Adverse Gastrointestinal Research Articles

Clinical Impact of Drug–Drug Interaction Between Aspirin and Prednisolone at a Cancer Center

BackgroundAdverse gastrointestinal (GI) events are complications in aspirin and prednisolone cotherapy. The prevalence of adverse GI events would be expected to be increased with cotherapy due to the overlapping toxicities of the 2 drugs. However, there is a dearth of literature investigating how often this interaction causes clinically important adverse GI events. ObjectivesThis retrospective study aimed to determine the prevalence of adverse GI events associated with the coadministration of aspirin and prednisolone. The use of gastroprotectant agents was also studied. MethodsThe medical records of patients with cancer prescribed aspirin and prednisolone therapy between January 2007 and June 2011 were analyzed. The duration of aspirin–prednisolone overlap, prevalence of adverse GI events, and details on the concurrent use of other medications were evaluated. ResultsThe study included data from 142 patients (male, 64.8%; mean [SD] age, 67.4 [11.0] years). A total of 78.9% of the patients were on some form of gastroprotectant, the most common class of which was proton pump inhibitors. The prevalence of adverse GI events was 4.2% (6 patients). Four patients had presented with GI symptoms (abdominal pain, diarrhea, dysphagia, and vomiting); 3 patients had signs of GI injury (duodenal ulcers, iron deficiency anemia, and a Mallory-Weiss tear). The Naranjo algorithm classified 5 patients experienced possible adverse drug reactions (ADRs), and 1 as a probable ADR. ConclusionOur study found that the prevalence of adverse GI events was low and managed to establish a weak association between the occurrence of events and the coadministration of aspirin and prednisolone. This finding, together with the concurrent prescription of gastroprotectants, suggests that the clinical impact of the aspirin and prednisolone DDI is minimal.

Credulous Fondness for Celecoxib

The American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults1 lists “Non-Cox-selective NSAIDs [nonsteroidal anti-inflammatory drugs], oral.” The rationale focuses on risk of gastrointestinal (GI) bleeding, and the recommendation is to avoid chronic use. Perhaps the notorious Celecoxib Long-term Arthritis Safety Study (CLASS),2 whose authors were six employees of and 10 consultants for celecoxib's (Celebrex, Pfizer, New York, NY) vendor, persuaded the panelists. Submitted to JAMA as a 6-month trial, CLASS was the combination of results of a 12-month and a 15-month trial, each completed when CLASS was submitted to JAMA. Neither trial was disclosed to JAMA, nor the fact that CLASS was not actually a single trial. The authors also changed the outcomes and analysis for their report, without disclosing these changes. Almost all ulcer complications after the first 6 months occurred in the celecoxib groups.3 In participants taking aspirin, rates of ulcer complications and symptomatic ulcers were not different between celecoxib and standard NSAIDs. NSAIDs, including Celebrex, increase the risk of serious adverse GI events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly adults are at high risk for serious GI events.4 Why not add celecoxib to the list of PIMs? Especially because its safety in chronic use is unlikely to be any better than that of conventional NSAIDs. The enduring credulous fondness for celecoxib is perplexing. Conflict of Interest: I, Thomas E. Finucane, MD, have no conflict of interest with regard to the contents of this letter. Author Contributions: TF is responsible for the entire content. Sponsor's Role: None.

Gastrointestinal Events with Clopidogrel: A Nationwide Population-Based Cohort Study

Clopidogrel prevents cardiovascular events, but has been linked with adverse gastrointestinal (GI) complications, particularly bleeding events. We aimed to investigate the risk of adverse GI events in patients treated with clopidogrel. A nationwide population-based cohort study based on linkage of three administrative registries in Denmark. All individuals who redeemed at least one prescription of clopidogrel from 1996 to 2008 were included as exposed subjects (n = 77,503). For each exposed subject, three matched controls were randomly selected from the background population (n = 232,510). Follow-up began on January 1, 1996, and was censored on December 31, 2007, or if patients emigrated or died. The study endpoint was the occurrence of any gastritis, GI ulcer or bleeding. Analyses were adjusted for comorbidity and medication. Regardless of dose, adjusted odds ratios associating clopidogrel use with the study endpoint were statistically significant and followed a dose-response pattern. The crude absolute risk of GI events were: never users: 2.2 %; <0.1 defined daily dose (DDD) of clopidogrel per day: 7.1 %; 0.1-0.39 DDD: 6.0 %; 0.4-0.79 DDD: 5.7 %; ≥0.80 DDD: 4.4 %. Adjusted odds ratios were: <0.1 DDD: 1.34, 95 % CI: 1.26-1.42; 0.1-0.39 DDD: 1.58, 95 % CI: 1.48-1.68; 0.4-0.79 DDD: 1.91, 95 % CI: 1.77-2.06; ≥0.80 DDD: 1.77, 95 % CI: 1.66-1.89, all p-values < 0.01. Depending on the dose, numbers needed to harm ranged from 58 to 33 patients receiving 12 months of clopidogrel treatment. The well-known cardioprotective effect of clopidogrel must be carefully weighed against an increased risk of GI events.

Gastrointestinal Effects of the Addition of Ascorbic Acid to Aspirin

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been associated with the damage to the gastrointestinal tract. One proposed mechanism of injury to the gastrointestinal mucosa by NSAIDs is oxygen radical-dependent microvascular injury. There is reasonable evidence to support the benefit of the addition of ascorbic acid, an ingredient with antioxidant properties, to moderate the adverse gastrointestinal (GI) effects of aspirin. Pharmacokinetic data have demonstrated that aspirin and ascorbic acid combination therapy can assist in mitigating the decrease in levels of ascorbic acid secondary to aspirin monotherapy. Endoscopic evaluation has demonstrated that the addition of ascorbic acid to aspirin significantly improves Lanza scores and rates of blood loss when compared to aspirin administration alone. When taken with ascorbic acid, the patient-reported tolerability of aspirin has been shown to be comparable to paracetamol and placebo. The existing body of evidence is relevant to short-term therapy with analgesic aspirin doses, and extrapolation to long-term therapy with low-dose aspirin is not appropriate. The purported benefit of an aspirin and ascorbic acid combination is a local observance and is not suspected to influence the adverse GI effects experienced as a result of systemic prostaglandin inhibition. Nevertheless, ascorbic acid may be a viable addition to the strategies employed to improve the gastrointestinal tolerability of aspirin.

Adverse events from calcium supplementation: Relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation

The clinical effects of calcium supplements on adverse events reporting have not been well described. This study reviews randomized controlled trial (RCT) evidence of adverse events to clarify the epidemiology of these events. The hypothesis that patient self-report of myocardial infarction (MI) is increased in individuals receiving calcium supplementation is because of an increase in non-MI events incorrectly perceived by the patient as being because of MI, is examined. In seven RCTs summary self-reported gastrointestinal (GI) adverse event rates were more common in participants receiving calcium. These were described as constipation, excessive abdominal cramping, bloating, upper GI events, GI disease, GI symptoms, and severe diarrhoea or abdominal pain (calcium 14.1%, placebo 10.0%), relative risk (RR) 1.43 95% confidence interval (CI) 1.28 to 1.59, p < 0.001. Adjudicated functional GI hospitalizations in one study were calcium 6.8%, placebo 3.6% (RR 1.92, 95% CI 1.21-3.05, p = 0.006). Direct comparison of self-reported and adjudicated MI events in the two trials of dietary calcium supplementation showed self-reported MI rates of 3.6% in the calcium group and 2.1% in the placebo group. After adjudication the MI rates were 2.4% in the calcium group and 1.6% in the placebo group (RR 1.45, 95% CI 0.88-2.45, p = 0.145). These data support the hypothesis that calcium tablets increase the incidence of adverse GI events, which may account for an increase in self-reported MI in calcium treated patients but not controls.

The Pattern of Use of Oral NSAIDs with or without Co-prescription of Gastroprotective Agent for Arthritic Knee by Korean Practitioners

PurposeThe aim of this study was to describe the patterns of use of non-steroidal anti-inflammatory drugs (NSAIDs) for arthritic knees in clinical practice, particularly focusing on the co-prescription of gastroprotective agents for patients with risk factors for adverse gastrointestinal (GI) events.Materials and MethodsEach cross-sectional cohort was a group of outpatients visiting 111 physicians who had prescribed NSAIDs for the patients' arthritic knees for more than three consecutive months. A self-administered questionnaire was completed by each patient and physician.ResultsNine hundred and forty five patients (48%) of the whole 1,960 patients belonged to the group with a high or very high risk for NSAID-induced gastropathy determined by northern California Health Maintenance Organization guidelines. Overall, only less than half of the patients were given co-prescription of gastroprotective agents, regardless of the presence or absence of GI symptoms and irrespective of the level of risk for NSAID-induced gastropathy.ConclusionsThe physician prescribing NSAIDs for arthritic knees should monitor any GI symptoms and the patient monitor anylevel for NSAIDinduced gastropathy, and be willing to add gastroprotective agents as necessary in order to prevent serious adverse GI events.

Abstract P156: Dyspepsia and Disease Burden among Patients with Atrial Fibrillation

Objective: Many agents used in treating atrial fibrillation (AF) have potential gastrointestinal (GI) tolerability issues. Treatment-related adverse GI events are a common reason for noncompliance to treatment. The current analysis describes the prevalence of dyspepsia in relation to anticoagulant use among AF patients. Methods: Data were obtained from the 2009 National Health and Wellness Survey (N=75,000), an annual cross-sectional Internet-based survey of US adults. Respondents answered general demographic and health-related questions. A CHADS 2 score (an index of stroke risk) was calculated for each patient using demographic and clinical characteristics. Results: A total of 1297 patients (1.7%) reported a diagnosis of AF. Of these patients, 41% (n= 535) also reported a physician-diagnosed GI condition; 84% of these (n=449) were consistent with dyspepsia (ulcers, abdominal bloating, abdominal pain, gastroesophageal reflux disease/acid reflux, or heartburn). Compared with AF patients without dyspepsia (n=848), those with dyspepsia were younger (mean 62.9 vs 66.0 years, p &lt;0.05) and more likely to be female (43% [193 of 449] vs 31% [260 of 848], p &lt;0.05). AF patients with dyspepsia were in poorer health than those without dyspepsia, as evidenced by a higher CHADS 2 score (1.9 vs 1.4, p &lt;0.05); this difference was more pronounced in patients aged &gt;65 years and in those with CHADS 2 score &gt;2. Despite this, significantly fewer AF patients with dyspepsia, than those without, were taking a prescription medication to treat their AF (67% [300 of 449] vs 73% [619 of 848]), p &lt;0.05) or an anticoagulant for stroke prevention (35% [158 of 449] vs 47% [394 of 848]), p &lt;0.05. Conclusions: One-third of AF patients in this analysis had dyspepsia. These patients reported a greater disease burden and stroke risk relative to AF patients without dyspepsia. Significantly fewer AF patients with dyspepsia, than those without, were taking a prescription to treat AF or an anticoagulant for stroke prevention. Poor GI tolerability may be significant in the AF population and should be considered when adherence to medication is critical, such as in high-risk populations.

Comparison of two questionnaires to assess gastrointestinal toxicity in dogs and cats treated with chemotherapy*

Questionnaires completed by pet owners are widely used instruments to monitor adverse gastrointestinal (GI) effects in the owners' animals undergoing chemotherapy and for reporting toxicoses in clinical trials; however, no questionnaires have been formally evaluated. This study compares two questionnaire-based evaluations of adverse GI events: a basic, open-ended questionnaire and a detailed questionnaire modelled after the grading in the Veterinary Co-operative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE). Owners completed both questionnaires after their dog or cat received moderately emetogenic chemotherapy. Results were used to derive toxicity grades for anorexia, vomiting and diarrhoea. We evaluated 123 pairs of questionnaires. Disagreement in grade of anorexia, vomiting and diarrhoea was found in 24, 7 and 13% of paired questionnaires, respectively (κ = 0.63, 0.83 and 0.71, respectively). Although 'good' to 'very good' agreement was found, the potential for only 'fair' agreement between questionnaire methods is of concern and suggests a need to adopt a standardized form.

Effects of Proton Pump Inhibitors on Adverse Gastrointestinal Events in Patients Receiving Clopidogrel

There has been recent concern regarding a possible adverse interaction between clopidogrel and proton pump inhibitors (PPIs), coupled with uncertainty as to whether PPIs genuinely help in reducing gastrointestinal (GI) harm. To perform a meta-analysis of GI outcomes in patients taking clopidogrel, with and without concomitant PPI. We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from inception to March 2010, and checked conference abstracts for randomized and non-randomized studies that reported on adverse GI events (haemorrhage, ulcer, perforation or obstruction) with PPI exposure in patients taking clopidogrel. Relevant studies were subcategorized according to the degree of aspirin (acetylsalicylic acid) co-administration and nature of GI events, where available. We performed random effects meta-analysis for risk of adverse GI events with PPI exposure in clopidogrel-treated patients, and assessed heterogeneity using the I2 statistic. Our review evaluated 71,277 participants in nine retrospective studies and one randomized trial. Exposure to PPI for patients receiving dual antiplatelet therapy (aspirin and clopidogrel in seven studies) was associated with a significant reduction in adverse GI events, odds ratio (OR) 0.38 (95% CI 0.21, 0.68; p=0.001; I2=17%). There was significant heterogeneity in the analysis of patients receiving clopidogrel monotherapy (two studies), and no definite benefit was found. Restricting the analysis to studies specifically reporting upper GI bleeds with any clopidogrel exposure yielded an OR of 0.31 (95% CI 0.19, 0.51; p<0.001; I2=27%) with associated PPI exposure. Use of PPIs is associated with a reduction in adverse GI events (particularly haemorrhages) in patients who are receiving dual antiplatelet therapy. Clinicians should carefully weigh up the evidence for potential GI benefits against the uncertainties surrounding any possible adverse cardiovascular impact of concomitant clopidogrel PPI therapy.

GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin

Objectives:GOAL (Gauging Osteoarthritis [OA] with Limbrel*Limbrel is manufactured by Primus Pharmaceuticals, Inc., Scottsdale, AZ, USA.), an open-label, post-marketing study was performed to determine the overall efficacy and gastrointestinal (GI) tolerability of flavocoxid, a novel, plant-based, anti-inflammatory medication, in a ‘real world’ clinical practice setting. To this end, the study enrolled several unique patient types including nonsteroidal anti-inflammatory drug (NSAID) naïve patients, those who had used NSAIDs in the past, regardless of outcome (positive or negative), and those who had previously taken a gastroprotective medication to improve GI tolerability or continued to take it as a precautionary measure to prevent NSAID-associated GI damage.Methods:A total of 1067 individuals at 41 rheumatology practices were enrolled and prescribed flavocoxid, 500 mg b.i.d., for 60 days. The Physician Global Assessment of Disease (PGAD) visual analog scale (VAS) was used as a global measure to assess the signs and symptoms of OA, including joint discomfort, functional stiffness, functional mobility and quality of life. In addition, overall tolerability and upper GI tolerability were assessed by individual questions scored on a 5-part Likert scale. The physicians also monitored any interruption in, or cessation of use of flavocoxid due to a GI issue as well as changes in the use of gastroprotective medications. Adverse event (AE) monitoring was also conducted.Results:Of the 1005 patients who completed all follow-up visits, physicians recorded an average improvement in VAS scores from 60.1 ± 18.8 at baseline to 42.5 ± 21.9 at 8 weeks (p < 0.001) in 65.8% of patients. The PGAD VAS noted the most significant improvement in those patients with moderate to severe OA (baseline VAS [0 = least severe, 100 = most severe]: 0–25mm, −3.5 ± 6.9; 26–50 mm, −10.1 ± 17.0; 51–75 mm, −19.3 ± 19.5; 76–100 mm, −29.6 ± 23.6; p < 0.001) and in those patients who were historically non-responders to NSAIDs (40.3 ± 21.1 vs. 66.3 ± 17.7 at baseline; p < 0.001). Patients who had previously responded well to NSAIDs had VAS scores of 42.6 ± 19.8 vs. 58.0 ± 18.0 (p < 0.001) and NSAID naïve subjects showed improvement in VAS scores from 60.5 ± 18.0 at baseline to 46.3 ± 23.7 (p < 0.001). The study recorded a low incidence (∼10%) of AEs reported to physicians and good overall tolerability to flavocoxid. Flavocoxid showed improved upper GI tolerability in almost 50% of previous NSAID users (p < 0.001) and reduced therapy interruption in ∼90% of previous NSAID users with a history of GI-related therapy interruptions (p < 0.0001). Finally, the use of flavocoxid resulted in a >30% reduction in or cessation of the use of gastroprotective medications such as proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2s) in subjects (p < 0.001).Conclusions:Within a ‘real world’ clinical rheumatology practice setting, flavocoxid demonstrated significant efficacy in the management of OA in multiple patient types and displayed significant potential for reducing the possibility of adverse GI side-effects and use of gastroprotective agents associated with more traditional OA medications. A limitation of this study was that it was open-label and not rigorously controlled. The large population may compensate for this lack of control.

Mycophenolate Mofetil Versus Enteric-Coated Mycophenolate Sodium: A Large, Single-Center Comparison of Dose Adjustments and Outcomes in Kidney Transplant Recipients

Although enteric-coated mycophenolate sodium (EC-MPS) was developed to reduce gastrointestinal (GI) side effects in kidney transplantation, a multicenter clinical trial of patients undergoing de novo renal transplantation found that efficacy failure and adverse GI event rates for EC-MPS were comparable with mycophenolate mofetil (MMF). A common strategy to mitigate mycophenolic acid-related GI adverse events includes dose manipulations such as split dosing, dose reduction, and discontinuation. Several studies have demonstrated that dose alterations with MMF are associated with poorer graft outcomes. To determine whether there was a clinically significant difference in dose alterations and outcomes with EC-MPS compared with MMF, we conducted a retrospective study comparing MMF and EC-MPS in all consecutive kidney transplants (n=1709) between 2000 and 2006. Graft survival between MMF and EC-MPS patients was not different during the study period (P=0.9928). The incidence of biopsy-proven acute rejection at 2 years was higher in the MMF group (30.2% MMF vs. 21.9% EC-MPS, P=0.0004). The adjusted risk of dose reductions was significantly higher in MMF-treated patients (hazard ratio=1.703, P<0.0001). Similarly, the adjusted risk of drug discontinuation was higher in the MMF group (hazard ratio=1.507, P=0.0002). EC-MPS patients also demonstrated a trend toward a lower incidence of infections and a significantly lower incidence of fungal infections. EC-MPS was associated with fewer dose reductions or discontinuations, which may have translated into the observed significantly lower incidence of biopsy-proven rejection. EC-MPS has become the mycophenolic acid agent of choice at this large center.

Adverse effects of nonsteroidal anti-inflammatory drugs on the colon

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and a growing body of evidence suggests that they have adverse effects in the lower gastrointestinal (GI) tract in addition to the well-described toxicity in the upper GI tract. Among NSAID users who develop adverse GI effects, the proportion with lower GI events is as high as 40%. Most of the available evidence is taken from case-control studies and case reports; no large, randomized, placebo-controlled study has specifically set out to determine the magnitude of NSAID toxicity on the colon. However, the data suggest that NSAIDs cause a primary macroscopic colitis, collagenous colitis, an increased risk of complicated diverticular disease, and exacerbations of preexisting inflammatory bowel disease. Treatment depends on withdrawal of the causative drug.

Prevention of NSAID-induced ulcers

Cyclooxygenase-2 (COX-2) selective inhibitors were developed as gastrointestinal (GI) safer alternatives to nonselective NSAIDs--providing equivalent analgesic and anti-inflammatory efficacy. Their GI sparing is impaired by concomitant aspirin use, and concerns regarding adverse cardiovascular effects have emerged. Risk factors for NSAID-related complications include a history of ulcer disease or bleeding, concomitant corticosteroid or anticoagulant therapy, use of high-dose or multiple NSAIDs (including low-dose aspirin), advanced age, and certain chronic diseases. If an NSAID must be used in a patient at risk, the lowest-risk NSAID should be used with, in many cases, cotherapy to reduce the risk for ulcers. COX-2 drugs have been associated with a significantly higher risk of vascular events than placebo or naproxen. This increase may be shared by nonselective NSAIDs and appears to be medication- and dose-dependent. Prostaglandin depletion is a central mechanism for NSAID ulcer development, and replacement therapy with misoprostol reduces NSAID toxicity; however, it is rarely used due to side effects. The acid suppression provided by traditional doses of histamine 2-receptor antagonists (H(2)RAs) does not prevent most NSAID-related gastric ulcers. Despite a single study demonstrating that H(2)RAs at double the dose may be effective, studies comparing such high doses with misoprostol or proton pump inhibitors (PPIs) for preventing NSAID ulcers are not available. PPIs are effective at single daily doses, do not demonstrate tachyphylaxis, and are superior to H(2)RAs and misoprostol in reducing ulcers and NSAID-associated dyspepsia. NSAID choice should be predicated by an assessment of an individual's cardiovascular and GI risk. For those with competing cardiovascular and GI risks, the tradeoffs between reducing adverse GI events (COX-2 inhibitor instead of a nonselective NSAID) must be explicitly weighed against concerns about cardiovascular side effects (naproxen instead of other agents). Considering cost is appropriate because it may not be feasible to recommend the "safest" regimen in every circumstance. The cost effectiveness of risk-reducing therapies is intimately tied to the patient's underlying risk. For those at highest GI risk, using a PPI and a low-dose COX-2 inhibitor seems appropriate for those without high cardiovascular risk. For patients whose cardiovascular risk parallels or exceeds GI concerns, naproxen with a PPI is recommended when non-NSAID approaches fail.

Safety of the Nonselective NSAID Nabumetone

Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.

Emerging pharmacologic options for treating postoperative ileus

Characteristics of the ideal drug therapy for postoperative ileus (POI); the pharmacology, efficacy, and safety of currently available nonselective opioid antagonists and the new peripherally selective opioid antagonists methylnaltrexone and alvimopan for the treatment of POI; and formulary considerations associated with the introduction of these new POI drug therapies are discussed. The ideal drug therapy for treating POI would selectively antagonize the inhibitory effects on the gastrointestinal (GI) tract of all of the potential factors implicated in the pathophysiology of POI (neurogenic, inflammatory, hormonal, and pharmacologic mediators). The most promising target to date is inhibition of the adverse GI effects of endogenous and exogenous opioids. Selective inhibition of the mu-opioid receptors in the GI tract, without reversing centrally mediated opioid-induced analgesia, may be beneficial in reducing POI. The nonselective opioid antagonists naloxone and nalmefene have not been studied for POI, and they cross the blood-brain barrier. Therefore, they are not appropriate for preventing or treating POI. The peripherally selective opioid antagonist methylnaltrexone shortens the duration of POI and the hospital length of stay (LOS). Alvimopan, a more extensively studied peripherally selective opioid antagonist, has been shown to reduce the duration of POI, frequency of postoperative nausea and vomiting, and hospital LOS. Both methylnaltrexone and alvimopan also appear effective for treating opioid-induced constipation. Preliminary results of a long-term study of alvimopan safety have revealed some potential concerns, and the significance of the adverse effects must be understood before the most appropriate role of alvimopan in patient care can be determined. Restricting the prescribing of new POI drug therapies to certain types of patients, surgeries, and prescribers; incorporating these therapies into preoperative and postoperative policies, procedures, and protocols; and the potential cost savings from reducing hospital LOS are among the considerations in adding these agents to health-system formularies. Peripherally selective opioid receptor antagonists are promising new drug therapies that can reduce the clinical and economic burden of POI.

Molecule of the Month

Emerging from the shadow of Vioxx™. Nonsteroidal antiimflammatory drugs (NSAIDs) are a class of medicines prescribed to treat acute and chronic pain [1]. NSAIDs reduce prostaglandin production by inhibition of cyclooxygenase (COX) to afford analgesia. However, while very effective for the treatment of pain and inflammation, this mechanism elicits adverse gastrointestinal (GI) and renal effects. The discovery of COX isoforms (COX-1 and COX- 2) and differential functions led to the development of selective COX-2 inhibitors for the treatment of pain that minimized the adverse GI effects [1]. In 1999 Pfizer launched Celebrex™ (30-fold selective COX-2 inhibitor) and Merck launched Vioxx ™ (272-fold selective COX-2 inhibitor) [2, 3]. It has been 28 months since Merck & Co. announced the results of the APPROVe trial and withdrew Vioxx™ from the market due to adverse cardiovascular events such as heart attack and stroke; as a result, over 27,000 lawsuits have been filed against the pharmaceutical giant [3]. The cardiovascular risks stems from the selective inhibition of COX-2 which reduces COX-2-mediated vasodilation and inhibition of platelet aggregation. Unlike the nonselective NSAIDs, which balance COX-1-mediated platelet activation with COX-2 vasodilation and platelet inhibition, selective inhibition of COX-2 with drugs like Vioxx may generate an imbalance that predisposes platelet aggregation and ischemia [1]. Despite the potential risks, arthritis patients clamored for the drug, as for many patients, only Vioxx™ relieved their arthritis pain. In November of 2006, Merck announced that it received an approvable letter from the FDA for Arcoxia™, a second generation COX-2 inhibitor with even greater COX-2 selectivity (344-fold) [1, 3]. Also in November of 2006, Merck announced the results of a large outcomes study, coined the MEDAL (Mulitnational Etoricoxib and Diclofenac Arthritis Longterm) program, which demonstrated that Arcoxia™ had similar rates of cardiovascular thrombotic events as Diclofenac™, the most prescribed traditional NSAID in the world [3]. In addition, the MEDAL study showed that Arcoxia™ had a lower rate of confirmed upper GI effects (including ulcers, bleeding and obstructions) than Diclofenac™. However, a recent article in the Wall Street Journal raised issues with the MEDAL study [4]. In the article, some doctors were quoted as saying that the study was of limited scope and questioned the comparison of Arcoxia™ to DiclofenacTM, which ‘...acts like a COX-2 inhibitor in the first place.’ They advocated comparing Arcoxia™ to a less-similar painkiller such as naproxen. Despite these issues, Arcoxia™ is currently available in 62 countries around the world, but sales in the US are pending an FDA decision that is expected in April of 2007 [3]. REFERENCES [1] Martina, S.D.; Vesta, K.S.; Ripley, T.L. Etoicoxib: A highly selective COX-2 inhibitor. Ann. Pharmacother. 2005, 39, 854-862. [2] For detailed information and press releases describing Celebrex™, see www.pfizer.com [3] For detailed information and press releases describing Vioxx™, Arcoxia™, the APPROVe and MEDAL studies see www.merck.com [4] Whalen, J. ‘Drug makers try to bring back Cox-2 inhibitors’ in the Wall Street Journal, Eastern edition, Jan. 19, 2007, B.1.

Pathological effects of drugs on the gastrointestinal tract: a review

Drug-induced injury of the gastrointestinal (GI) tract is increasingly common but generally under-recognized. Although there is an overwhelming number of drugs that are associated with adverse GI effects, there is a limited number of characteristic injury patterns that should prompt consideration of drug-induced GI pathology. These include the following: erosions, ulcers, and strictures; crystal deposition; parietal cell changes; reactive gastropathy; pseudodysplastic changes; microscopic colitis; infectious or necrotizing enterocolitis; ischemic colitis; focal active colitis; and increased epithelial apoptosis. This article reviews morphological and pathophysiological features of some of the more common and pathologically recognizable drug-related injury patterns and provides a practical guide for the recognition and diagnosis of drug-induced pathology in the upper and lower GI tract.

Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Cyclooxygenase‐2 Expression and Prostaglandin E2 production in Chondrocytes are Inhibited by the Combination of Avocado Soy Unsaponifiables (ASU) and Epigallocatechin gallate (EGCG)

Production of the pro-inflammatory mediator prostaglandin E2 (PGE2) is catalyzed by the cyclooxygenase-2 (COX-2) enzyme. Suppression of PGE-2 and COX-2 expression by non-steroidal anti-inflammatory drugs reduces pain and but causes gastrointestinal (GI) complications. Recently, ASU and EGCG from green tea extracts have been evaluated independently for providing relief in chronic inflammatory disorders. We hypothesize that the combination of ASU and EGCG inhibits COX-2 expression and PGE2 synthesis. Chondrocytes (5×105cells/well) from bovine and equine cartilage were incubated for 24 hrs with: control media alone, ASU (8.3 μg/ml NMX1000™-ASU), EGCG (0.4 μg/ml), or with the combination of ASU and EGCG. Cells were then activated with lipopolysaccharide (20 ng/ml) or IL-1β (10 ng/ml) for 1 or 24 hrs. Pre-treatment with the combination of ASU and EGCG profoundly suppressed COX-2 expression in activated chondrocytes by as much as 60%. This reduction was associated with decreased PGE2 production. The inhibitory effect of the combination was more pronounced than either agent alone. Our study demonstrates the combination of ASU and EGCG down-regulates the COX-2 gene that controls PGE2 synthesis. This combination may offer an alternative approach to reduce inflammation while minimizing adverse GI effects. Research supported by Nutramax Laboratories, Inc. and Mississippi State University.

Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin

Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin