Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ga...
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Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ganciclovir but has a relatively low bioavailability and this may be problematic in at-risk patients with malabsorption. The bioavailability and therefore therapeutic potential of oral ganciclovir in cystic fibrosis (CF) patients post-lung transplant (LT) might be expected to be inadequate given the high incidence of malabsorption in these patients. An 8 h pharmacokinetic study was performed in 12 CF patients 160 +/- 122 days post-transplant who had been taking 1 g oral ganciclovir tds for 3 days with food (plus normal enzyme supplements). Mean (range) serum creatinine was 150 mu mol/L (70-280). Blood was sampled at 0.5, 1, 2, 3, 4, 6 and 8 h post-final dose. Plasma was stored at -20 degrees C and later analysed by highperformance liquid chromatography. Mean peak concentration (C-min) was 4.8 mg/L (0.96-12.8), mean minimum concentration (C-min) was 3.6 mg/L (0.78-11.7) and mean area under the curve (AUC) was 35.4 mg.8 h/L (8-99). C-max, C-min and AUC correlated significantly with one another (P < 0.001) as well as with serum creatinine and creatinine clearance(P < 0.01). When corrected for alterations in renal function, plasma oral ganciclovir levels are as predicted for other transplant populations. Three days of oral ganciclovir results in therapeutically useful plasma drug levels in the CF LT population, despite a background of general malabsorption. C-max, C-min and AUC are highly correlated, allowing for the possibility of steady-state drug monitoring to confirm that the recommended dosing algorithm produces appropriate plasma levels.
The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h ...
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The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7: 00 AM to 7: 00 PM). 2'-5' Oligoadenylate synthetase activity in plasma at 24 h after IFN-alpha (10 MI. U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P<.05). The uptake of [H-3] thymidine by lymphocytes after 24-h incubation with IFN-alpha, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9: 00 AM than in the cells obtained at 9:00 PM (P<.01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P<.05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-alpha, which showed higher clearance for injections given at 9: 00 PM than for those at 9:00 AM (P<.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9: 00 PM than at 9: 00 AM (P<.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.
Following the identification of first pass metabolism issues with our recently described anti-HCMV compounds, the naphthyridines and isoquinolines, we have designed a class of novel metabolically stable and orally bio...
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Following the identification of first pass metabolism issues with our recently described anti-HCMV compounds, the naphthyridines and isoquinolines, we have designed a class of novel metabolically stable and orally bioavailable anti-HCMV agents, the dihydroisoquinolines. (C) 2000 Elsevier Science Ltd. All rights reserved.
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