Annemarie Hoffmann

Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers

The effect of grapefruit juice on the urinary excretion of 7-hydroxycoumarin after oral administration of 10 mg coumarin, as an index of cytochrome P450 dependent coumarin metabolism, has been investigated in an open, randomised cross over study in 13 healthy volunteers (7 female, 6 male).The percentage of 7-hydroxycoumarin found in urine was significantly decreased up to 8 h after simultaneous intake of 300 ml grapefruit juice. If the same volume of juice was swallowed 30 min prior to the administration of coumarin, 7-hydroxycoumarin excretion was delayed by up to 6 h. MRTexcr. of coumarin was 70 % extended by coadministration of grapefruit juice.It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways. The mechanism of cytochrome P450 inhibition by these flavonoids is still poorly understood.

Impact of CYP2E1 genotype in renal cell and urothelial cancer patients

Genetic polymorphisms of enzymes involved in carcinogen metabolism have been found to influence susceptibility to cancer. Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several drugs, precarcinogens and solvents to reactive metabolites. In the present study, we investigated the cytochrome P450 2E1 genetic polymorphism in renal cell/urothelial cancer patients from two German regions, Jena and Halle, different with respect to their environmental pollution degree in comparison with healthy controls from the same regions. DNA of peripheral white blood cells was isolated both from 224 renal cell/urothelial cancer patients and 304 controls. We focussed on polymorphisms in the promoter region and intron 6 of the CYP2E1 gene. The polymorphisms were identified as RFLPs by amplification of the appropriate DNA fragment and subsequent digestion with the restriction enzymes PstI, RsaI and DraI. In Jena as well as in Halle, the frequency distributions of the PstI/RsaI, DraI and combined DraI + PstI/RsaI genotypes showed no significant differences between controls and renal cell/urothelial cancer patients. We did not find significant differences between Jena and Halle. 86.2% of all subjects with a homozygote PstI/RsaI genotype also carried a heterozygote DraI genotype, whereas 5.1% of the subjects with a heterozygote PstI/RsaI genotype also carried a heterozygote DraI genotype. Renal cell cancer as well as urothelial cancer risk was not elevated in patients with heterozygote DraI, PstI/RsaI and combined DraI + PstI/RsaI genotypes (odds ratios slightly insignificantly increased). Interestingly enough, an association between these polymorphisms and renal cell cancer risk was found in the female subgroup but not in the male subgroup. The basis of these sex-specifically increased risks are different frequencies concerning heterozygote and homozygote genotypes in controls and cancer patients. In controls, the heterozygote genotype frequency was lower in females than in males. In renal cell cancer patients, the results were quite the contrary. Summing up, our results demonstrate an lack between CYP2E1 genetic polymorphism and renal cell/urothelial cancer risk.

Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity

SummaryThe activity of 7-ethoxycoumarin O-deethylase (ECOD) has been measured in liver biopsy samples from 23 patients (smokers and non-smokers) with different degrees of structural liver damage. The results, which reflect in vitro cytochrome P450-dependent biotransformation, were correlated with various measures of the P450-dependent in vivo elimination of caffeine and metamizol.The relatively non-specific, low affinity component of ECOD activity was significantly correlated with the kinetics of metamizol (mean residence time, apparent clearance, half-life, area under the concentration-time curve, and metabolite excretion in the urine). Thus, metamizol elimination, which is mainly due to P450 IIB, and the low affinity component of ECOD both reflect, at least in part, the activity of the same form of P450. In contrast, caffeine biotransformation, which is via P450 IA, was not correlated with ECOD activity.There was no relation between the kinetics of metamizol and caffeine, perhaps because of the inducing effect that smoking has on caffeine elimination.In patients with liver disease, smoking appears to alter the elimination of caffeine more than the degree of liver disease.

In vitro investigations of drug release and penetration — enhancing effect of ultrasound on transmembrane transport of flufenamic acid

Percutaneous absorption studies are performed in various in vitro models to determine the rate of drug absorption via the skin. We designed an phonophoretic drug delivery system to investigate the influence of ultrasound on transmembrane transport of different drugs. Phonophoresis is defined as the migration of drug molecules, contained in a contact agent, through the skin under the influence of ultrasound. We investigated the absorption of flufenamic acid in a buffer medium in dependence of ultrasound energy and application time. For evaluating membrane penetration of flufenamic acid, the concentration range of buffer solution was measured. Flufenamic acid was determined by using a fluorimetric method. Ultrasound energy was supplied for between 5 and 30 min at a range of intensities (0; 0.3; 0.6; 0.9; 1.2; 1.5 W/cm2). energy levels commonly used for therapeutic purpose. The pronounced effect of ultrasound on the transmembrane absorption of the drug was observed at all ultrasound energy level studied. The time of application was found to play an important role in delivery and transport of drug. Dependent on time, we observed an arise of temperature up to 4.5 degrees. It appears that there was no difference between an intensity of 0.3 and 1.5 W/cm2 and the measured drug concentrations in solution. The highest penetration was observed at an intensity of 1.0 W/cm2 after 30 min. These results were not significantly different from concentration in measurements after 30 min and 0.5 and 1.5 W/cm2. It seems that the arise of drug concentration is caused by effects of temperature and by variation of membrane delivery in dependence of temperature.

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.

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.

Rhabdomyolyse als seltene Komplikation einer Theophyllinintoxikation

ZusammenfassungFallbeschreibung: Es wird über einen 73-jährigen Mann mit Rhabdomyolyse im Rahmen einer akuten Theophyllinintoxikation berichtet. Nach unkontrollierter Einnahme einer unbekannten Menge eines retardierten Theophyllinpräparates in Kombination mit Furosemid wurde er mit Tachykardie, Übelkeit und motorischer Unruhe stationär aufgenommen. Der maximale Theophyllinspiegel betrug 66,5 mg/l. Initial lagen eine Hypokaliämie (2,8 mmol/l), Hyponatriämie (123 mmol/l) sowie erhöhte Werte für Myoglobin (3 789 μg/l) und Kreatinkinase (32,29 μmol/l/s) vor. Es erfolgten die unverzügliche orale Gabe von Aktivkohle in Kombination mit Hämodialyse (CVVH) und forcierter Diurese sowie die intravenöse Gabe von Kaliumchlorid, Natriumchlorid und Metoprolol. Die Serumwerte für Theophyllin, Kreatinkinase und Myoglobin normalisierten sich innerhalb kurzer Zeit, ohne dass ein sekundärer Anstieg des Theophyllinspiegels aufgetreten wäre. Schlussfolgerung: Rhabdomyolysen sind seltene Komplikationen einer Theophyllinintoxikation. In der Literatur sind bislang nur wenige Fälle mitgeteilt worden. Der vorliegende Fallbericht unterstreicht die Notwendigkeit einer schnellen Diagnose und konsequenten Therapieeinleitung, um ein akutes Nierenversagen oder einen letalen Verlauf zu vermeiden. Basierend auf Pathogenese und Epidemiologie theophyllininduzierter Rhabdomyolysen werden Risikofaktoren und Therapieprinzipien formuliert und anhand der Literaturübersicht diskutiert.AbstractCase Report: A case of a 73-year-old male with theophylline overdose complicated by rhabdomyolysis is reported. After uncontrolled self-medication with an unknown number of theophylline slow release 350 mg tablets and furosemide 40 mg tablets he was admitted with unspecific clinical signs like tachyarrhythmia, vomiting and restlessness. Maximum theophylline concentration was 66.5 mg/l, other abnormal laboratory findings included hypokalemia (2.8 mmol/l) and hyponatremia (123 mmol/l). The maximum creatinkinase level was measured after admission (32.29 μmol/s/l) accompanied by a serum myoglobin level of 3,789 μg/l. Immediate treatment with oral activated charcoal and continuous veno-venous hemodialysis (CVVH) was instituted, together with intravenous potassium and sodium chloride substitution, forced diuresis and continuous administratin of intravenous metoprolol. The theophylline, creatinkinase and myoglobin levels decreased rapidly and there was no second rise in theophylline found. The patient survived without sequelae. Conclusion: Rhabdomyolysis is a rare complication of theophylline intoxication. In literature only a small number of cases are reported. Our results illustrate the necessity of a purposeful and fast management to successfully prevent renal failure or death. Some pathogenetic mechanisms of theophylline-induced rhabdomyolysis, epidemiologic data, risk factors and therapeutical principles will be demonstrated by a detailed literature survey.

Schwere Elektrolytstörung und Ödeme unter Therapie mit Rosiglitazon

Zusammenfassung.Fallbeschreibung: Es wird über einen 49-jährigen Mann mit vorbestehender Leberschädigung berichtet, der unter Therapie mit zuerst für 2 Monate 4 mg und später für 5 Monate 8 mg Rosiglitazon mit schweren Elektrolytstörungen und Gesichtsödem zur stationären Aufnahme kam. Die initialen Elektrolytspiegel lagen bei: Natrium 110 mmol/l, Kalium 3,3 mmol/l, Calcium 2,0 mmol/l, Chlorid 81 mmol/l. Eine bereits bekannte Hypercholesterinämie verschlechterte sich massiv auf Werte bis 28,5 mmol/l. Unter Substitutionstherapie mit Natriumchloridinfusion und Kalium normalisierte sich der Elektrolythaushalt rasch, die Hypercholesterinämie war nach Absetzen des Medikaments über mehrere Wochen rückläufig, der Allgemeinzustand des Patienten besserte sich deutlich. Schlussfolgerung: Rosiglitazon ist in Deutschland seit Juli 2000 zugelassen. Obwohl eine Lebertoxizität bei Rosiglitazon bezweifelt wird, ist die Gabe dennoch bei Leberschädigung kontraindiziert. Gerade bei der Verschreibung neuer Medikamente ist besonderes Augenmerk auf die Beachtung von Kontraindikationen und Komedikation zu legen, da die Wirk- (und Nebenwirk-)Mechanismen häufig noch nicht in allen Einzelheiten bekannt sind. Interaktionen zwischen verschiedenen Medikamenten und Einflüsse vorbestehender Erkrankungen werden häufig erst bei breier Anwendung festgestellt.Abstract.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 elctrolyte level normalized rapidly. The hypercholesterolemia improved over several weeks after stopping the drug, and the general condition of the patient improved clearly. Conclusion: Rosiglitazione 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.

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.

Phonophorese von Salicylsäure in der Pharmakotherapie rheumatischer Erkrankungen

Bei der topischen Applikation von Salicylsauresalbe kann durch die gleichzeitige Anwendung von Ultraschall eine Resorptionsverbesserung bei Patienten mit rheumatischen Erkrankungen erreicht werden.