Differences in erythrocyte phospholipid membrane long-chain polyunsaturated fatty acids and the prevalence of fatty acid desaturase genotype among African Americans and European Americans.

Numerous studies have reported an association between genetic variants in fatty acid desaturases (FADS1 and FADS2) and plasma or erythrocyte long chain polyunsaturated fatty acid (PUFA) levels. Increased levels of n-6 PUFAs have been associated with inflammation and several chronic diseases, including diabetes and cancer. We hypothesized that genetic variants of FADS that more efficiently convert precursor n-6 PUFA to arachidonic acid (AA) may explain the higher burden of chronic diseases observed in African Americans. To test this hypothesis, we measured the level of n-6 and n-3 PUFAs in erythrocyte membrane phospholipids and genotyped the rs174537 FADS variants associated with higher AA conversion among African American and European American populations. We included data from 1,733 individuals who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using gas chromatography. Generalized linear models were used to estimate association of race and genotype on erythrocyte phospholipid membrane PUFA levels while controlling for self-reported dietary intake. We found that African Americans have higher levels of AA and a higher prevalence of GG allele compared to whites, 81% vs 43%, respectively. Homozygous GG genotype was negatively associated with precursor PUFAs (linoleic [LA], di-homo-γ-linolenic [DGLA]), positively associated with both product PUFA (AA, docosahexaenoic acid [DHA]), product to precursor ratio (AA to DGLA), an indirect measure of FADs efficiency and increased urinary isoprostane F2 (F2-IsoP) and isoprostane F3 (F3-IsoP), markers of oxidative stress. Increased consumption of n-6 PUFA and LA resulting in increased AA and subsequent inflammation may be fueling increased prevalence of chronic diseases especially in African descent.

Smoking and red blood cell phospholipid membrane fatty acids.

Smoking is associated with lower n-3 long chain polyunsaturated fatty acids (LCPUFA) concentrations; however, limited studies have accounted for dietary PUFA intake or whether tobacco dose or smoking duration influences this association. We measured red blood cell phospholipid (RBC) membrane concentrations of fatty acids in 126 current smokers, 311 former smokers, and 461 never smokers using gas liquid chromatography and tandem mass spectrometry. Smokers had lower RBC membrane percentages of total n-3 LCPUFAs compared to former smokers or never smokers (median percent: 5.46, [interquartile range (IQR) 4.52, 6.28] versus 6.39; [IQR: 5.18, 7.85] versus 6.59; [IQR 5.34, 8.01]) (p<0.001) and this association remained after adjusting for dietary PUFA intake. Duration of smoking and cigarettes per day were not associated with RBC membrane n-3 LCPUFA differences. Smoking is associated with lower n-3 LCPUFA RBC membrane percentages and this association was not influenced by diet or smoking dose or duration.

American Gastroenterological Association Institute Guideline on the Medical Management of Microscopic Colitis

This article has an accompanying continuing medical education activity on page e17. Learning Objective: Upon completion of this test, successful learners will be able to: (1) learn first-line treatment for the induction of remission in microscopic colitis; (2) identify the expected clinical benefi ts and adverse effects of induction therapy for microscopic colitis; (3) understand the in-dications for and dosing of maintenance therapy for microscopic colitis; (4) consider medications that may precipitate microscopic colitis especially in those who are refractory to medical therapy; and (5) become familiar with treatment strategies for microscopic colitis refractory to first-line therapy.

Cyclooxygenase-2 expression in Barrett's esophagus.

Barrett's epithelium is a recognized premalignant condition for esophageal adenocarcinoma. Nonsteroidal antiinflammatory drugs (NSAIDs) decrease the relative risk of colon cancer in humans and the esophageal tumor load in carcinogen-treated mice. Previous studies provided conflicting results for COX-2 activity in Barrett's mucosa. Pinch mucosal biopsies were collected from Barrett's and adjacent normal esophageal mucosa from 17 patients with Barrett's esophagus. Low-grade dysplasia was found in seven patients. COX-2 protein was undetectable in normal esophageal mucosa. COX-1 protein expression did not vary between normal and Barrett's epithelium. Increased COX-2 protein was detected in Barrett's epithelium in seven patients (41%) but did not differ with or without dysplasia (43% vs 40%). In conclusion, COX-2 protein is increased in 41% of patients with Barrett's epithelium compared to normal esophageal mucosa but did not differ with or without dysplasia. COX-2 induction may be an early event in the development of Barrett's esophagus.

Diversification of cyclooxygenase-2-derived prostaglandins in ovulation and implantation.

Previous observations of ovulation and fertilization defects in cyclooxygenase-2 (COX-2)-deficient mice suggested that COX-2-derived ovarian prostaglandins (PGs) participate in these events. However, the specific PG and its mode of action were unknown. Subsequent studies revealed that mice deficient in EP(2), a PGE(2)-receptor subtype, have reduced litter size, apparently resulting from poor ovulation but more dramatically from impaired fertilization. Using a superovulation regimen and in vitro culture system, we demonstrate herein that the ovulatory process, not follicular growth, oocyte maturation, or fertilization, is primarily affected in adult COX-2- or EP(2)-deficient mice. Furthermore, our results show that in vitro-matured and -fertilized eggs are capable of subsequent preimplantation development. However, severely compromised ovulation in adult COX-2- or EP(2)-deficient mice is not manifested in immature (3-wk-old) COX-2- or EP(2)-deficient mice, suggesting that the process of ovulation is more dependent on PGs in adult mice. Although the processes of implantation and decidualization are defective in COX-2(-/-) mice, our present results demonstrate that these events are normal in EP(2)-deficient mice, as determined by embryo transfer and experimentally induced decidualization. Collectively, previous and present results suggest that whereas COX-2-derived PGE(2) is essential for ovulation via activation of EP(2), COX-2-derived prostacyclin is involved in implantation and decidualization via activation of peroxisome proliferator-activated receptor delta.

Use of healthcare resources among medically and surgically treated patients with gastroesophageal reflux disease: a population-based study.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disorder that may be effectively managed medically or surgically. Direct evaluations of medical resource use are needed to better understand the relative costs of these alternatives. This study compared medical care use for a group of patients receiving surgical treatment for GERD with that for a comparable group of patients receiving medical management. STUDY DESIGN: We conducted a retrospective matched cohort study of Tennessee Medicaid (TennCare) patients with GERD undergoing surgical treatment in 1996 and a group of patients who received medical therapy during the same period. Administrative TennCare data provided computerized records that could be used to identify patients and measure healthcare use. There were 7,502 people who met all of the conditions for inclusion in the study, including at least two encounters with a diagnosis of GERD. One hundred thirty-five of these who underwent fundoplication constituted the surgically treated cohort. The 250 persons in the medically treated cohort were selected randomly from the remaining nonsurgical patients and matched to the surgical cohort by age, gender, race, managed care organization, and acid suppression drug use in the baseline year. The principal outcome of interest was total use of medical resources, including prescription medication. RESULTS: The surgical and medical cohorts did not differ significantly by demographic characteristics or by baseline use of pharmaceuticals. During the baseline year the surgically treated patients were prescribed 302 (95% CI: 270-334) days ofGERD treatment and the matched medical patients were prescribed 292 (95% CI: 267-317) days of GERD treatment. Surgically treated patients used more GERD-related outpatient resources (physician visits and diagnostic testing) in the baseline year, particularly in the 3 months before operation, when they had a mean of more than four outpatient encounter-days. In the followup year, use of GERD-related pharmaceuticals decreased markedly in the surgical cohort. These patients were prescribed an average of 123 days (95% CI: 94-153) of therapy, which was only 36% of that for medical patients (339 days [95% CI: 308-370]). More than 29% of surgical patients were prescribed no GERD-related drugs in the followup year compared with 6% of the medically treated group. The mean number of inpatient days for the fundoplication procedure was 3.2 (95% CI: 2.7-3.6), with a range of 0 to 13 days. There were no differences between the two groups in other healthcare use. CONCLUSIONS: Our results show that in a 1-year period of followup, surgical treatment of severe gastroesophageal reflux disease led to a 64% postsurgical reduction in GERD medication use, with no increase in use of other medical services.

Contraindicated use of cisapride: impact of food and drug administration regulatory action.

CONTEXT: Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. OBJECTIVE: To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. DESIGN AND SETTING: Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). PARTICIPANTS: Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. MAIN OUTCOME MEASURES: Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. RESULTS: In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. CONCLUSION: The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.

Colorectal cancer screening 2000: the role of colonoscopy in average-risk individuals.

Colorectal cancer fulfills all of the criteria of a disease process that is suitable for a screening program. Several screening tests are effective in preventing mortality from colorectal cancer and are widely recommended. Despite the lack of direct comparisons, there is compelling indirect evidence that programs using colonoscopy as the primary tool are likely to be more effective than programs using fecal occult blood testing or flexible sigmoidoscopy as initial strategies. Colonoscopy-first programs are more expensive initially, but their cost effectiveness may prove to be comparable with the currently recommended programs in certain settings.

Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study.

BACKGROUND: Previous observational studies have provided limited information on the effect of specific nonsteroidal anti-inflammatory drugs (NSAIDs) and different patterns of use (duration and dose) on the incidence of colorectal cancer. OBJECTIVE: To determine how patterns of use (duration, dose, and specific drug) of NSAIDs affect incidence of colorectal cancer. DESIGN: Population-based retrospective cohort study. SETTING: Tennessee Medicaid Program, 1985-1992. SUBJECTS: Enrollees (n = 104217) aged 65 years or older with at least 5 years of enrollment. MAIN OUTCOME MEASURES: Incident histologically confirmed colorectal cancer. RESULTS: Users of nonaspirin NSAIDs for at least 48 months of the previous 5 years had a relative risk (RR) of 0.49 (95% confidence interval [CI], 0.24-1.00) for colon cancer when compared with those with no use of NSAIDs. Among those with more than 12 months of cumulative use, those using NSAIDs in the past year (recent users) had an RR of 0.61 (95% CI, 0.48-0.77), whereas those with no recent use had an RR of 0.76 (95% CI, 0.50-1.15). No specific NSAID offered a unique protective effect and low doses of NSAIDs appeared to be at least as effective as higher doses. Protection was most pronounced for right-sided lesions. The RR among recent users with more than 12 months of cumulative use was 0.81 (95% CI, 0.49-1.32) for rectal cancer, 0.77 (95% CI, 0.55-1.08) for left-sided colon cancer, and 0.48 (95% CI, 0.34-0.68) for right-sided colon cancer. CONCLUSIONS: In this elderly population, long-term use of nonaspirin NSAIDs nearly halved the risk of colon cancer. This study was consistent with previous studies that suggest that duration of use but not daily dose of NSAIDs is an important factor for chemoprevention. Our data also suggest that the protective effect is shared by most NSAIDs, and not confined to a small number of these drugs.

No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.

Calcium channel antagonists are commonly used drugs that have recently been reported to be associated with an increased incidence of gastrointestinal hemorrhage. We performed a retrospective cohort study among 105,824 enrollees of the Tennessee Medicaid program 65 years of age or older between 1984 and 1986. Exposure to calcium channel blockers and other medications was determined from pharmacy files. Hospitalization for bleeding peptic ulcers was identified by hospital claims and verified by a review of the medical record. Univariate estimates of relative risk for current users of calcium channel blockers and beta-blocker users were 1.8 (95% confidence interval (CI) 1.2-2.7) and 1.1 (95% CI 0.7-1.6) (reference group was nonuse of either). After adjustment for potential confounders, the relative risks for bleeding peptic ulcer among current users of calcium channel blockers and beta blockers were 1.1 (95% CI 0.7-1.7) and 1.0 (95% CI 0.7-1.6), respectively, when compared with those who used neither drug. In this population, after controlling for important confounders, there was no increased risk for hospitalization with bleeding peptic ulcer among users of calcium channel blockers.

Colorectal cancer and nonsteroidal anti-inflammatory drugs.

The authors have presented a concise review of the studies which evaluate the risk of colorectal cancer among NSAID users. Animals studies have clearly documented a protective effect of NSAIDs in preventing colon cancers in a carcinogen-induced (AOM) model. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that they must be playing a role very early in the adenoma-to-carcinoma sequence of events. Several studies have indicated that treatment of FAP patients with NSAIDs causes a regression of adenomas that were already present prior to initiation of NSAID therapy. Many epidemiological studies have examined the relationship between aspirin use and colorectal cancer. Most of these studies have shown a marked decrease in the relative risk (40-50%) of colorectal cancer among continuous aspirin users. The appropriate dose and duration of aspirin treatment for optimal effects are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is their ability to inhibit cyclooxygenase. Presently, it is not clear whether inhibition of cyclooxygenase-1 or -2 effects on other signaling pathways are required for the protective effect of aspirin and other NSAIDs. The authors and others have demonstrated that COX-2 is upregulated from 2- to 50-fold in 85-90% of colorectal adenocarcinomas, which makes the COX-2 enzyme a possible target. Drugs are currently under development at several pharmaceutical companies that preferentially inhibit either COX-2 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, then these newly developed, more selective NSAIDs may play a role in future chemoprevention strategies.

Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention.

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.

Cyclooxygenase, NSAIDs, and colorectal cancer.

Prevention of human diseases has become a major focus of biomedical investigators around the world. Our current screening and treatment regimens for colorectal cancer are not effective, as indicated by the fact that this disease is the second leading cause of death from cancer in the United States. Recently published reports indicate that continuous use of aspirin reduces the relative risk of colorectal cancer by about 50%. Other work demonstrates that NSAIDs cause regression of adenomas in patients with familial adenomatous polyposis and prevent the development of colon tumors in carcinogen-treated animals. This review is a summary of the literature and includes an analysis of recent reports indicating the potential molecular basis for the chemoprotective effects of NSAIDs.

Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs.

OBJECTIVE: To quantify medical care costs for the diagnosis and treatment of gastrointestinal disorders attributable to use of nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin in elderly persons. DESIGN AND SETTING: Retrospective cohort study of 75,350 Tennessee Medicaid enrollees at least 65 years of age. MEASUREMENTS: The cohort was classified by baseline NSAID use as nonusers (no use preceding 1988), occasional users (< 75% of days) or regular users (> or = 75% of days). For the follow-up year (1989), we calculated annual rates of utilization of and Medicare/Medicaid payments for: medical care for NSAID-associated gastrointestinal disorders; hospitalizations/emergency department visits for peptic ulcers, gastritis/duodenitis, and gastrointestinal bleeding; outpatient upper and lower gastrointestinal tract radiologic and endoscopic examinations; and histamine2 (H2)-receptor antagonist, sucralfate, and antacid prescriptions. Rates were adjusted for demographic characteristics and baseline health care utilization. RESULTS: Among nonusers of NSAIDs, the adjusted mean annual payment for all types of medical care for study gastrointestinal disorders was $134. This increased to $180 among occasional users, an excess of $46 (p < .001); and to $244 among regular users, an excess of $111 (p < .001, comparison with both nonusers and occasional users). Cohort members with any baseline year NSAID use had an adjusted mean annual payment of $191, $57 (p < .001) higher than that for nonusers. In both users and nonusers of NSAIDs, medications and inpatient care accounted for the largest component of costs. Among regular NSAID users, excess payments increased with baseline NSAID dose: $56, $120, and $157 for less than 1, 1 to 2, and more than 2 standard units per day, respectively (p < .01, linear trend). CONCLUSIONS: Nonsteroidal anti-inflammatory drug (NSAID) use in elderly patients was associated with substantial excess costs and utilization of medical care for gastrointestinal disorders.

The risks and costs of upper gastrointestinal disease attributable to NSAIDs.

NSAIDs, including both aspirin and nonaspirin NSAIDs, are among the most frequently used drugs, and their use may result in serious adverse gastrointestinal outcomes and significant medical costs. The increased risks for adverse upper GI hemorrhage and peptic ulcer disease associated with NSAID use have been demonstrated in observational studies and clinical trials; an overview of these results is presented in this article. The magnitude of these risks should play an important role in clinical decision making and should influence decisions regarding the use of this class of drugs.

Effect of a prior-authorization requirement on the use of nonsteroidal antiinflammatory drugs by Medicaid patients.

BACKGROUND: Prior authorization--mandatory advance approval for the use of expensive medications--is now the primary method by which Medicaid programs control expenditures for drugs. However, whether this policy reduces expenditures for specific drugs without causing the unwanted substitution of other drugs or medical services has been largely unstudied. We evaluated the effects of a prior-authorization policy involving nongeneric nonsteroidal antiinflammatory drugs (NSAIDs) in the Medicaid program in Tennessee. METHODS: We compared monthly Medicaid expenditures that were potentially affected by the policy change during the year before and the two years after its implementation. We studied prescriptions for NSAIDs, other analgesic or antiinflammatory drugs, and psychotropic drugs, as well as outpatient services and inpatient admissions for the management of pain or inflammation. RESULTS: At the midpoint of the base-line year, 495,821 people were enrolled in Medicaid. During that year, mean annualized Medicaid expenditures for NSAID prescriptions amounted to $22.41. Expenditures decreased by 53 percent (95 percent confidence interval, 48 to 57 percent) during the next two years, for an estimated savings of $12.8 million. The reduction in expenditures resulted from the increased use of generic NSAIDs, as well as from a 19 percent decrease in overall NSAID use (95 percent confidence interval, 13 to 25 percent). There was no concomitant increase in Medicaid expenditures for other medical care. Regular users of nongeneric NSAIDs, those most affected by the policy change, had similar reductions in NSAID expenditures and use, with no increase in expenditures for other medical care. CONCLUSIONS: Prior-authorization requirements may be highly cost effective with regard to expenditures for NSAIDs, drugs that have very similar efficacy and safety but substantial variation in cost.

Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons.

To determine the incidence rate of serious ulcer disease among users and nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs), a retrospective cohort study was done on 103,954 elderly Tennessee Medicaid recipients with 209,068 person-years of follow-up from 1984 to 1986. There were 1,371 patients hospitalized with peptic ulcer disease or upper gastrointestinal hemorrhage identified by Medicaid hospital claims and verified by review of the medical record. Ulcer hospitalization rates by NSAID exposure category, duration of use, and daily dose were determined. The rates of ulcer hospitalization among nonusers and current users of NSAIDs were 4.2 and 16.7 per 1,000 person-years, respectively, an excess rate among current users of 12.5 (95% confidence interval (CI) 11.4-13.6) per 1,000 person-years. Among new users, the ulcer hospitalization rates were 26.3 per 1,000 person-years during the first 30 days of use and 20.9 per 1,000 person-years over the next 31-180 days, representing excess ulcer hospitalization rates of 22.1 (95% CI 18.6-25.6) and 16.7 (95% CI 13.1-20.1) per 1,000 person-years, respectively. For long-term users (180 days or more of continuous NSAID use), the ulcer hospitalization rate remained elevated at 15.3, an excess of 12.0 (95% CI 10.3-13.6) hospitalizations per 1,000 person-years. The excess hospitalization rates per 1,000 person-years increased with increasing dose from 6.0 (95% CI 4.0-8.0) for the lowest dose category to 17.8 (95% CI 15.5-20.1) for the highest. The excess rate of ulcer hospitalization for elderly NSAID users is high. These drugs should be used with caution in elderly persons, and alternatives to NSAID therapy should be strongly considered.