Application of in Vitro T Cell Assay Using Human Leukocyte Antigen-Typed Healthy Donors for the Assessment of Drug Immunogenicity.

It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles.

Reducing warfarin medication interactions: an interrupted time series evaluation.

BACKGROUND: Computerized decision support reduces medication errors in inpatients, but limited evidence supports its effectiveness in reducing the coprescribing of interacting medications, especially in the outpatient setting. The usefulness of academic detailing to enhance the effectiveness of medication interaction alerts also is uncertain. METHODS: This study used an interrupted time series design. In a health maintenance organization with an electronic medical record, we evaluated the effectiveness of electronic medical record alerts and group academic detailing to reduce the coprescribing of warfarin and interacting medications. Participants were 239 primary care providers at 15 primary care clinics and 9910 patients taking warfarin. All 15 clinics received electronic medical record alerts for the coprescription of warfarin and 5 interacting medications: acetaminophen, nonsteroidal anti-inflammatory medications, fluconazole, metronidazole, and sulfamethoxazole. Seven clinics were randomly assigned to receive group academic detailing. The primary outcome, the interacting prescription rate (ie, the number of coprescriptions of warfarin-interacting medications per 10 000 warfarin users per month), was analyzed with segmented regression models, controlling for preintervention trends. RESULTS: At baseline, nearly a third of patients had an interacting prescription. Coinciding with the alerts, there was an immediate and continued reduction in the warfarin-interacting medication prescription rate (from 3294.0 to 2804.2), resulting in a 14.9% relative reduction (95% confidence interval, -19.5 to -10.2) at 12 months. Group academic detailing did not enhance alert effectiveness. CONCLUSIONS: This study, using a strong and quasi-experimental design in ambulatory care, found that medication interaction alerts modestly reduced the frequency of coprescribing of interacting medications. Additional efforts will be required to further reduce rates of inappropriate prescribing of warfarin with interacting drugs.

Environmental risk assessment of six human pharmaceuticals: are the current environmental risk assessment procedures sufficient for the protection of the aquatic environment?

In this study, exposure and ecotoxicity data of six human pharmaceuticals (carbamazepine, clofibric acid, diclofenac, ofloxacin, propranolol, and sulfamethoxazole) were collected, including our own experimental data and literature data. From this data collection, the two-tiered European draft guideline on the environmental risk assessment of human pharmaceuticals was tested. Measured environmental concentrations in effluents from France and in effluents and surface waters from Germany were compared to the predicted environmental concentrations (PECs) in both countries. In a similar manner, predicted no-effect concentrations (PNECs) derived from acute data and PNECs derived from chronic data were estimated for each pharmaceutical and corresponding PEC/PNEC ratios then were compared in both countries. Globally, results demonstrated that all environmental concentrations (predicted or measured) for each considered pharmaceutical exceeded the 10-ng/L cutoff value, which requires the implementation of the second-tier assessment based on ecotoxicity data. Moreover, the six pharmaceuticals showed a relatively limited acute toxicity, and carbamazepine and propranolol were inaccurately identified as having negligible risks under the current European draft procedure. Such results lead to discussion of the actual procedure on pharmaceuticals, especially on the need of appropriate ecotoxicity tests.

Sequential assessment of an antidrug antibody response in a patient with a systemic delayed-onset sulphonamide hypersensitivity syndrome reaction.

A 19-year-old man was treated with trimethoprim-sulphamethoxazole intermittently over 4 weeks. He developed a rash and fever. Despite treatment with low-dose methylprednisolone, his condition worsened. He developed a confluent erythematous macular eruption, elevated liver enzymes, lymphadenopathy, polyserositis and eosinophilia. A tentative diagnosis of sulphonamide hypersensitivity syndrome reaction (SHSR) was made and a serum sample (acute) was obtained to screen for antibodies associated with SHSR. Intravenous methylprednisolone sodium succinate (250 mg every 6 h for 48 h) was administered. The patient's condition improved, and he was discharged with oral prednisone. A convalescent serum sample was obtained 14 weeks later. By Western blotting and enzyme-linked immunosorbent assay (ELISA), antisulphamethoxazole IgG antibodies were detected in the acute serum sample, supporting the clinical diagnosis of SHSR. Contrary to expectations, antibodies were not detected in the convalescent serum sample by immunoblotting. Antisulphamethoxazole antibodies were detected by ELISA in the convalescent serum, but the titre was decreased approximately 45-fold. One possible explanation for the decrease in antibody concentration in the convalescent sample was the administration of high-dose glucocorticoids to the patient following collection of the acute serum sample.

Risk-benefit analyses of drugs: fundamental considerations and requirements from the point of view of the biometrician. Problems in the assessment of the combination of trimethoprim with sulfamethoxazole.

Risk-benefit analyses are a prerequisite for a rational decision about therapies, e.g. drugs. Ingredients of a risk-benefit analysis are: 1. quality and quantity of the benefit; 2. quality and quantity of the harm; 3. benefit and harm of the natural history of the disease; 4. benefit and harm of therapeutic alternatives; 5. commensurability of harm and benefit; 6. consideration of all types of adverse drug reactions together. The available evidence was not suitable for a sound risk-benefit analysis of the use of trimethoprim-sulfamethoxazole. However, there seems to be enough evidence to restrict the use of trimethoprim-sulfamethoxazole in diseases with a benign prognosis and/or when there are therapeutic alternatives with a smaller risk/benefit ratio. Reliable rules for risk-benefit analyses have to be developed and the necessary information has to be gained also in methodologically sound phase IV research.

Management of recurrent urinary tract infections with patient-administered single-dose therapy.

In a randomized crossover trial, 38 women with recurrent urinary tract infections were assigned to use either continuous prophylaxis with trimethoprim-sulfamethoxazole or intermittent self-administered therapy (single-dose trimethoprim-sulfamethoxazole taken for acute urinary symptoms). The infection rate for patients on prophylaxis was 0.2 episodes/patient-year compared with 2.2 infections/patient-year for patients on self-administered therapy (p less than 0.001). Thirty-five of thirty-eight symptomatic episodes diagnosed by patients as infection were confirmed microbiologically, and 30 of the 35 infections responded clinically and microbiologically to patient-administered therapy with single-dose trimethoprim-sulfamethoxazole. No complications were seen in the 5 patients in whom therapy failed. The annual costs of prophylaxis and self-therapy were similar ($256 and $239, respectively) and both were less expensive than conventional therapy in women having 2 or more infections per year. In selected women, self-therapy is efficacious and economical compared with conventional therapy or prophylaxis.

Management of acute dysuria. A decision-analysis model of alternative strategies.

A decision-analysis model was developed to estimate the effects and costs of alternative initial management strategies for women presenting with dysuria and pyuria. We compared days of morbidity and direct medical costs associated with single-dose and multiple-dose regimens of amoxicillin and trimethoprim-sulfamethoxazole and examined the cost-effectiveness of doing an initial urine culture. We used varying assumptions for prevalence of etiologic agents, treatment efficacy, frequency of side effects, and duration of symptoms. Single-dose regimens were preferable to multiple-dose regimens of either drug, and trimethoprim-sulfamethoxazole was preferable to amoxicillin. Single-dose trimethoprim-sulfamethoxazole therapy resulted in the fewest expected symptom-days (2.7) and the lowest expected cost (+54). The advantage of single-dose strategies in minimizing expected symptom-days resulted largely from the threefold to fourfold increase in the incidence of side effects reported with multiple-dose therapy. Obtaining an initial urine culture in all patients reduced expected symptom-days by about 10% but increased expected cost by about 40%.

Acute cystitis: a prospective study of laboratory tests and duration of therapy.

The efficacy of single-dose therapy with trimethoprim-sulfamethoxazole (TMP-SMZ) and the cost-effectiveness of routine urinalyses and cultures were studied in a prospective randomized trial of 200 women who presented with symptoms of acute lower urinary tract infection. Without the physician's knowledge of the results of urinalysis or culture, the patients were randomly assigned to receive either a single dose or a 10-day multiple-dose course of TMP-SMZ and were followed up for 6 months. Of the 136 patients with positive urine cultures, 68 received single-dose therapy with TMP-SMZ--10 of whom had relapses--and 68 received multiple-dose therapy with TMP-SMZ--only 2 of whom had relapses (P less than 0.02). Fifteen patients in each treatment group experienced reinfection. Side effects of rash and vaginitis were more common in patients who received multiple-dose therapy, but they were mild and well tolerated. Of the 51 patients with urethral syndrome, 48 became asymptomatic after therapy. None of the following tests predicted treatment outcome: pretreatment urinalysis, urine culture or susceptibility testing, antibody-coated bacteria testing, or routine follow-up urinalyses or urine cultures. Empiric therapy with TMP-SMZ in selected women with symptoms of acute uncomplicated urinary tract infection seems practical, safe, and cost-efficient. Considerable savings can be achieved by reserving urinalyses and urine cultures for patients with persistent or recurrent symptoms. Higher cure rates can be expected in patients who receive a standard 10-day course of therapy with TMP-SMZ compared with those who receive single-dose therapy with TMP-SMZ.

Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs.

During the decade 1968-1978 the Danish Board of Adverse Reactions to Drugs received 572 (6% of the total number) reports on hepatotoxicity. Halothane amounted to one fourth of the reported cases. Among the 94 psychotropic-induced adverse drug reactions 54 cases were attributed to chlorpromazine, 10 to tricyclic antidepressants, and only 2 to benzodiazepines. Considering the drug consumption data, the combination trimethoprim-sulfamethoxazole is nearly five times more frequently associated with hepatotoxicity than administration of sulfamethizole. Almost two thirds of the hepatotoxic reactions were classified as cytotoxic. Halothane, oxyphenisatin, rifampicin, alfa-methyldopa, papaverine, phenytoin, and ajmaline were almost exclusively related to cytotoxic reactions. Excluding the halothane-induced hepatotoxic reactions, the relative mortality of the cytotoxic (6%) reactions is not significantly different from that of the cholestatic (3%) ones. Thirteen percent of the patients with halothane-induced hepatotoxicity died.