Search

Background: Because the majority of migraineurs are young women in their peak reproductive years, it is important to understand the possible effects on the pharmacokinetics of both medications when sumatriptan is coadministered with an oral contraceptive (OC).Objectives: The primary objective of this study was to assess the effect of multiple dosing of the OC norethindrone 1 mg/ethinyl estradiol 0.035 mg (NE/EE) on the single-dose pharmacokinetics of sumatriptan in healthy volunteers. Secondary objectives were to determine the effect of a single dose of sumatriptan on the multiple-dose pharmacokinetics of NE and EE, and to assess the safety and tolerability of the combination.Methods: This was an open-label, 1-sequence, crossover study in healthy women who had been receiving NE/EE for at least 3 months. Subjects received 1 cycle of NE/EE, consisting of 21 days of OC and 7 days of placebo. They also received a single dose of sumatriptan 50 mg on the last day of the OC or placebo regimen. Blood samples for the determination of plasma sumatriptan concentrations were collected on days 21 and 28, and blood samples for the determination of plasma NE and EE concentrations were collected on days 20 and 21. Treatments were compared by analysis of variance. Equivalence between treatments was to be concluded if the 90% CI for the ratio of reference to test means for loge-transformed parameters (area under the plasma concentration-time curve [AUC] and maximum measured plasma concentration [Cmax] for each analyte fell within the interval 0.80 to 1.25.Results: Twenty-six women (mean age, 29.8 years; age range, 18–44 years; weight range, 52–82 kg) participated in the study. The 90% CI for the ratio of refence to test means for the AUC extrapolated to infinity (AUC∞) of sumatriptan was 1.11 to 1.22, and the 90% CIs for the AUC over the dosing interval at steady state (AUCτ) of NE and EE were 0.96 to 1.00 and 0.91 to 0.97, respectively. The 90% CIs for the ratio of reference to test means for the Cmax of sumatriptan, NE, and EE were a respective 1.05 to 1.30, 0.76 to 0.88, and 0.88 to 1.04. Study treatments were well tolerated. Adverse events were mild or moderate, and there were no clinically significant changes in vital signs or laboratory values.Conclusions: The extent of absorption (AUC) of sumatriptan, NE, and EE was similar after oral administration of sumatriptan and NE/EE, both alone and in combination. Thus, in the opinion of the study investigators, there were no clinically relevant changes in the AUC of any of the medications when sumatriptan and NE/EE were administered concomitantly compared with administration alone. The results of this study suggest that dose adjustment is not necessary when sumatriptan is administered concomitantly with NE/EE in healthy premenopausal women. [Copyright &y& Elsevier]

Background: Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4.Objective: This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan. A secondary objective was to assess the safety and tolerability of combining these agents.Methods: This was an open-label, randomized, 2-way crossover study in healthy volunteers. During treatment period 1, subjects received either a single oral dose of sumatriptan 50 mg (sumatriptan alone) or clarithromycin 500 mg orally every 12 hours on days 1 to 3 and a single oral dose of sumatriptan 50 mg plus a single oral dose of clarithromycin 500 mg on the morning of day 4 (combination treatment). During treatment period 2, they received the alternative regimen. Equivalence between sumatriptan alone and combination treatment was concluded if the 90% CI for the ratio of reference to test means of loge-transformed data for area under the plasma concentration-time curve extrapolated to infinity (AUC∞) and maximum plasma concentration (Cmax) fell within the interval from 0.8 to 1.25.Results: In the 24 evaluable subjects (12 men, 12 women) included in the pharmacokinetic analysis, mean sumatriptan AUC∞ and Cmax values after administration of combination treatment were 9% and 14% higher, respectively, than the corresponding values after administration of sumatriptan alone. The 90% CI for the ratio of reference to test means for AUC∞ was 1.03 to 1.15. The 90% CI for the ratio of reference to test means for Cmax was 1.03 to 1.26, above the traditional bioequivalence criterion. All other pharmacokinetic parameters tested, including nonparametric analysis of the time to Cmax, met the criterion for equivalence between treatments. Both treatments were well tolerated in the 27 subjects (13 men, 14 women) included in the safety analysis.Conclusions: The extent of absorption of sumatriptan was similar after oral administration alone and in combination with clarithromycin dosed to steady state. These data are consistent with previous reports that sumatriptan is unaffected by coadministration with the potent CYP3A4 inhibitor clarithromycin, supporting concomitant administration of these agents without the need for dose adjustment of sumatriptan in the acute treatment of migraine. [Copyright &y& Elsevier]

Management of water resources is essential to maintain sustainable agricultural productivity and preserve groundwater and surface ecosystems. The long-term sustainability of these systems depends on the understanding of complex surface-groundwater flow interactions at different temporal and spatial scales, and the impacts of agricultural practices on water use. To support these efforts, an integrated AnnAGNPS-MODFLOW modeling technology is proposed and evaluated. It combines the capability of the AnnAGNPS model to detailed characterization of farming practices with groundwater flow estimation tools of the MODFLOW model. The AnnAGNPS-MODFLOW model was evaluated in Upper Sunflower River watershed at the Lower Mississippi River Alluvial Plain. The integrated modeling technology in conjunction with observed values of streamflow at the outlet and well water levels were used to estimate irrigation strategies with application rates varying in time and space at field scale. Utilization of improved irrigation characterization have provided evidence of the sensitivity of streamflow and groundwater levels to irrigation strategies. Simulation results indicate that a reduction of irrigation application rates by 20–40% can impact aquifer long-term water levels. This finding supports the need to investigate more efficient irrigation strategies to promote the aquifer sustainable use. The proposed technology provides a management tool critical to understanding and evaluating the impact of agricultural practices, irrigation, and aquifer recharge strategies that are important to sustaining water resources in irrigated agricultural watersheds. • Integrated AnnAGNPS-MODFLOW modeling technology for assessing the impact of farming practices on groundwater resources. • Estimation of irrigation rates varying in time and space at field scale using iterative optimization procedure. • Quantification of relationships between surface streaflow loads, irrigation adoption, and aquifer levels. [ABSTRACT FROM AUTHOR]