ABSTRACT
The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.
Subject(s)
Migraine Disorders/drug therapy , Nitric Oxide Synthase Type II/antagonists & inhibitors , Sulfones/pharmacokinetics , Sulfones/therapeutic use , Adult , Area Under Curve , Female , Half-Life , Humans , Male , Nitrates/blood , Nitric Oxide/blood , Nitric Oxide/metabolism , Sulfones/pharmacology , Tyrosine/analogs & derivatives , Tyrosine/bloodABSTRACT
To evaluate methodology for in vivo interaction studies of benzodiazepines (BZs) and ketoconazole (KCZ) in animal models, this study assessed the pharmacokinetics and electroencephalographic (EEG) effect of KCZ, and suitable dosage regimens of KCZ to maintain sufficiently high KCZ concentrations to inhibit metabolism of BZs in rats. Rats were injected intraperitoneally (i.p.) with KCZ 10 mg kg(-2). No significant EEG change was detected regardless of serum KCZ concentration, indicating that the EEG changes after both BZ and KCZ administration can be attributed entirely to BZ. Serum KCZ concentrations showed an apparent nonlinear pattern of decline with a short half-life (1.38 h). An additional dose of 5 mg kg(-1) i.p. given 180 min after the initial dose sustained KCZ concentrations above 2 pg mL(-1) until at least 500 min after the initial dose. These results provide the basis for design of animal models for in vivo assessment of interactions of BZs and KCZ.
Subject(s)
Anti-Anxiety Agents/antagonists & inhibitors , Antifungal Agents/pharmacokinetics , Electroencephalography/drug effects , Ketoconazole/pharmacokinetics , Animals , Anti-Anxiety Agents/metabolism , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Biological Availability , Chromatography, High Pressure Liquid , Half-Life , Injections, Intraperitoneal , Ketoconazole/administration & dosage , Ketoconazole/pharmacology , Male , Metabolic Clearance Rate , Midazolam/antagonists & inhibitors , Midazolam/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
This article reviews the literature on the plasma concentration-effect relationships for benzodiazepines, in humans and in experimental animals. Only literature that explicitly links pharmacokinetics to pharmacodynamics is included. The following questions are evaluated. Can concentration-effect relationships be demonstrated? If so, are these relations stable? Are the influences of specific factors such as age and disease on these relationships established? It is clear that, when studies are conducted and interpreted appropriately, relations can be found for a wide range of benzodiazepine effects. These include objective measures such as electroencephalography, semisubjective measures such as psychomotor performance, and subjective measures such as mood/sedation scales. A generally applicable model of the relationship which will allow prediction of effect is, however, not yet established. The relationship appears to be dependent on route and rate of administration, because of factors such as distributional delay, formation of active metabolites and, probably, acute tolerance. Furthermore, intra- and interindividual variability is considerable, probably due to varying experimental conditions and intrinsic interindividual differences. The limited data available on factors influencing the plasma concentration-effect relationships for benzodiazepines demonstrate clear changes in the pharmacodynamics after multiple doses, suggesting the development of tolerance, and a subsensitivity in patients with panic disorder. The influence of factors such as age, disease and drug interactions on the pharmacokinetic-pharmacodynamic relationship remains less clear.
