caa a22 4500 477126200 CHVBK 20180405111650.0 cr unu---uuuuu 170330e19970901xx s 000 0 eng 10.1023/A:1012138320003 doi (NATIONALLICENCE)springer-10.1023/A:1012138320003 Application of Pharmacodynamic Modeling for Designing Time-Variant Dosing Regimens to Overcome Nitroglycerin Tolerance in Experimental Heart Failure [Elektronische Daten] [John Bauer, Joseph Balthasar, Ho-Leung Fung] Purpose. Prolonged continuous administration of nitroglycerin (NTG) leads to hemodynamic tolerance. We used a previously developed pharmacokinetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this model, may allow avoidance of tolerance development upon continuous NTG inftision. Methods. Simulation experiments (using ADAPT II) were performed to evolve a time-variant infusion regimen that would theoretically provide sustained hemodynamic effect (30% reduction in left ventricular end-diastolic pressure, LVEDP) throughout 10 hours of drug dosing. A computer controlled infusion pump was utilized to deliver this time-variant input. Infusion experiments were then conducted in CHF rats to challenge the predictability of the applied PK/PD model. Results. Simulations showed that exponentially increasing input functions provided more sustained LVEDP effects when compared to linear or hyperbolic input functions delivering the same total NTG dose. A computer-selected infusion regimen of 6.56e0.00156×minutes μg/min was anticipated to provide the desired hemodynamic profile in our animal model. Experiments conducted in rats with congestive heart failure (n = 4) confirmed the prediction of sustained hemodynamic effect without tolerance (28 ± 4% reduction in LVEDP at 10 hrs). Conclusions. These findings support the utility of our PK/PD model of NTG tolerance in predicting NTG action, and serve as an example of therapeutic optimization through PK/PD considerations. Plenum Publishing Corporation, 1997 pharmacodynamics nationallicence nitroglycerin nationallicence nitrate nationallicence tolerance nationallicence hemodynamics nationallicence Bauer John Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut Balthasar Joseph Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut Fung Ho-Leung Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/9(1997-09-01), 1140-1145 0724-8741 14:9<1140 1997 14 11095 https://doi.org/10.1023/A:1012138320003 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012138320003 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bauer John Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut NATIONALLICENCE 700 1- Balthasar Joseph Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut NATIONALLICENCE 700 1- Fung Ho-Leung Department of Pharmaceutics, School of Pharmacy, State University of New York, 14260, Buffalo, New York aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/9(1997-09-01), 1140-1145 0724-8741 14:9<1140 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer