Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC)--an investigation in a department of surgical medicine.

In the multifactorial aetiology of hepatocellular carcinoma (HCC), an association and interaction between genetic polymorphisms of xenobiotic metabolizing enzymes, lifestyle factors, and cancer risk has been postulated. N-acetyltransferase (NAT2) is involved in the metabolic activation and detoxification of aromatic amines. Aromatic amines are potential hepatocarcinogens in humans. In the present study, we investigated if genetic NAT2 polymorphism is related to HCC. Genotyping of NAT2 was performed in 70 HCC patients and 87 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results of this investigation show that 46 out 70 HCC patients (65.7%) and 50 out of 87 controls (57.5%) were of the slow acetylator genotypes. The frequency of distribution of slow and rapid acetylators (genotypes) was not significantly different between cases and controls (p > 0.05). Slow acetylator genotypes were not associated with a significantly increased HCC risk (odds ratio, 1.4; 95% confidence interval, 0.74-2.72). A significant association between NAT2 genetic polymorphism and HCC was observed among smokers. Slow acetylator genotypes significantly increased the HCC risk in cigarette smokers (odds ratio, 3.5; 95% confidence interval, 1.38-9.05). Our results suggest that genetic NAT2 polymorphism may play a role in lifestyle factors-related hepatocarcinogenesis. NAT2 activity may be particulary critical in smoking related hepatocarcinogenesis.

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.

Pharmacokinetics of oxaliplatin during chronomodulated infusion in metastatic gastrointestinal cancer patients: a pilot investigation with preliminary results.

Several clinical trials have demonstrated that the three-drug combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of 5-FU during chronomodulated infusion are available but up to now not for oxaliplatin. In this pilot study, the platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of oxaliplatin, 5-FU and LV in 7 patients with metastatic gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal drug delivery rate of: oxaliplatin (25 mg/m2/d, peak at 16:00 hours), 5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.

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.

[Severe electrolyte imbalance and edema in therapy with rosiglitazone]. / Schwere Elektrolytstörung und Odeme unter Therapie mit Rosiglitazon.

CASE REPORT: A case of a 49-year-old male with preexisting liver damage is reported. The patient was admitted to hospital with severe electrolyte disorder and face edema after therapy first with 4 mg for 2 months and later for 5 months with 8 mg rosiglitazone. The initial electrolyte values were: sodium 110 mmol/l, potassium 3.3 mmol/l, calcium 2.0 mmol/l, chloride 81 mmol/l. An already known hypercholesterolemia worsened substantially to values up to 28.5 mmol/l. Under substitution therapy with sodium chloride infusion and potassium, the electrolyte level normalized rapidly. The hypercholesterolemia improved over several weeks after stopping the drug, and the general condition of the patient improved clearly. CONCLUSION: Rosiglitazone has been certified in Germany since July 2000. Although a liver toxicity with rosiglitazone has been denied, the administration of this drug in patients with liver damage is contraindicated. Especially when prescribing new drugs one has to pay special attention to contraindications and comedication since often not all therapeutic mechanisms and side effects are fully known/understood. Interaction between different drugs and their influences on existing diseases are only noticed after a widespread application of the drug.

Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study.

OBJECTIVE: To estimate incidence rates of drug-related hospitalizations (DRHs) in a longitudinal population-based study with prospective event assessment. DESIGN: Cohort study and time-trend analysis. SETTING: All departments of internal medicine and emergency departments in the urban regions of Jena and Rostock, Germany, serving about 520,000 residents. PARTICIPANTS: All patients admitted between October 1997 and March 2000. Patients with severe cutaneous reactions were excluded. MAIN OUTCOME MEASURES: Incidence of DRH was defined by symptoms or diagnoses at admission that were very likely, likely, or possibly caused by prescription medications, according to a standardized assessment. RESULTS: The incidence of DRH was 9.4 admissions per 10,000 treated patients [95% confidence interval (CI) 9.0-9.9]. Rates were highest for antithrombotics with 26.9 admissions per 10,000 treated patients (95% CI 23.6, 30.1). Most frequent events were gastroduodenal lesions and bleeding (45%). Digitalis preparations showed a linearly increasing trend from 2/10,000 to 14/10,000 during ten quarters ( P<0.0001), which was exclusively attributable to digitoxin, the major source of digitalis in the study area (93%). The incidence of DRH increased with age (4/10,000 to 20/10,000). The mean length of stays in patients with DRH was 13+/-10.6 days. Cumulative direct costs for hospitalization were Euro 4 million in the two urban study areas. The annual direct costs for Germany were estimated to be Euro 400 million. CONCLUSIONS: DRHs are a considerable public health and economic burden. A longitudinal design can observe changes in population-based incidence over time. This approach can be used for public-health planning or to evaluate outcomes of quality management programs designed to reduce drug-induced illness.