The overall objective of our research is to examine the relationship between the pharmacokinetics and the pharmacodynamics of nitroglycerin (NTG) and its dinitrate metabolites. We believe that much of the controversy in the literature concerning the efficacy of oral and long-acting nitrates might be explained in terms of the generation of sufficiently high concentrations of the dinitrate metabolites, particularly following oral NTG dosing. Although animal studies have shown these metabolites to be considerably less active than the parent NTG, no analytical methods have been available to quantitate the dinitrate metabolites. We have developed such a method and have shown in preliminary studies that the dinitrate metabolite concentrations observed are sufficiently high, relative to NTG concentrations so that pharmacodynamic responsses to the metabolites might be expected.
The specific aims of this proposal are: 1. Validate the analytical and sample handling procedures for the dinitrate metabolites; 2. Determine the pharmacokinetics of NTG and metabolites following intravenous, sublingual, topical and oral dosing of NTG in healthy volunteers; 3. Use a dog model to investigate individually the pharmacokinetics of the 1,2- and 1,3-dinitrate metabolites and to investigate the possibility of a pharmacokinetic interaction between these metabolites and the parent drug; 4. Measure Laser-Doppier Velocimentry response to various doses of nitroglycerin; 5. In patients with stable angina pectoris compare the efficacy of two different oral doses of NTG, a sublingual dose and a placebo solution employing graded treadmill exercise testing; and 6 in patients in the Cardiac Care Unit receiving NTG as an intravenous infusion measure NTG and metabolite levels in arterial and venous blood samples and compare these values with hemodynamic parameters.
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