1,000 research outputs found
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
Letter to the editor by Drs. Gatti and Bertazzoli entitled "Evaluation of isolated case reports on hepatotoxicity”
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
6 Jahre Erfahrungen mit einem Arzneimittelberatungsdienst fĂĽr 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
Developing a Model for Quantifying QTc-Prolongation Risk to Enhance Medication Safety Assessment: A Retrospective Analysis
There are currently no established methods to predict quantitatively whether the start of a drug with the potential to prolong the QTc interval poses patients at risk for relevant QTc prolongation. Therefore, this retrospective study aimed to pave the way for the development of models for estimating QTc prolongation in patients newly exposed to medications with QTc-prolonging potential. Data of patients with a documented QTc prolongation after initiation of a QTc-prolonging drug were extracted from hospital charts. Using a standard model-building approach, general linear mixed models were identified as the best models for predicting both the extent of QTc prolongation and its absolute value after the start of a QTc-time-prolonging drug. The cohort consisted of 107 adults with a mean age of 64.2 years. Patients were taking an average of 2.4 drugs associated with QTc prolongation, with amiodarone, propofol, pipamperone, ondansetron, and mirtazapine being the most frequently involved. There was a significant but weak correlation between measured and predicted absolute QTc values under medication (r = 0.262, p < 0.05), as well as for QTc prolongation (r = 0.238, p < 0.05). As the developed models are based on a relatively small number of subjects, further research is necessary to ensure their applicability and reliability in real-world scenarios. Overall, this research contributes to the understanding of QTc prolongation and its association with medications, providing insight into the development of predictive models. With improvements, these models could potentially aid healthcare professionals in assessing the risk of QTc prolongation before adding a new drug and in making informed decisions in clinical settings
The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity
The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases
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
Characterization of ligand-induced thermal stability of the human organic cation transporter 2 (OCT2)
Introduction: The human organic cation transporter 2 (OCT2) is involved in the transport of endogenous quaternary amines and positively charged drugs across the basolateral membrane of proximal tubular cells. In the absence of a structure, the progress in unraveling the molecular basis of OCT2 substrate specificity is hampered by the unique complexity of OCT2 binding pocket, which seemingly contains multiple allosteric binding sites for different substrates. Here, we used the thermal shift assay (TSA) to better understand the thermodynamics governing OCT2 binding to different ligands.Methods: Molecular modelling and in silico docking of different ligands revealed two distinct binding sites at OCT2 outer part of the cleft. The predicted interactions were assessed by cis-inhibition assay using [H]1-methyl-4-phenylpyridinium ([H]MPP) as a model substrate, or by measuring the uptake of radiolabeled ligands in intact cells. Crude membranes from HEK293 cells harboring human OCT2 (OCT2-HEK293) were solubilized in n-Dodecyl-β-D-Maltopyranoside (DDM), incubated with the ligand, heated over a temperature gradient, and then pelleted to remove heat-induced aggregates. The OCT2 in the supernatant was detected by western blot.Results: Among the compounds tested, cis-inhibition and TSA assays showed partly overlapping results. Gentamicin and methotrexate (MTX) did not inhibit [H]MPP uptake but significantly increased the thermal stabilization of OCT2. Conversely, amiloride completely inhibited [H]MPP uptake but did not affect OCT2 thermal stabilization. [H]MTX intracellular level was significantly higher in OCT2-HEK293 cells than in wild type cells. The magnitude of the thermal shift (ΔT) did not provide information on the binding. Ligands with similar affinity showed markedly different ΔT, indicating different enthalpic and entropic contributions for similar binding affinities. The ΔT positively correlated with ligand molecular weight/chemical complexity, which typically has high entropic costs, suggesting that large ΔT reflect a larger displacement of bound water molecules.Discussion: In conclusion, TSA might represent a viable approach to expand our knowledge on OCT2 binding descriptors
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