There is now a multitude of technologic and pharmacologic options available to clinicians caring for patients with gastrointestinal (GI) bleeding; however, drugs and technology are no substitute for understanding and properly executing the basic management principles of GI bleeding. This article focuses on the most common causes of GI bleeding and emphasizes the importance of the primary care provider's role in the management of these patients. Also, by answering questions we are commonly asked as gastroenterology consultants, we hope to provide insight into current diagnostic and therapeutic options and the most appropriate use of these options.     

Economic evaluation of rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis

BACKGROUND: Results of phase III clinical trials of rofecoxib, a selective inhibitor of cyclooxygenase 2, have shown that osteoarthritis patients treated with rofecoxib had significantly fewer clinically significant gastrointestinal (GI) adverse events than those who received nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: This paper explores the potential economic implications of the use of rofecoxib versus nonselective NSAIDs for the treatment of osteoarthritis via a decision analytic model based on rofecoxib clinical data and the published literature. METHODS: Base-case 1-year analyses were done with data on GI adverse events, specifically perforations, ulcers, and bleeds (PUBs), obtained from a prespecified pooled analysis of the rofecoxib clinical trials. Analyses were also performed using pooled results of two 12-week endoscopic surveillance trials, with adjustments for silent ulcers of 40% and 85%. RESULTS: Under base-case conditions, the expected cost savings in GI problems and comedications averted with rofecoxib versus NSAIDs was 0.81 dollars per day, representing an 85% offset of the difference in drug price. For rofecoxib versus NSAIDs, the expected cost per PUB avoided with rofecoxib was 4738 dollars, and expected cost per year of life saved was 18,614 dollars. In analyses based on endoscopic data, therapy with rofecoxib was less expensive than therapy with NSAIDs, regardless of silent ulcer adjustment. Results were most sensitive to prophylactic GI comedication rates, and were robust over a range of model assumptions and costs. CONCLUSIONS: In this analysis based on differences in clinically significant GI events for osteoarthritis patients, cost differences between rofecoxib and NSAIDs were markedly offset by expected cost savings in GI problems and comedications averted with rofecoxib. Costs per year of life saved with rofecoxib versus NSAIDs were well within accepted benchmarks for cost-effectiveness. When endoscopic data alone were considered, rofecoxib was cost saving across all assumptions about silent ulcer rates.     

Treatment and prevention of NSAIDs-induced gastrointestinal injury--the role of gastroenterologist

According to many clinical researches, it is obvious that patients taking NSAIDs including low-dose aspirin have upper GI injury frequently than those without. Recently, the GI event of those medicines becomes more serious clinical problem in Japan in which aging population is getting larger year by year. Evaluation of GI risk and appropriate use of anti -ulcer drugs, especially proton-pump inhibitors, are recommended for the prevention. Additionally, the close communication and cooperation between doctors who prescribe the medicines and gastroenterologists is essential for minimizing such adverse reaction. Here we describe on the role of gastroenterologists on the prevention of GI event caused by NSAIDs and aspirin.     

Chitosan-based gastrointestinal delivery systems.

Chitosan, a natural polymer obtained by alkaline deacetylation of chitin, is non-toxic, biocompatible, and biodegradable. These properties make chitosan a good candidate for the development of conventional and novel gastrointestinal (GI) drug and gene delivery systems. The objective of this review is to summarize the recent applications of chitosan in oral and/or buccal delivery, stomach-specific drug delivery, intestinal delivery, and colon-specific drug delivery. The use of chitosan for targeting of drugs to each of these sites in the GI tract is illustrated by examples supported by in vivo studies. Chitosan appears to be a promising material for GI drug and gene delivery applications as many derivatives and formulations are being examined.