Risk of esophageal and gastric adenocarcinomas in relation to use of calcium channel blockers, asthma drugs, and other medications that promote gastroesophageal reflux.

Incidence of adenocarcinomas of the esophagus and gastric cardia has risen dramatically over the past 2 decades in the U. S., for reasons that are not yet clear. A number of common medications (e.g., calcium channel blockers, tricyclic antidepressants, and certain asthma medications) promote gastroesophageal reflux by relaxing the lower esophageal sphincter (LES). Reflux is thought to increase cancer risk by promoting cellular proliferation, and by exposing the esophageal epithelium to potentially genotoxic gastric and intestinal contents. Recent studies have suggested that calcium channel blockers may also increase cancer risk by inhibiting apoptosis. Using personal interview data from a multicenter, population-based case-control study conducted between 1993 and 1995 in three areas of the U. S., we evaluated whether the use of LES-relaxing drugs was associated with increased risk of adenocarcinomas of the esophagus and gastric cardia. Cases of esophageal adenocarcinoma (n = 293) and gastric cardia adenocarcinoma (n = 261) were compared with general population controls (n = 695). Information on additional case groups of esophageal squamous cell carcinoma (n = 221) and noncardia gastric cancer (n = 368) were also available for comparison. Overall, 27.4% of controls had used one or more of these drugs for at least 6 months, compared with 30.2% of esophageal adenocarcinoma and 23.8% of gastric cardia adenocarcinoma cases. The adjusted odds ratios (ORs) for ever use were 1.0 [95% confidence interval (CI) = 0.7-1.5] and 0.8 (95% CI = 0.5-1.1), respectively. There was little evidence of increasing risk with increasing duration of use of all LES-relaxing drugs together. We found an increased risk of esophageal adenocarcinoma among persons reporting use of asthma drugs containing theophylline (OR = 2.5; 95% CI = 1.1-5.6) or beta agonists (OR = 1.7; 95% CI = 0.8-3.8). Risks were higher among long-term users (>5 years) of these drugs (OR = 3.1; 95% CI = 0.9-10.3 and OR = 2.3; 95% CI = 0.8-7.0, respectively). In contrast, there was no evidence that the use of calcium channel blockers or other specific groups of drugs increased the risk of any of the cancers studied. These results provide reassuring evidence that the increases in incidence of adenocarcinomas of the esophagus and gastric cardia are not likely to be related to the use of LES-relaxing drugs as a group, or calcium channel blockers in particular, but they do suggest that persons treated for long-standing asthma may be at increased risk of esophageal adenocarcinoma.

Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer.

Regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are at reduced risk of colon cancer, but the evidence for protective effects of NSAIDs elsewhere in the digestive tract is scant. We investigated the association between the use of NSAIDs and risk of esophageal and gastric cancer, using data from a large population-based, case-control study. Cases were individuals, ages 30-79 years, diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or noncardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were selected by random digit dialing and through the rosters of the Health Care Financing Administration. After controlling for the major risk factors, we found that current users of aspirin were at decreased risk of esophageal adenocarcinoma [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.24-0.58], esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28-0.87), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31-0.68), but not of gastric cardia adenocarcinoma (OR, 0.80; 95% CI, 0.54-1.19), when compared to never users. Risk was similarly reduced among current users of nonaspirin NSAIDs. The associations with current NSAID use persisted when we excluded use within 2 or 5 years of reference date, which might have been affected by preclinical disease in cases, and when we restricted analyses to subjects reporting no history of chronic gastrointestinal symptoms. Our findings add to the growing evidence that the risk of cancers of the esophagus and stomach is reduced in users of NSAIDs, although whether the association is causal in nature is not clear.

Drug interactions with antisecretory agents.

Antisecretory agents may affect the absorption, metabolism, and renal excretion of other drugs. Inhibition of gastric acid secretion may decrease the gastrointestinal absorption of drugs such as ketoconazole that dissolve poorly in the absence of adequate acid. With anti-secretory agents, the drug interaction mechanism most likely to result in adverse effects is the inhibition of hepatic oxidative drug metabolism, primarily a problem with cimetidine. Omeprazole also appears to inhibit the hepatic metabolism of some drugs, but available evidence indicates that it interacts with fewer drugs than cimetidine and the magnitude of the inhibition is lower. Cimetidine decreases the renal clearance of procainamide and its active metabolite, N-acetylprocainamide, probably through interference with active renal tubular secretion. In therapeutic doses, other H2-receptor antagonists probably have minimal effects on renal procainamide elimination.

Letter. Meperidine and combination oral contraceptives.

PIP: The interaction between meperidine and combination oral contraceptives cited in an article by Stambaugh and Wainer "is hardly accepted as fact." His own reference book considers the reaction the least significant of several because documentation is poor, potential harm to the patient is slight, and incidence of interaction is low. In discussing the clinical significance of the interaction his book stated it was based on "preliminary information from urinary excretion data."^ieng

Effect of antacid and ascorbic acid on serum salicylate concentration.

To determine the effect of antacid or ascorbic acid administration on plateau serum salicylate concentrations, nine healthy subjects were given each of the following treatments by balanced block design: choline salicylate (equivalent to 3.76 or 5.62 Gm/day of aspirin); choline salicylate plus magnesium-aluminum hydroxide (120 ml/day); or choline salicylate plus ascorbic acid (3 Gm/day). In subjects developing a control serum salicylate level above 10 mg/dl, antacid administration produced a decrease in serum salicylate level (mean 19.8 mg/dl vs. 15.8 mg/dl) (P less than 0.01). Ascorbic acid administration was not associated with a significant change in serum salicylate. The reduction in serum salicylate following antacid appears to be due to antacid-induced alkalinization of the urine with resultant increase in renal salicylate clearance. Antacid administration should be considered a potential cause of altered serum salicylate concentration in patients receiving large doses of salicylate.

Cyclosporine-drug interactions and the influence of patient age.

Cyclosporine-drug interactions in adult transplant patients and the impact of age were studied. The medical records of transplant patients receiving cyclosporine therapy were identified. Data on patient demographics, cyclosporine dosages, dosage form, blood trough concentrations, clinical laboratory test values, and concurrent medications were collected. One-compartment models for oral and i.v. administration were used to fit cyclosporine concentration data to population pharmacokinetic and statistical models. Nonlinear mixed-effect modeling (NONMEM) software was used. The influence of covariates, including but not limited to concomitant medications and age, on cyclosporine pharmacokinetics was evaluated. The records of 100 patients (36 women and 64 men) were reviewed. A mean +/- S.D. of 9 +/- 2 and 9 +/- 1 medications per day were consumed by patients < 60 and > or = 60 years old, respectively. Mean population pharmacokinetic values of 0.407 L/hr/kg for clearance, 4.0 L/kg for volume of distribution, 31% for bioavailability, and 10.6 hours for half-life were determined on the basis of 569 blood cyclosporine levels. Twelve medications (sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone) with previously unconfirmed pharmacokinetic interactions with cyclosporine were identified as interacting. There was no correlation between age and interactions. Patients taking cyclosporine were at risk for pharmacokinetic drug interactions when cyclosporine was used in combination with sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone. Transplant patients 60-75 years of age had cyclosporine-drug interactions similar to those in younger patients.

Drug interactions with antibacterial agents.

Antibacterial drugs, such as quinolones, macrolides, rifampin, isoniazid, and trimethoprim-sulfamethoxazole, can interact with other drugs in a wide variety of clinically significant ways. They are frequently administered with other prescription and nonprescription medications. Antibacterial agents may interact by causing a change in the pharmacokinetics or pharmacodynamics of a second drug. In other cases, the antimicrobial may be affected by the action of another drug. Interactions involving antimicrobials often result from alterations in the absorption of the antimicrobial from the gastrointestinal tract or changes in the hepatic metabolism or renal elimination of the drugs concurrently administered. While certain classes of antibacterial drugs are known to interact with many other drugs, the interaction potential of most classes of antimicrobials is not uniform among members of the class. This diversity in interaction potential provides the clinician with an opportunity to avoid potential interactions by means of appropriate drug selection. An understanding of the common, clinically significant drug interactions involving antibacterial agents will enable the physician to avoid unnecessary adverse drug reactions.

Overview of the safety profile of the H2-receptor antagonists.

Reports of adverse drug reactions due to histamine H2-receptor antagonists (H2RAs) are rare considering their wide usage. Cimetidine produces central nervous system and endocrine toxicities more often than other H2RAs. Drug-drug interactions are of potentially greater concern with H2RAs, especially because the critically ill patient routinely receives many drugs. H2RAs may alter the absorption, metabolism, or renal excretion of concurrently administered drugs. Gastrointestinal absorption of drugs, such as ketoconazole, that dissolve poorly in the absence of adequate acid may be reduced. Inhibition of hepatic oxidative drug metabolism of agents such as warfarin, theophylline, and phenytoin, is primarily a problem with cimetidine. Adverse effects will be seen in predisposed individuals and the time course will depend on the pharmacokinetics of the object drug. The other H2RAs are less likely to inhibit drug metabolism and affect renal clearance of procainamide than is cimetidine.

Drug interaction exposures in an ambulatory Medicaid population.

The incidence of selected potential drug-drug interactions (DDIs) in a population of ambulatory patients was studied using data extracted from the automated records of Medicaid drug benefit programs. The system to extract DDI data was devised to assist peer review committees in drug use review. The system yields two types of reports: (1) individual patient profiles and (2) summary reports of all potential DDIs detected within the Medicaid population being reviewed. Potential drug interactions are classified as major, moderate or minor and by route of drug administration. Three months of drug claims from two Medicaid programs were reviewed for potential DDIs involving digitalis preparations, antihypertensive agents (rescinnamine, deserpidine, guanethidine, methyldopa, reserpine, Rauwolfia serpentina extracts) and coumarin anticoagulants. The overall incidence of potential DDI exposures for the three classes was 2.7%, based on drug profiles of 333,641 patients. DDI exposure monitoring can be a useful tool in acquiring further knowledge of DDIs occurring in ambulatory patients.

Nonsteroidal antiinflammatory drug discontinuation in patients with osteoarthritis.

OBJECTIVE: To determine whether discontinuation patterns differed among nonsteroidal antiinflammatory drugs (NSAID) prescribed to treat osteoarthritis (OA). METHODS: In a retrospective cohort study of Health Maintenance Organization enrollees, 1405 patients with OA aged 45 and older who received a new prescription for one of 4 NSAID were followed for 12 months. Survival analysis was used to evaluate time to discontinuation, used here as a relative measure of both drug efficacy and tolerability. RESULTS: Rates of NSAID discontinuation during the study period were high; only 15 to 20% of those started on a study NSAID were still using the same drug at the end of the 12 month followup period. Using a proportional hazards model to adjust for covariates, the risk of discontinuation did not differ when comparing the agent with the longest duration of use, piroxicam (the referent), to enteric coated aspirin [relative risk (RR) 1.10, 95% confidence interval (CI) 0.93 to 1.30]. Adjusted rates of discontinuation were significantly higher for ibuprofen (RR 1.43, 95% CI 1.22 to 1.69) and for naproxen (RR 1.40, 95% CI 1.19 to 1.65) when compared to piroxicam. CONCLUSION: NSAID discontinuation rates are high among patients with OA and risk of discontinuation differed between NSAID, even after controlling for the effects of such variables as age, disease severity, and concomitant therapy.

Performance of community pharmacy drug interaction software.

OBJECTIVE: To evaluate the performance of computerized drug-drug interaction (DDI) software in identifying clinically important drug-drug interactions. DESIGN: One-time performance test of computer systems using a standard set of prescriptions. SETTING: Community pharmacies or central corporate locations with pharmacy terminals identical to those used in actual pharmacies. PARTICIPANTS: Chain and health maintenance organization (HMO) pharmacies with seven or more practice sites in Washington State. A total of nine different DDI software programs were installed in 516 community pharmacies represented by these chains and HMOs. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of software in detecting 16 well-established DDIs contained within six fictitious patient profiles. RESULTS: The software systems failed to detect clinically relevant DDIs one-third of the time. Sensitivity of the software programs ranged from 0.44 to 0.88, with 1.00 being perfect; specificity ranged from 0.71 to 1.00; positive predictive value ranged from 0.67 to 1.00; and negative predictive value ranged from 0.69 to 0.90. For software packages that were installed at different locations, between-installation differences were observed. CONCLUSION: The performance of most DDI-detecting software programs tested in this study was suboptimal. Improvement is needed to advance their contribution to detection of DDIs.

Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer.

OBJECTIVE: The incidence of esophageal adenocarcinoma has risen rapidly in the past two decades, for unknown reasons. The goal of this analysis was to determine whether gastroesophageal reflux disease (GERD) or the medications used to treat it are associated with an increased risk of esophageal or gastric cancer, using data from a large population-based case-control study. METHODS: Cases were aged 30-79 years, newly diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or non-cardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were chosen by random digit dialing and from Health Care Financing Administration rosters. Data were collected using an in-person structured interview. RESULTS: History of gastric ulcer was associated with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4-3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2-9.3). Ever having used H2 blockers was unassociated with esophageal adenocarcinoma risk (OR 0.9, 95% CI 0.5-1.5). The odds ratio was 1.3 (95% CI 0.6-2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8-5.6) when use in the 5 years prior to the interview was disregarded. Risk was also modestly increased among users of antacids. Neither GERD symptoms nor use of H2 blockers or antacids was associated with risk of the other three tumor types. CONCLUSIONS: Individuals with long-standing GERD are at increased risk of esophageal adenocarcinoma, whether or not the symptoms are treated with H2 blockers or antacids.