Hereditäre Defekte hepatobiliärer Transportproteine

Zusammenfassung: Eine gestörte Funktion hepatobiliärer Transportproteine kann zu schweren hereditären cholestatischen Leberkrankheiten führen. Die progressive familiäre intrahepatische Cholestase (PFIC) manifestiert sich im frühen Kindesalter. Varianten des FIC1-Aminophospholipidtransporters (ATP8B1-Gen) verursachen sowohl die PFIC1 als auch die benigne rekurrente intrahepatische Cholestase vom Typ1 (BRIC1). Ein Funktionsverlust der Gallensäuren-Effluxpumpe BSEP (ABCB11) führt zu PFIC2 oder BRIC2. Eine häufige BSEP-Variante, der V444A-Polymorphismus, wird häufig bei verschiedenen Arten von Cholestase gefunden, u.a. bei medikamentös induzierten Leberschäden. Schließlich führt die Dysfunktion des "multidrug resistance gene product 3" (MDR3, ABCB4) zu PFIC3, die mit niedrigen biliären Phospholipiden und - aufgrund von Gallengangsschädigungen - hohen GGT-Konzentrationen im Serum einhergeht. Alle drei Transportergene sind auch mit gewissen Formen der intrahepatischen Schwangerschaftscholestase assoziiert. Die Behandlungsoptionen umfassen die Gabe von Ursodeoxycholsäure (UDCA) bei milderen Verlaufsformen bis hin zur Lebertransplantation bei schweren pädiatrischen cholestatischen Leberkrankheite

6 Jahre Erfahrungen mit einem Arzneimittelberatungsdienst für Patienten

Zusammenfassung : Hintergrund und Ziel: : Viele Patienten sind nur ungenügend über ihre Arzneimitteltherapie informiert. Daher besteht bei ihnen der Bedarf an zusätzlichen Informationen über Arzneimittel. Die Erfahrungen mit einem Arzneimittelberatungsdienst für Patienten werden hier berichtet. Patienten und Methodik: : Der Beratungsdienst war über Telefon, E-Mail sowie auf dem Postweg erreichbar und richtete sich zu Beginn an Patienten in Sachsen, seit 2005 an Personen aus ganz Deutschland. Sowohl demographische wie auch arzneimitteltherapiebezogene Daten der Patienten wurden erfasst und mittels einer relationalen Datenbank analysiert. Alle an den Beratungsdienst gerichteten Anfragen zwischen August 2001 und Januar 2007 wurden ausgewertet. Ergebnisse: : 5 587 Anfragen wurden registriert. 61,4% der anfragenden Personen waren weiblich und 33,8% männlich (Geschlecht unbekannt bei 4,8% aufgrund anonymer Anrufe). Allgemeiner Informationsbedarf zu Arzneimitteln und Therapie (27,5%) und Fragen zu Nebenwirkungen (24,7%) waren die am häufigsten genannten Anfragegründe. Die am meisten nachgefragte Arzneistoffgruppe stellten Arzneimittel für das kardiovaskuläre System mit 34,4% dar, gefolgt von Pharmaka für neuropsychiatrische Erkrankungen mit 15,1%. Schlussfolgerung: : Die Ergebnisse dieser Auswertung zeigen einen offensichtlichen Bedarf an einem Arzneimittelberatungsdienst für Patienten. Dieser lässt sich möglicherweise auf Zeitmangel bei den Ärzten zurückführen. Ein unabhängiger und fachkundiger Arzneimittelinformationsdienst vermag die Qualität der medizinischen Versorgung sowie die Zufriedenheit der betroffenen Patienten zu verbesser

Evaluation of medication safety in the discharge medication of 509 surgical inpatients using electronic prescription support software and an extended operational interaction classification

Purpose: Our aim was to study drug interactions and dose adjustments in patients with renal impairment in the discharge medication of surgical inpatients and to evaluate the strengths and limitations of clinical decision support software (CDSS) for this task. Methods: This was a cross-sectional study involving 509 surgical patients of a primary care hospital. We developed a customized interface for the CDSS MediQ, which we used for automated retrospective identification of drug interactions in the patients' discharge medication. The clinical relevance of the interactions was evaluated based on the Zurich Interaction System (ZHIAS) that incorporates the operational classification of drug interactions (ORCA). Prescriptions were further analyzed for recommended dose adjustments in patients with a glomerular filtration rate <60ml/min. Results: For the total of 2,729 prescriptions written for the 509 patients enrolled in the study, MediQ generated 2,558 interaction alerts and 1,849 comments. Among these were ten "high danger” and 551 "average danger” alerts that we reclassified according to ORCA criteria. This reclassification resulted in ten contraindicated combinations, 77 provisionally contraindicated combinations, and 310 with a conditional and 164 with a minimal risk of adverse outcomes. The ZHIAS classification also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 56 prescriptions without a recommended dose adjustment for impaired renal function. Conclusions: CDSS identified a large number of drug interactions in surgical discharge medication, but according to ZHIAS criteria only a minor fraction of these appeared to involve a substantial risk to the patient. CDSS should therefore aim at reducing over-alerting and improve usability in order to become more efficacious in terms of the prevention of adverse drug events in clinical practic

Performance of different data sources in identifying adverse drug events in hospitalized patients

Purpose: The incidence of adverse drug events (ADE) is an important parameter in determining the quality of medical care. We identified the probability that a specific data source would identify ADEs in patients on the oncology ward, that could be assigned to one substance. Methods: We captured all medical adverse events (AE) from five different data sources. Each AE was determined to be drug-related according to the WHO criteria and classified according to the severity, category, and causality of the ADE. Results: The study recorded 129 patients with 252 hospitalizations over a 5-month period. A total of 3,341 medical events were captured and resulted in 1,121 ADEs. In 122 patients, at least one ADE (95%) was observed. Only 39 hospitalizations were believed not to have an ADE (15%). No ADE was captured by all data sources. The patient record captured 550, the nursing record 569, the laboratory tests 387, the questionnaire 63, and the event monitoring during grand rounds 141 ADEs. Only the nursing record and the laboratory tests had a significantly different probability of observing indicative ADEs. Conclusion: For all AEs reported in the data sources, physicians and nurses were the best source for ADEs. Data sources differed in identifying indicative ADEs and were influenced by specific patient parameter

Arzneimittelinteraktionen mit antiretroviralen Medikamenten

Zusammenfassung: Arzneimittelwechselwirkungen sind bei der Behandlung von HIV-Infizierten häufig, da die hochaktive antiretrovirale Therapie immer mehrere Wirkstoffe beinhaltet. Dazu kommen oft Medikamente gegen opportunistische Infektionen und Begleiterkrankungen. Alle Proteaseinhibitoren führen zu einer Inhibition von CYP3A, das im Metabolismus von rund 50% aller Arzneistoffe wichtig ist, beispielsweise Simvastatin, Atorvastatin, Sildenafil und Clarithromycin. Ritonavir ist von allen Proteaseinhibitoren der stärkste Hemmstoff der CYP3A-Aktivität. Dies wird auch genutzt, um die Bioverfügbarkeit anderer Proteaseinhibitoren zu erhöhen. Durch die nichtnukleosidischen Reverse-Transkriptase-Inhibitoren Efavirenz und Nevirapin wird die CYP3A-Aktivität in der Dauertherapie gesteigert. Um Interaktionen vorzubeugen, müssen zu Beginn und bei Therapieende die Dosierungen von CYP3A-Substraten angepasst werden. Interaktionen können auch durch die Beeinflussung von glukuronidierenden Enzymen oder Transportproteinen entstehen. So wird P-Glykoprotein durch Ritonavir gehemmt, was zu einer Erhöhung der Exposition gegenüber vielen Chemotherapeutika führ

Thiopurine S -methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs

Objective: More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed. Methods: The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing. Results: The inter-individual TPMT activity showed a range from 23nmol MTG/g*Hb*h−1 to 97nmol MTG/g*Hb*h−1 with a median of 56nmol MTG/g*Hb*h−1. Using a cut-off concentration of 45.5nmol MTG/g*Hb*h−1, a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%. Conclusions: This study defines the cut-off value for the TPMT phenotyping assay at 45.5nmol/g*Hb*h−1, beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60

Comparative evaluation of three clinical decision support systems: prospective screening for medication errors in 100 medical inpatients

Purpose: Clinical decision support systems (CDSS) are promoted as powerful screening tools to improve pharmacotherapy. The aim of our study was to evaluate the potential contribution of CDSS to patient management in clinical practice. Methods: We prospectively analyzed the pharmacotherapy of 100 medical inpatients through the parallel use of three CDSS, namely, Pharmavista, DrugReax, and TheraOpt. After expert discussion that also considered all patient-specific clinical information, we selected apparently relevant alerts, issued suitable recommendations to physicians, and recorded subsequent prescription changes. Results: For 100 patients with a median of eight concomitant drugs, Pharmavista, DrugReax, and TheraOpt generated a total of 53, 362, and 328 interaction alerts, respectively. Among those we identified and forwarded 33 clinically relevant alerts to the attending physician, resulting in 19 prescription changes. Four adverse drug events were associated with interactions. The proportion of clinically relevant alerts among all alerts (positive predictive value) was 5.7, 8.0, and 7.6%, and the sensitivity to detect all 33 relevant alerts was 9.1, 87.9, and 75.8% for Pharmavista, DrugReax and TheraOpt, respectively. TheraOpt recommended 31 dose adjustments, of which we considered 11 to be relevant; three of these were followed by dose reductions. Conclusions: CDSS are valuable screening tools for medication errors, but only a small fraction of their alerts appear relevant in individual patients. In order to avoid overalerting CDSS should use patient-specific information and management-oriented classifications. Comprehensive information should be displayed on-demand, whereas a limited number of computer-triggered alerts that have management implications in the majority of affected patients should be based on locally customized and supported algorithm

Drugs and hepatic transporters: A review

The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ABC and the SLC families mediate the uptake of endogenous compounds and xenobiotics into the hepatocyte as well as their elimination from the cells. Multiple processes are involved. The uptake of xenobiotics in hepatocytes is mediated by organic anion transporting polypeptides (OATPs) and by organic anion and cation transporters (OATs and OCTs). The elimination of drugs and metabolites from the liver cell back to the bloodstream is accomplished mainly by multidrug resistance-associated protein 3 (MRP3) and MRP4, while the elimination towards the biliary canaliculi is mediated by several different transporters (MRP2, BCRP, MDR1 and MATE1). Since bile acids and their salts are toxic detergents for hepatocytes, they have to be eliminated efficiently. This task is accomplished by the bile salt export pump BSEP. Two further transporters, MDR3 and ATP8B1 are involved in the proper constitution of bile. All these transporters can be influenced, mainly inhibited by a number of drugs, but also by metabolites from endogenous compounds such as estrogens. Additionally, rare monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis type 2 by genetic modifications in BSEP that lead to a loss of transporter function. Functional impairment of other transporters by genetics or by drugs also leads to liver injury, a potentially life-threatening disease that is still not fully understood. Hence, the interplay between drugs and hepatic transporters is multiple, and the knowledge of this interplay helps in understanding the etiology and molecular mechanisms behind some forms of (drug-induced) liver injury