[Analysis of hospital admissions associated with digitalis glycosides]. / Fingerhut--ein alter Hut?: Eine Analyse stationärer Aufnahmen durch digitalisassoziierte unerwünschte Arzneimittelwirkungen.

BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.

Adverse drug reaction monitoring in Jena. Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions.

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area--Jena and Weimar--were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000-2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.

Monitoring of a single post-infusion blood sample to estimate the actual peak and trough concentration of tobramycin in critically ill patients.

UNLABELLED: The therapy of critically ill patients with aminoglycoside antibiotics requires a careful dosing to achieve effective drug concentrations and to avoid toxic effects. OBJECTIVE: To evaluate if a single blood sample per dosing interval 3 or 8 hours after infusion of tobramycin is appropriate to estimate the actual serum concentration 30 minutes after infusion (Cpeak30) and at the end of the dosing interval (C22h) in critically ill patients. METHODS: A total of 32 patients of the intensive care unit (ICU) with an individualized once-daily dosing regimen involved in an intensified drug monitoring of tobramycin were analyzed retrospectively. The first day, serum concentrations 3 and 8 hours after the end of infusion (C3h and C8h) were both used for calculations of Cpeak30 and C22h performed by a one-compartmental Bayesian estimation method (ABBOTTBASE). The subsequent days, each calculation included a single blood sample (C3h or C8h) as well as the corresponding available monitoring data of the previous dosing intervals. Estimation error was analyzed including bias and precision. The influence of some factors such as severity of illness (APACHE II score) and renal function (creatinine clearance) on the estimation error was investigated by multiple linear regression analysis (MLRA). RESULTS: In the first monitored dosing interval, Cpeak30 was overestimated and C22h underestimated by 1.72 and -0.29 microg/ml on median, respectively. The maximum deviation from the true Cpeak30 and C22h was -9.20/+8.57 and -1.90 microg/ml, respectively. The first day, prediction of potentially toxic C22h above 1 mg/ml by an estimation value above 1 mg/ml was possible in 4 of 6 cases only. The subsequent days, mean error (ME) of peak estimations of -0.34 microg/ml and a root mean squared error (RMSE) of 1.84 microg/ml indicated a small underestimation when C3h was used and an overestimation when C8h was used for calculation (ME 1.04 and RMSE 2.83 microg/ml). The difference on ME and RMSE was statistically significant. C22h values outside of the target range (a total of 10 observations) were predicted with sensitivity of 60% in each case. Prediction error of increased C22h was partly considerable and showed the trend to greater underestimation with increasing C22h in MLRA. Increasing serum creatinine (beta = 0.429, p = 0.011) and decreasing creatinine clearance (beta = -0.324, p = 0.039) were only identified as variables affecting the trough level in MLRA. CONCLUSIONS: In the critically ill, C3h but not C8h of tobramycin permitted the estimation of the Cpeak30 in most cases with satisfactory bias and precision starting with 2nd monitored dosing interval. However, high trough levels requiring an adjustment of dose or dosing interval could not be safely predicted; prediction error was intolerable when C22h exceeded the target range of trough level. Data indicate that at least in patients with any sign of renal dysfunction, the measuring of the interesting levels should be preferred to the tested single-point based estimations.