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A pharmacokinetics and pharmacodynamic model of nitroglycerin (NTG) effects on cerebral blood flow (CBF) and mean velocity (MV)
Author(s) -
Shang E.,
Forrest A.,
Ma Q.,
Fucile N. W.,
Bednarczyk E. M.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.231
Subject(s) - cerebral blood flow , pharmacodynamics , medicine , anesthesia , clinical pharmacology , pharmacokinetics , migraine , blood flow , pharmacology , cardiology
Background GTN has been widely used in clinical medicine, as well as in a variety of experimental headache models. To date, no studies modeling GTN concentration against brain blood flow have been published. In this study, we comodeled GTN concentrations against two pharmacodynamic (PD) effects: CBF and middle cerebral artery (MCA) MV in a GTN induced headache model. Methods Healthy volunteers received intravenous GTN at 0.125, 0.25 and 0.5 mcg/kg/min in a stepped infusion. Arterial GTN concentrations were measured by GC‐EC. CBF was measured by H 2 15 O PET and MV with transcranial Doppler. A Hill‐type PD model was fit to the measurements of CBF and MV using maximum likelihood (ADAPT II). Model discrimination was by Akaike's Information Criterion (ADAPT II). Results Estimated parameters are listed in the following (see Table) Conclusions Our findings represent the first report of modeling of arterial concentrations of GTN against CBF and MV. This may provide a useful tool for assessing the effect of anti‐migraine medications on brain blood flow using the GTN headache model. Clinical Pharmacology & Therapeutics (2005) 77 , P89–P89; doi: 10.1016/j.clpt.2004.12.231N = 9 Mean S.D.CLt (L/min) 0.949 1.2 CBF (mL/min/100 kg) E o 49.2 5.6fE max 0.329 0.20 MV of MCA (cm/sec) E o (R/L) 74.0/72.0 11/12fE max (R/L) −0.172/−0.172 0.055/0.050(CLt: total serum clearance; E 0 : baseline effect; fE max : maximal change of PD parameters following GTN; R/L: right and left MCV). Models of GTN pharmacokinetics r 2 = 0.847) and PD effects were adequately fitted (r 2 CBF = 0.792; r 2 TCD = 0.706).