Lack of pharmacodynamic interaction between pentoxifylline and warfarin in the rat.
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Pentoxifylline is a new hemorrheologic agent which decreases platelet aggregation and reduces fibrinogen levels. Its ability to affect the coagulation cascade was studied in rats with and without the coadministration of warfarin. There was no significant difference between the prothrombin time ratio (PTR) of the warfarin group (1.51 +/- 0.38) and the combination drug group (1.47 +/- 0.30) at 6 hours. Likewise, there was no significant difference between the PTR of the control group (1.09 +/- 0.07) and the group administered pentoxifylline alone (1.05 +/- 0.06). Although the mechanisms of action of the two drugs may overlap, the pharmacodynamic activity of warfarin was not significantly altered when pentoxifylline was coadministered.Keywords:
Pentoxifylline
Pharmacodynamics
Prothrombin time
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Ciprofloxacin Prolonged‐Release Tablets Do Not Affect Warfarin Pharmacokinetics and Pharmacodynamics
The purpose of this study was to determine whether the pharmacokinetics of warfarin and ciprofloxacin PR (a prolonged-release formulation of ciprofloxacin) were altered after coadministration. Eighteen healthy male volunteers were given a single oral 7.5-mg dose of warfarin, a single oral 500-mg dose of ciprofloxacin PR, or both drugs administered together in a randomized, open-label, 3-way crossover study. Ciprofloxacin concentrations, warfarin (R)- and (S)-enantiomer concentrations, prothrombin time, and activated partial thromboplastin time were measured over 120 hours following study drug administration. There were no significant differences in pharmacokinetic or pharmacodynamic parameters among treatments. A slightly greater value of half-life for (R)-warfarin was observed when coadministered with ciprofloxacin PR compared with warfarin administered alone (52.6 vs 50.1 hours, P = .029). This difference is not considered clinically relevant, because the values remain similar. These results show that warfarin pharmacokinetics and pharmacodynamics are not altered with concomitant administration of ciprofloxacin PR.
Pharmacodynamics
Crossover study
Prothrombin time
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Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single‐dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics, and plasma protein binding were examined in 12 healthy mate volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.
Warfarin Sodium
Pharmacodynamics
Prothrombin time
Elimination rate constant
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Pentoxifylline is a new hemorrheologic agent which decreases platelet aggregation and reduces fibrinogen levels. Its ability to affect the coagulation cascade was studied in rats with and without the coadministration of warfarin. There was no significant difference between the prothrombin time ratio (PTR) of the warfarin group (1.51 +/- 0.38) and the combination drug group (1.47 +/- 0.30) at 6 hours. Likewise, there was no significant difference between the PTR of the control group (1.09 +/- 0.07) and the group administered pentoxifylline alone (1.05 +/- 0.06). Although the mechanisms of action of the two drugs may overlap, the pharmacodynamic activity of warfarin was not significantly altered when pentoxifylline was coadministered.
Pentoxifylline
Pharmacodynamics
Prothrombin time
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1 In five volunteers taking daily subtherapeutic doses of warfarin the addition of ranitidine 200 mg twice daily for 14 days did not affect prothrombin time or plasma warfarin concentration. 2 Ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat. 3 Ranitidine had no effect on pentobarbitone sleeping time in the rat whereas cimetidine significantly prolonged the sleeping time. 4 The interaction between cimetidine and oral anticoagulants is unrelated to histamine H2-receptor antagonism.
Cimetidine
Pharmacodynamics
Prothrombin time
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Pharmacodynamics
Prothrombin time
Andrographis Paniculata
Concomitant
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Warfarin, a racemic mixture of R- and S-enantiomers, exerts its anticoagulant effect by interfering with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X and proteins C and S. Warfarin displays stereospecific pharmacokinetic and pharmacodynamic properties, and the isomers are differentially metabolized by cytochrome p450 isozymes. Among patients treated with warfarin, there is little correlation among dose, serum concentration, and therapeutic effect, necessitating individualized dosing guided by therapeutic monitoring of the prothrombin time. The pharmacokinetic and pharmacodynamic properties of warfarin as well as its narrow therapeutic index make it particularly susceptible to interactions with other prescription and nonprescription drugs, including dietary supplements. Numerous drug compounds are reported to interact with warfarin, necessitating increased prothrombin time monitoring and warfarin dosing adjustments to maintain safe and effective anticoagulation.
Pharmacodynamics
Therapeutic index
Prothrombin time
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Citations (108)
The oral anticoagulant warfarin is clinically administered as a racemic mixture of two enantiomers, (R) and (S). Many relevant drug interactions with warfarin have been attributed to the specific metabolic inhibition of the elimination of the more pharmacologically active (S)‐enantiomer. To investigate reports that acetaminophen can potentiate the anticoagulant effect of warfarin, 20 healthy male volunteers were each given single oral 20 mg doses of racemic warfarin on three separate occasions: (1) alone, (2) after 1 day of acetaminophen (4 g/d), and (3) after 2 weeks of acetaminophen (4 g/d). The urinary excretion pattern of acetaminophen and its metabolites was not significantly altered over its course of administration. The (R)‐ and (S)‐enantiomers of warfarin exhibited significantly different pharmacokinetic properties. However, acetaminophen did not alter the disposition of either (R)‐ or (S)‐warfarin. All subjects exhibited a pharmacodynamic response to racemic warfarin. The response was not significantly altered in the presence of acute or chronic acetaminophen dosing, as assessed by prothrombin time and factor VII concentrations.
Pharmacodynamics
Acetaminophen
Prothrombin time
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Citations (62)
1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC0–t) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC0–t and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC0–t and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.4. Coadministration of warfarin had no markedly effects on the AUC0–t and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC0–t and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.
Pharmacodynamics
Prothrombin time
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Systematic evidence regarding herb‐drug interactions is lacking. This study investigated herb‐drug interactions with warfarin. S‐warfarin concentration and response (prothrombin complex activity) data from healthy subjects (n = 24) who received a single warfarin dose (25 mg) and either St John's wort, Asian ginseng, Ginkgo biloba, or ginger were analyzed using a population pharmacokinetic‐pharmacodynamic modeling approach. The ratio of S‐warfarin apparent clearance (CL/F) compared to control was 1.39 ± 0.06 and 1.14 ± 0.04 after St John's wort and Asian ginseng pretreatment, respectively. Other pharmacokinetic and pharmacodynamic parameters were unaffected. Coadministration of St John's wort significantly increased S‐warfarin CL/F, whereas treatment with Asian ginseng produced only a moderate increase in CL/F. Ginkgo and ginger did not affect the pharmacokinetics of warfarin in healthy subjects. None of the herbs studied had a direct effect on warfarin pharmacodynamics. Studies in anticoagulated patients are warranted to assess the clinical significance of these herb‐drug interactions.
Pharmacodynamics
Prothrombin time
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Citations (96)