Prophylactic aspirin and risk of peptic ulcer bleeding.

OBJECTIVE--To determine the risks of hospitalisation for bleeding peptic ulcer with the current prophylactic aspirin regimens of 300 mg daily or less. DESIGN--A case-control study with hospital and community controls. SETTING--Hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth. SUBJECTS--1121 patients with gastric or duodenal ulcer bleeding matched with hospital and community controls. RESULTS--144 (12.8%) cases had been regular users of aspirin (taken at least five days a week for at least the previous month) compared with 101 (9.0%) hospital and 77 (7.8%) community controls. Odds ratios were raised for all doses of aspirin taken, whether compared with hospital or community controls (compared with combined controls: 75 mg, 2.3 (95% confidence interval 1.2 to 4.4); 150 mg, 3.2 (1.7 to 6.5); 300 mg, 3.9 (2.5 to 6.3)). Results were not explained by confounding influences of age, sex, prior ulcer history or dyspepsia, or concurrent non-aspirin non-steroidal anti-inflammatory drug use. Risks seemed particularly high in patients who took non-aspirin non-steroidal anti-inflammatory drugs concurrently. CONCLUSION--No conventionally used prophylactic aspirin regimen seems free of the risk of peptic ulcer complications.     

Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: application to antipsychotic drugs.

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects.     

Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women.

OBJECTIVE--To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of myocardial infarction. DESIGN--Matched case-control study. SETTING--16 centres in Austria, France, Germany, Switzerland, and the United Kingdom. SUBJECTS--Cases were 153 women aged 16-44 with a myocardial infarction event. Controls were 498 women (at least 3 controls per case) unaffected by myocardial infarction who were matched with their corresponding case for age and for hospital or community setting within four months of the index infarction. MAIN OUTCOME MEASURES--Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables. RESULTS--The estimated odds ratio for myocardial infarction of third compared with second generation oral contraceptives among all 651 study subjects was 0.36 (95% confidence interval 0.1 to 1.2) (P = 0.11). The odds ratio for the United Kingdom and Germany alone was 0.45 (0.1 to 1.8) (P = 0.26). Other odds ratios for the five countries were 3.1 (1.5 to 6.3) (P = 0.003) for use of second generation products v no current use and 1.1 (0.4 to 3.4) (P = 0.9) for use of third generation products v no current use. Among the confounding variables the independent contribution of smoking (for which adjustment was made in the above estimates) proved to be important (10.1 (5.7 to 17.9), P < 0.001). CONCLUSION--An odds ratio of 0.45 with wide confidence intervals shows that third generation oral contraceptives compared with second generation products are associated with a reduced risk of myocardial infarction or with no difference. This finding from an interim analysis should be interpreted with extreme caution. However, the excess risk of venous thromboembolism associated with the use of third generation products may be balanced by the reduced risk of myocardial infarction associated with the same products.     

Agranulocytosis and Antithyroid Drugs

Propylthiouracil and methimazole are used widely in the treatment of hyperthyroid disorders. The most important complication of the use of these drugs is depression of the neutrophilic granulocyte count. Granulocytopenia occurs in about 4 percent and agranulocytosis occurs in about 0.3 percent of treated patients. Although this depression of the granulocyte count is reversible after the drug is discontinued, serious infection frequently accompanies agranulocytosis and accounts for almost all deaths related to the drugs. It is important to be aware of the clinical features of granulocytopenic reactions due to antithyroid drugs.     

Implication of therapeutic outcomes associated with molecular characterization of paediatric aplastic anaemia

ObjectivesSevere aplastic anemia is characterized by a hypocellular bone marrow and peripheral cytopenia. Mesenchymal stem cells (MSCs) play a crucial role in haematopoietic stem cells (HSCs) development and the development of microenvironment suitable for hematopoiesis. Molecular characterization of telomere maintenance pathway and gene expression profiling of MSCs can be important for the therapeutic interventions among paediatric aplastic anaemia patients.MethodsThe study involved paediatric aplastic anaemia patients (n = 10) and age matched paediatric healthy donors (n = 8). Peripheral blood samples were collected from the individuals. Average leucocyte telomere length and gene expression of the telomere maintenance genes were determined by quantitative real time PCR. Microarray based gene expression profiles (GSE33812) of MSCs for five paediatric aplastic anaemia patients were analyzed compared to five healthy controls and the data was downloaded from the GEO database.ResultsThe telomere length was significantly shorter among paediatric AA patients compared to age matched healthy donors. Interestingly, one subgroup (n = 2) of paediatric AA patients has moderate telomere length comparable to age matched healthy donors. Based on the gene expression analysis of telomere maintenance pathway, TERF2 was significantly downregulated among paediatric patients with shorter telomere length but not among paediatric patients with moderate telomere length. Gene expression profiling of MSCs revealed three differentially expressed genes (GAS2L3, MK167 and TMSB15A) among the patients and was associated with therapeutic outcome.ConclusionTelomere length estimation and gene expression patterns of the MSCs and telomere length maintenance pathway may serve as a potential biomarker and could be associated with therapeutic choice of paediatric aplastic anaemia patients.     

Drug-induced Blood Dyscrasias in Sweden

Cases of drug-induced aplastic anaemia, haemolytic anaemia, thrombocytopenia, and agranulocytosis reported to the Swedish Adverse Drug Reaction Committee during the five-year period 1966-70 have been analysed and compared with cases of the same cytopenias from “all” causes. Oral diuretics were a dominant cause of drug-induced thrombocytopenia, methyldopa of haemolytic anaemia, and oxyphenbutazone of aplastic anaemia. Computer systems should help such studies, particularly in showing a changing pattern of complications and causes.     

Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme.

OBJECTIVE--To examine the relation between the use of aspirin and non-steroidal anti-inflammatory drugs and the presence of asymptomatic colorectal adenomas. DESIGN--Case-control study of subjects participating in a randomised controlled trial of faecal occult blood screening for colorectal cancer. Data on analgesics and other drugs were obtained from a questionnaire which was mainly concerned with diet and was administered by an interviewer. SETTING--Nottingham. SUBJECTS--147 patients with positive results in faecal occult blood tests who were found to have colorectal adenomas (cases), 153 age and sex matched control subjects with negative results in such tests (negative controls), and 176 control subjects with positive results in the tests who were found not to have colorectal adenomas (positive controls). MAIN OUTCOME MEASURES--Relative risk of developing colorectal adenomas according to frequency and duration of use of analgesics. RESULTS--Cases reported taking less aspirin and non-steroidal anti-inflammatory drugs than the negative controls, with the estimated relative risk for any use being 0.49 (95% confidence interval 0.3 to 0.8). The inverse association was less strong when cases were compared with the positive controls (0.66 (0.4 to 1.1)). The association was specific for aspirin and non-steroidal anti-inflammatory drugs there being no association with paracetamol or other drugs. Prescribed use of non-steroidal anti-inflammatory drugs for longer than five years was associated with the lowest risk (0.21 (0.1 to 0.8)), although the numbers reporting prolonged prescribed use were small. CONCLUSIONS--These findings support the hypothesis that aspirin and non-steroidal anti-inflammatory drug use protects against the development of colorectal neoplasia.     

Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism

ObjectiveAgranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism.MethodsThis retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed.ResultsAgranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 10⁹/L and 0.14 (0.02-0.29) × 10⁹/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day.ConclusionsPatients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.     

Analgesic use and the risk of renal cell carcinoma – Findings from the Consortium for the Investigation of Renal Malignancies (CONFIRM) study

PurposeThe incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC.MethodsA population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use.ResultsThe analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13–1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23–2.39) but not men (OR 0.83, 95% CI 0.58–1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054).ConclusionThis study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.     

Immunosuppressive therapy of cyclosporin A for severe benzene-induced haematopoietic disorders and a 6-month follow-up

Long-term exposure to benzene can potentially result in severe haematotoxicities, including pancytopaenia, aplastic anaemia and myelodysplastic syndrome, which are often accompanied by life-threatening symptoms and high mortality. Previous studies demonstrate that benzene-induced haematotoxicities are immune-mediated and that cyclosporin A is a prominent treatment in acquired aplastic anaemia. This study aims to evaluate the potential role of cyclosporin A immunosuppressive therapy for severe benzene-induced haematotoxicity. Between January 2002 and December 2008, 41 patients with severe benzene-induced haematopoietic disorders from five hospitals were enrolled in the study, 22 patients received cyclosporin A, supportive treatments and/or oral testosterone undecanoate, 19 patients were treated with supportive treatments and/or oral testosterone undecanoate as the control group, and a 6-month follow-up was conducted. The results showed that in the cyclosporin A group, 19 of 22 patients (86.36%) had responded to the treatments completely or partially with increased platelets, white blood cells and hemoglobulin counts by the fourth week (P = 0.005), the sixth week (P = 0.001) and the third month post-treatment (P = 0.034), respectively. However, in the control group treated by supportive methods, only 5 of 19 patients (26.32%) responded to the treatments partially (P < 0.001). Cyclosporin A in conjunction with supportive treatments may be an effective treatment modality for patients with severe benzene-induced haematopoietic disorders, which in turn implies that these haematotoxicities are immune-mediated.     

Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs,aspirin, and corticosteroids.

Although non-steroidal anti-inflammatory drugs are known to cause peptic ulcer and its complications, controversy exists about the number of deaths from ulcer which are attributable to their use. A case-control study was therefore performed to determine whether prior use of non-steroidal and other anti-inflammatory compounds was associated with an increased case fatality rate from complications of peptic ulcer. Non-steroidal anti-inflammatory drugs were used by 39% of a series of 80 patients who had died from peptic ulcer complications and by 37% of 160 controls who were survivors matched for sex, age, ulcer site, and nature of complication (odds ratio 1.1; 95% confidence interval 0.6 to 2.1). Similarly, the rates of prior use of aspirin by cases and controls were almost identical (odds ratio 1.2; 95% confidence interval 0.5 to 1.9). Thus neither nonsteroidal anti-inflammatory drugs nor aspirin were associated with increased case fatality rates from peptic ulcer complications. In contrast, corticosteroids were associated with an increased mortality (odds ratio 4.2; 95% confidence interval 0.9 to 25.6). Although this increase in the estimated relative risk was not statistically significant, a review of the case records indicated that most deaths in steroid users were due to serious sepsis, indicating that there might be a causal association between use of the drugs and the mode of death.     

Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.

OBJECTIVE--To compare safety of salmeterol and salbutamol in treating asthma. DESIGN--Double blind, randomised clinical trial in parallel groups over 16 weeks. SETTING--General practices throughout the United Kingdom. SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner (n = 3516). INTERVENTIONS--Salmeterol (Serevent) (50 micrograms twice daily) or salbutamol (200 micrograms four times a day) randomised in the ratio of two patients taking salmeterol to one taking salbutamol. All other drugs including prophylaxis against asthma were continued throughout the study. MAIN OUTCOME MEASURES--All serious events and reasons for withdrawals (medical and non-medical) whether or not they were considered to be related to the drugs. RESULTS--Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol (2.91% v 3.79%; chi 2 = 13.6, p = 0.0002). Mortality and admissions to hospital were as expected. There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry. Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event. CONCLUSIONS--Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted. Overall control of asthma was better in patients allocated to salmeterol. Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment.     

Agranulocytosis, aplastic anemia, and leukemia: relevance to arachidonic acid metabolism

Several agents including drugs, chemicals and viruses are known to induce agranulocytosis, aplastic anemia, and leukemia. The recent identification, characterization and cloning of several peptide regulatory factors, including granulocyte-macrophage-colony stimulating peptide regulatory factor (GM-CSF), erythropoietin, and interleukins and a study of their actions, suggest that agents producing agranulocytosis, aplastic anemia, and leukemia may interfere with the action of these factors. The agents that are capable of inducing these diseases and the various peptide regulatory factors have positive and/or negative actions on the prostaglandin system. Prostaglandins are known to be involved in the maturation and differentiation of the progenitor cells of the bone marrow and in erythropoietin-mediated erythropoiesis. Since prostaglandins influence immune response, modify genetic damage induced by drugs and chemicals, modulate gene action, and have feed-back control on the actions of peptic regulatory factors, it is likely that prostaglandins are involved in the pathogenesis of agranulocytosis, aplastic anemia, and leukemia. If so, this may lead to new therapeutic strategies in these hematological conditions.     

Psychiatric and cardiovascular comorbidities in patients with diabetes mellitus starting antiobesity drugs

The aim of the study was to assess whether the baseline risk of psychiatric and cardiovascular disease in patients with diabetes mellitus differs between those starting to use antiobesity drugs and those not starting to use these drugs. A retrospective nested case-control study within the General Practice Research Database (1987-2002) was done. The cohort included all patients with diabetes mellitus (n = 141,164). Information on patient characteristics (general, cardiovascular, and psychiatric characteristics) was extracted from the medical records. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A total of 511 patients starting to use antiobesity drugs (cases) and 3,065 controls were included in the study cohort. Starters were younger and more frequently female. Of the starters, 91.8% did not receive any dietary advice before starting treatment. Depression (in the year before index date) was associated with the use of antiobesity drugs (OR 2.2; 95% CI 1.7-2.8), as was anxiety (OR 1.6; 95% CI 1.1-2.4). Of the cases, 25.2% had multiple cardiovascular risk factors (>4) compared to 19.0% of the controls. The baseline risk for psychiatric disorders and cardiovascular disease was found to be higher in patients with diabetes mellitus starting to use antiobesity drugs compared to patients with diabetes mellitus not starting such treatment.     

Allogeneic bone marrow transplantation for leukaemia and aplastic anaemia. Results of the Leipzig BMT Group

In acute leukaemias there was a stable plateau in the survival curve at 45% after two years if grafted in first complete remission (n = 20) but only 13% of the patients are disease-free alive if grafted in a more advanced stage of the disease (n = 8). In 16 patients transplanted for chronic myeloid leukaemia the overall survival is 40%, in cases with graft-versus-host disease (GVHD) prevention by cyclosporine survival rate could be improved. Only 8 patients with severe aplastic anaemia, partially in low performance status were able to be transplanted; three died of infections, another by acute GVHD. The fatal complications in our study characterize the international well-known major problems in BMT: GVHD, interstitial pneumonitis, infections, graft failure in aplastic anaemia and recurrence of leukaemia, especially in more advanced leukaemia stage.     

Treatment of severe aplastic anaemia with antilymphocyte globulin or bone-marrow transplantation.

Fifty-three patients with severe aplastic anaemia were admitted to this hospital between January 1976 and June 1980, of whom three arrived in terminal condition and died before treatment for their basic disease could be given. Thus 50 patients were treated and evaluated in a prospective study according to one protocol. Eighteen patients with an HLA-identical sibling underwent bone-marrow transplantation with the aim of achieving haematopoietic chimerism. Thirty-two patients without an HLA-identical sibling were given antilymphocyte globulin with or without an infusion of HLA-haplotype-identical marrow. All these 32 patients received low-dose androgens after the procedure. In the first group eight patients (44%) survived. In the two other groups, 22 patients survived (69%), of whom 20 were completely self-sustaining (63%). Engraftment and graft-versus-host disease did not occur in the group who received antilymphocyte globulin and haploidentical marrow, and the haematopoietic reconstitutions in these patients were all autologous. These results confirm the efficacy of antilymphocyte globulin in the treatment of severe aplastic anaemia and show that such treatment is at least as good as bone-marrow transplantation. Its mechanism of action remains unknown, but most patients with aplastic anaemia have a pool of haematopoietic stem cells able to repopulate the marrow after this type of treatment.     

Role of drugs in traffic accidents.

Serum samples from 201 drivers who presented at emergency departments within six hours after being injured in a road accident and 325 control drivers selected randomly at petrol stations were screened for drugs by combined thin-layer and gas chromatography. Blood alcohol concentrations were also measured, and a questionnaire on the subjects'' state of health and use of drugs administered. At interview 30 patients (15%) and 44 controls (13%) said that they had taken drugs in the previous 24 hours. Four patients (2%) and six controls (2%) said that they had taken psychotropic drugs, but serum analysis detected psychotropic drugs in 10 patients (5%) and eight controls (2.5%). Diazepam was found in 16 of the 18 subjects in whom psychotropic drugs were detected. Alcohol was detected in 30 patients (15%) and three controls (1%). Drug use appeared to be somewhat lower in Finland than in other Western countries, and illness to be a more important traffic hazard than drugs in general. Interview was not a reliable method of establishing whether drivers had taken psychotropic drugs. Taking diazepam may increase the risk of being involved in a traffic accident, but alcohol was the most powerful risk factor.     

Avian exposure and bronchogenic carcinoma.

OBJECTIVE--To investigate the association between bird keeping and risk of lung cancer. DESIGN--Case-control study asking detailed questions on exposure to domestic birds and other pets, smoking, and various demographic and potentially confounding variables. SETTING--District general hospital; current admissions interviewed in hospital or recent admissions interviewed at home. PATIENTS--143 patients with lung cancer, 143 controls with heart disease, and 143 controls with orthopaedic conditions individually matched for age, sex, date of admission, and current or past admission. MAIN OUTCOME MEASURES--Odds ratios for lung cancer in relation to various aspects of bird keeping, after adjustment for smoking and other relevant confounding variables. RESULTS--Risk of lung cancer was not significantly associated with household exposure to pet birds at any time or at various specific periods in life, or to keeping large numbers of birds. For specific types of birds no association was seen for living in households with budgerigars or canaries but risk was significantly associated with keeping pigeons (odds ratio 3.53, 95% confidence interval 1.56 to 7.98). This remained significant after regression analysis to account for confounding variables (3.9, 1.2 to 12.62) in both sexes and all age groups. CONCLUSION--Bird keeping may confer some risk of lung cancer but the relation is not as strong as previously reported.