The association of nonsteroidal anti-inflammatory drugs with upper gastrointestinal tract bleeding.

To evaluate the risk of developing upper gastrointestinal (UGI) bleeding from nonsteroidal anti-inflammatory drugs (NSAIDs), a retrospective (historical) cohort study was performed, using a computerized data base including 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. Comparing 47,136 exposed patients to 44,634 unexposed patients, the unadjusted relative risk for developing UGI bleeding 30 days after exposure to a NSAID was 1.5 (95% confidence interval 1.2 to 2.0). Univariate analyses demonstrated associations between UGI bleeding and age, sex, state, alcohol-related diagnoses, preexisting abdominal conditions, and use of anticoagulants. This association between NSAIDs and UGI bleeding was unchanged after adjusting for these potential confounding variables using logistic regression. A linear dose-response relationship and a quadratic duration-response relationship were demonstrated. Non-steroidal anti-inflammatory drugs are associated with UGI bleeding, although the magnitude of the increased risk is reassuringly small.

The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.

To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.

Upper gastrointestinal tract bleeding from oral potassium chloride. Comparative risk from microencapsulated vs wax-matrix formulations.

A retrospective cohort study was performed to assess the relative risk of upper gastrointestinal (UGI) tract bleeding from two formulations of potassium chloride. Relevant information was obtained from 1980 through 1984 Medicaid billing data from the states of Michigan, Minnesota, Florida, and Ohio. After patients with a history of UGI tract bleeding prior to their first prescription for either of the two potassium chloride preparations under study were excluded, data were analyzed for 28,790 patients (143,512 patient-months) dispensed a microencapsulated formulation exclusively and 76,118 patients (560,341 patient-months) dispensed a wax-matrix formulation exclusively. The risk of UGI tract bleeding within 30 days after each prescription for the drug of interest was examined. After sampling from the undiseased study subjects and adjusting for multiple potential confounding variables using logistic regression, an odds ratio (95% confidence interval) of 0.67 (0.52 to 0.85) was observed.

Oral contraceptives and other risk factors for gallbladder disease.

Prior studies of the association between oral contraceptives (OCs) and gallbladder disease (GBD) have yielded conflicting results. To clarify this association, a retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. The crude relative risk (RR) and 95% confidence interval (CI) for symptomatic GBD resulting in medical care was 1.14 (CI 1.09 to 1.20), with a clear dose-response (P less than 0.001). Age markedly modified the effect of OCs on GBD. The RR (CI) decreased from 3.1 (2.7 to 3.6) in women 15 to 19 years old to 1.2 (0.9 to 1.5) in women 40 to 44 years old, providing an explanation for previously conflicting reports. The effects of a number of other risk factors on GBD, some which have been controversial, were also confirmed. Adjustment for these did not change the results. In conclusion, OCs are risk factors for GBD, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.

PIP: To clarify the association between oral contraceptives (OCs) and gallbladder disease (GBD), a retrospective (historical) cohort study was performed with 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared to 341,478 nonusers. There were 12,292 cases of GBD that required medical attention during the 2-year study, giving an overall prevalence rate of 25.6/1000 persons over the 2 years. Of the 138,943 OC users in this study, 3889 had GBD, giving a prevalence of 28.0/1000 persons in the 2-year study. Of the 341,478 nonusers, 8403 had GBD, resulting in a prevalence rate of 24.6/1000 persons in these 2 years. The overall prevalence rate in the unexposed subjects in Michigan was higher than that in Minnesota (28.5 vs. 12.3/1000 persons in the 2 year, respectively). This difference in prevalence by state may rest in part from differences in urbanization or to the known differences in racial distribution. Comparing Minnesota with Michigan, blacks are markedly underrepresented (5.9% versus 35.6%), Indians are overrepresented (3.9% versus 0.37%), and Orientals are overrepresented (5.7% versus 0.48%). Alternatively, this difference in prevalence by state may result from administrative dissimilarities between the 2 Medicaid programs, such as in differences in the number of diagnoses that can be provided per visit and the number of visits that can be included on each claim form. The results indicate that subsequent analyses need to be state specific or state adjusted. The crude relative risks confidence intervals for the effect of OCs on GBD were 1.14 overall, 1.08 for Michigan, and 1.39 for Minnesota. While the proportion of subjects using OCs decreased with advancing age, the prevalence of GBD increased steadily with age in both users and nonusers. Stratification by 5-year age intervals revealed age to be a strong modifier of the effect of OCs on GBD, with younger women at a higher risk of GBD from OCs than middle-aged women. The effects of a number of other risk factors on GBD also were confirmed. Adjustment for these failed to change the results. The relationship between OCs and GBD remained statistically significant even after age, state, and each confounding variable was controlled for logistic regression. In sum, OCs are risk factors for GBD, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.

National drug formularies: lessons from Latin America.

Although pharmaceuticals comprise up to 40% of the health care budget in developing countries, the majority of the population does not have access to many of the essential drugs needed to treat prevalent diseases. This situation demands the development of a national formulary of essential drugs for the public sector. The approach used in developing countries is to select drugs of choice for the treatment of prevalent morbidities and avoid therapeutic duplication, unacceptably dangerous drugs, or drugs of unproven efficacy. Drugs are selected based on a review of the prevalent morbidities, health care worker training, patient characteristics, and efficacy/risk information resulting from scientifically sound studies. An added component to the formulary is the inclusion of concise, unbiased prescribing information for each drug selected. A number of product selection guidelines were proven to be effective in establishing and maintaining an essential drug formulary for developing countries. These guidelines include: 1. Selection of drugs with proven efficacy and acceptable risk; 2. Selection of minimum number of drugs needed to treat the prevalent diseases; 3. Inclusion of new products only if they are found to have distinct advantages over products currently in use; 4. Inclusion of combination products only when they provide true benefit over single ingredients; 5. Selection of drugs with clear "drug of choice" indications for prevalent diseases; 6. Evaluation of the administrative and cost impact of products; and 7. Selection of drugs with established high quality.

The Medicaid drug program in Louisiana: critique of the Hefner-Pracon Study.

Critiqued is a study that concluded a restrictive state Medicaid formulary caused an adverse impact on health and increased the cost of nondrug services. The study is criticized because the state's drug restrictions were not of major import, the before and after date were handled in a simplistic manner, and no distinction was made between correlation and causation. Readers should proceed cautiously before accepting the results of research projects sponsored or disseminated by interested parties.

Use of computerized databases to survey drug utilization in relation to diagnoses.

Many studies of drug utilization have suffered from the absence of information on the indications for therapy. A few data sets on drug utilization are available which include indication information. In addition, a number of computerized collections of medical billing data now exist in North America which can be used for such studies. These include data from the Kaiser Permanente Medical Plan; the Group Health Cooperative of Puget Sound; the Commission on Professional and Hospital Activities' Professional Activity Study; the U.S. state of Rhode Island; the Saskatchewan Health Plan in Canada; and Medicaid, the state run but federally financed health insurance plan for economically or medically needy individuals in the United States. These databases have a number of general advantages and disadvantages, which are reviewed. In addition, the differences among these databases are also explored. Finally, examples are presented demonstrating how these databases can be used for: 1) descriptive research on drug utilization, 2) evaluating the appropriateness of drug utilization, and 3) interventions designed to improve the appropriateness of prescribing.

N-methyl-N'-nitro-N-nitrosoguanidine-induced resistance to ionizing radiation.

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pretreatments increase the resistance of Escherichia coli to gamma-radiation. The increased resistance is dependent on functional polA, recA, recB, recC, and lexA genes and is partly dependent on recN. The MNNG-induced resistance is additive to resistance induced by pretreatment with gamma-radiation but not by increases induced by hydrogen peroxide. The MNNG-induced resistance occurs in adaptive response mutants and at pretreatment levels of MNNG that do not activate cells to reactivate UV-inactivated lambda phage. The MNNG-induced resistance appears to be distinct from other inductions to gamma-radiation resistance.

Reversion instability in the galactose operon of Escherichia coli.

The gal-3 mutation, which had been shown previously to produce unstable revertants, was combined in three instances with recA, a mutation which suppresses recombination. Unstable revertants were produced in the gal-3 recA recombinants qualitatively as frequently as in the absence of the recA gene, and it is concluded that a recombination mechanism is not the basis of the instability observed.

An oxygen enhancement ratio in an Escherichia coli strain lacking both the iron and manganese superoxide dismutases.

A mutant of Escherichia coli lacking both the iron and manganese superoxide dismutases, shows an oxygen effect and therefore the oxygen effect is not dependent directly upon the superoxide radical.

Carbohydrate Accumulation and Metabolism in Escherichia coli: Characteristics of the Reversions of ctr Mutations.

The reversion behavior of pleiotropic carbohydrate mutants, previously designated as ctr, was studied. The mutants revert to complete restoration of the wild-type phenotype, as well as to a spectrum of partial wild-type phenotypes. Lac(+) reversions were found in the lac region (11 min) and some Mal(+) reversions occurred at malB (79 min), at a distance from the site of the ctr mutations (46 to 47 min). About one-third of Lac(+) and Mal(+) revertants were constitutive for uptake of their respective substrates, and one-third modified for inducibility. The remaining third were not distinguishable from wild type. Induction of a ctr mutation in a lac constitutive strain, either operator or repressor mutant, did not affect lactose metabolism. A polar-like ctr mutant, deficient in both enzyme I and heat-stable protein of the phosphoenolpyruvate-dependent phosphotransferase strain was also described. Partial revertants of ctr were still found to lack enzyme I.