TY  - JOUR
A1  - Arimany-Nardi, Cristina
A1  - Minuesa, Gerard
A1  - Pastor-Anglada, Marçal
A1  - Keller, Thorsten
A1  - Erkizia, Itziar
A1  - Koepsell, Hermann
A1  - Martinez-Picado, Javier
T1  - Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions
JF  - Frontiers in Pharmacology
N2  - Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.
KW  - hOCT1
KW  - pharmacogenetics
KW  - lamivudine
KW  - HIV infection
KW  - therapy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165236
VL  - 7
IS  - 175
ER  - 
TY  - JOUR
A1  - Salinger, Tim
A1  - Hu, Kai
A1  - Liu, Dan
A1  - Taleh, Scharoch
A1  - Herrmann, Sebastian
A1  - Oder, Daniel
A1  - Gensler, Daniel
A1  - Müntze, Jonas
A1  - Ertl, Georg
A1  - Lorenz, Kristina
A1  - Frantz, Stefan
A1  - Weidemann, Frank
A1  - Nordbeck, Peter
T1  - Association between Comorbidities and Progression of Transvalvular Pressure Gradients in Patients with Moderate and Severe Aortic Valve Stenosis
JF  - Cardiology Research and Practice
N2  - Background. Fast progression of the transaortic mean gradient (P-mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. Methods. This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index >= 30 Kg/m(2), and history of smoking) were analyzed. Patients were divided into slow (P-mean < 5 mmHg/year) or fast (P-mean >= 5 mmHg/year) progression groups. Results. A total of 402 patients (mean age 78 +/- 9.4 years, 58% males) were included in the study. Mean follow-up duration was 3.4 +/- 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 +/- 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 +/- 1.5 vs 2.9 +/- 1.7; P = 0.036). Patients in slow progression group had more often coronary heart disease (49.2% vs 33.6%; P = 0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 +/- 32.6 mg/dl vs 110.8 +/- 36.6 mg/dl; P = 0.005). Conclusion. These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.
KW  - Valvular heart-desease
KW  - Prognostic impact
KW  - Risk-factors
KW  - Chronic heart-failure
KW  - Prevalence
KW  - mild
KW  - statins
KW  - therapy
KW  - mortality
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227291
ER  -