warfarin and bucolome

Although bucolome has been used empirically to enhance and stabilize warfarin action in some institutes, the clinical risks and benefits of this combination are unclear. In the present study, warfarin monotherapy (WM) and bucolome combination (BC) therapy were compared in anticoagulation therapy.One hundred and ninety-five patients indicated for anticoagulation therapy were randomly assigned to WM (n = 98) or BC (bucolome 300 mg/day, n = 97). The dosage of warfarin was optimized in each patient to maintain the international normalized ratio (INR) level in the appropriate zone, ie, 1.6-2.6 for lower risk and 2.0-3.0 for higher risk patients. The clinical characteristics, clinical events, and time in therapeutic range (TTR) were evaluated and compared between the two groups. TTR was calculated using Rosendaal's linear interpolation method.The optimal dosage of warfarin was 3.3 ± 1.0 mg/day in WM and 1.4 ± 0.5 mg/day in BC (P < 0.001). During the observation period of 18 ± 6 months, no serious complication was observed and INR was measured 11 ± 3 times in each case. TTR was 0.61 ± 0.13 in WM and 0.62 ± 0.14 in BC (NS), but TTR in the WM subgroup with warfarin > 3 mg (0.58 ± 0.13) was lower than in the WM subgroup with warfarin ≤ 3 mg (0.64 ± 0.13, P = 0.026) and BC (P = 0.042).BC reduced the optimal dosage of warfarin without increasing clinical events. There was no significant difference in TTR between WM and BC, but BC may have benefits in selected cases, such as warfarin resistance.

Topics: Aged; Anticoagulants; Barbiturates; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Risk Factors; Treatment Outcome; Warfarin

We have studied the possibility that low-dose treatment utilizing the inhibition that may occur between two drugs at the same site of human serum albumin (HSA) improves the pharmacological effects. The purpose is to elucidate the differences in the binding capacities of sites I and II of HSA between pre-haemodialysis (HD) and post-HD in patients with end-stage renal disease.. We evaluated free fractions of site probes, (14)C-warfarin (site I) and (14)C-diazepam (site II), by ultrafiltration in serum between pre-HD and post-HD. To investigate effects on the binding capacities of HSA sites, free fractions of site probes were calculated from the radioactivities measured with a liquid scintillation counter. Endogenous uraemic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulphate (IS) and hippurate (HA), were determined by HPLC. Free fatty acid (FFA) as an endogenous substance was determined with an automatic multi-item simultaneous analyser.. The concentrations of HSA and FFA increased significantly (post-HD/pre-HD ratio: 1.18 +/- 0.10, 5.46 +/- 4.91), the concentrations of IS and HA decreased significantly (post-HD/pre-HD ratio: 0.69 +/- 0.10, 0.33 +/- 0.15) and CMPF concentrations did not alter significantly (post-HD/pre-HD ratio: 0.97 +/- 0.12, P = 0.471). The free fractions of (14)C-warfarin decreased in all 14 patients at site I at post-HD compared to pre-HD (post-HD/pre-HD ratio: 0.59 +/- 0.13). The free fractions of (14)C-diazepam at site II remarkably decreased in 10 of 14 patients (post-HD/pre-HD ratio: 0.61 +/- 0.17) and unexpectedly increased in 4 (post-HD/pre-HD ratio: 1.08 +/- 0.06) post-HD compared to pre-HD. In these four patients, when we investigated the influences of these variation factors on the reduction of the binding capacities of site II, [FFA]/[HSA] increased significantly post-HD, compared to pre-HD (post-HD/pre-HD ratio: 6.91 +/- 6.58). ([FFA]/[HSA] ratios of the 4 patients were from 1.22 to 3.55, the highest for the 14 patients post-HD, but the ratios of the other 10 were below 1.2 post-HD.). The binding capacity of site II was unexpectedly decremented by the effects of the remarkable elevation of FFA. Therefore, monitoring the binding capacity of site II in HD is important for patients with end-stage renal disease in the efficacious administration plan using the binding inhibition of HSA.

Topics: Adult; Aged; Barbiturates; Binding Sites; Carbon Radioisotopes; Diazepam; Diuretics; Fatty Acids, Nonesterified; Female; Furans; Furosemide; Hippurates; Humans; Indican; Kidney Failure, Chronic; Male; Middle Aged; Propionates; Protein Binding; Renal Dialysis; Serum Albumin; Treatment Outcome; Warfarin

The objective of this study was to investigate the stereoselective influence of bucolome on the pharmacokinetics and pharmacodynamics of warfarin in Japanese inpatients with heart disease. Thirty patients were administered a fixed-maintenance dose of warfarin alone once a day for at least 7 days. The other 25 patients were concomitantly administered warfarin and a 300 mg dose of bucolome once a day, and blood samples were collected on days 1, 4, 7, 14, or 21 after administration of bucolome. Serum concentration of warfarin enantiomers was measured by a chiral reversed-phase HPLC-ultraviolet detection method. The PT-INR was used as a measure of the pharmacodynamic effect of warfarin. Coadministration of bucolome and warfarin had no effect on serum (R)-warfarin concentration and significantly increased serum (S)-warfarin concentration compared with warfarin alone. The PT-INR of warfarin alone was significantly lower with bucolome cotreatment. These results indicate that the augmented anticoagulant effect of warfarin by bucolome is due to inhibition of (S)-warfarin metabolism in vivo. When bucolome is added to a stabilized regimen of warfarin therapy, the dose of warfarin should be reduced by about 30% to 60%, and caution should be exercised during the first 7 days after coadministration of bucolome.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Barbiturates; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart Diseases; Humans; Japan; Male; Metabolic Clearance Rate; Middle Aged; Stereoisomerism; Time Factors; Warfarin

We present herein a review of 95 patients who underwent valve replacement with the CarboMedics (CM) valve prosthesis between April 1990 and December 1992. The operative mortality for the entire group was 4.2%: 0% following aortic valve replacement (AVR), 2.7% following double valve replacement (DVR). All patients were prescribed warfarin and bucolome for anticoagulation, and were followed up for a mean period of 29.9 months. Late mortality was 8.4%; 3.1% following AVR, 10.8% following MVR, and 12.5% following DVR. There were no cases of mechanical prosthetic valve failure, significant hemolysis, infective prosthetic valve endocarditis, or bleeding complications. After 44 months of follow-up, the actuarial freedom from complications was calculated as: thromboembolism, 97.8 +/- 1.6%; valve thrombosis, 97.8 +/- 1.1%; paravalvular leak, 96.7 +/- 1.9%; and reoperation, 98.9 +/- 1.1%. The overall survival rate was 84.3 +/- 6.3% and all survivors showed a significant improvement in NYHA functional class, from 81% in classes III and IV preoperatively to 99% in classes I and II postoperatively. The CM valve exhibited no significant differences in hemolytic parameters or hemodynamic performance after isolated AVR or MVR compared with the similar type of St. Jude Medical bileaflet valve. The evidence provided by the present study therefore suggests that the CM valve prosthesis can achieve excellent mid-term clinical results and hemodynamic performance with a low incidence of thromboembolism and valve thrombosis.

Topics: Adolescent; Adult; Aged; Aortic Valve; Barbiturates; Female; Follow-Up Studies; Heart Valve Prosthesis; Hemodynamics; Hemolysis; Humans; Male; Middle Aged; Mitral Valve; Postoperative Complications; Survival Rate; Thromboembolism; Thrombosis; Warfarin

Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter-patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach.. In vitro data regarding the enzymatic kinetics of (S)-warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)-warfarin and its inter-patient variation (assessed using the standard deviation of its natural logarithm (σ)) were predicted using a physiologically based population pharmacokinetic simulator (Simcyp(TM) ) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and σ values predicted under various conditions (the prediction study).. The σ values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter-patient variation, as clinically observed. In the prediction study, the σ value of the bucolome co-administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter-patient variation of (S)-warfarin pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Anticoagulants; Barbiturates; Computer Simulation; Cytochrome P-450 CYP2C9 Inhibitors; Drug Therapy, Combination; Fluconazole; Humans; Models, Biological; Warfarin

Bucolome, a nonsteroidal antiinflammatory drug, enhances the effects of warfarin. In the present study, the effects of combination therapy (bucolome+warfarin) vs. warfarin alone on atrial fibrillation were investigated.. Combined therapy resulted in a decrease in the warfarin dose to approximately one-third. The fluctuations of the international normalized ratio and the time in therapeutic range were similar in both groups. There was no adverse effect in either group. Interestingly, uric acid was lower in the bucolome group.. Bucolome enhanced the effects of warfarin, resulting in a decreased dose of warfarin without adverse effects and it showed similar anticoagulant stability to warfarin alone.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Atrial Fibrillation; Barbiturates; Blood Coagulation; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; International Normalized Ratio; Japan; Male; Middle Aged; Retrospective Studies; Stroke; Treatment Outcome; Warfarin

Bucolome, a nonsteroidal anti-inflammatory drug, has often been coadministered to patients who take warfarin as an anticoagulant. This combination increases the anticoagulant effect, which is most likely due to the interaction of bucolome with the pharmacokinetics (PK) or pharmacodynamics (PD) of warfarin. More than 30 years ago the mechanism of this interaction was reported to be inhibition of warfarin protein binding by bucolome, and the inhibition of warfarin metabolism by bucolome was also recently reported. Here, we examined daily doses of warfarin and its anticoagulant effect (thrombo-test, TT) in outpatient prescriptions in five hospitals to elucidate the drug interaction and the usefulness of this drug combination. Among the warfarin prescriptions, 78 were for patients also taking bucolome and 99 were for patients not taking bucolome. The daily dose of warfarin in patients taking bucolome was significantly lower than those without bucolome (ca. 40%). TT in patients taking bucolome was significantly lower as compared to those not taking bucolome. Control of the anticoagulant effect was greater with coadministration of bucolome and warfarin than with warfarin alone. PK and PD analysis of our results suggests that the improved therapeutic effect resulting from coadministration of warfarin with bucolome was due to lower and less patient-to-patient variation of intrinsic hepatic clearance (CL(int)) of warfarin, since bucolome decreased the high CL(int) but did not have a great effect on the low CL(int). In conclusion, administration of bucolome in warfarin therapy is useful to control the anticoagulant effect of warfarin. Attention should also be paid to the enzymatic inhibition by bucolome on the PK of coadministered drugs.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Barbiturates; Drug Prescriptions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Warfarin

Intraluminal ureteral hematoma is a rare disease and only a few cases have been previously described. We report a case of intraluminal ureteral hematoma induced by anticoagulant therapy. A 65-year old man having the oral anticoagulant therapy for prevention of secondary thrombolism following atrial fibrillation was referred to us for gross hematuria. Ultrasound sonography (US) revealed right renal mild wide pelvis. Computed tomography (CT) showed the right ureteral submucosal hematoma. This ureteral hematoma penetrated the ureteral mucosa and caused macrohematuria. The patient had been anticoagulated on Warfarin with Bucolome for 18 days, so the prothrombin times (PT) was found to be excessively prolonged beyond the normal therapeutic range. The oral anticoagulation was stopped and intravenous Vitamin K2 was given, so PT was normalized. Though estimate hemorrhage quantity reached 1,200 ml, we had no blood transfusion. The hematoma was completely diminished 4 months later, no reccurence has been occurred. Bucolome has especially pharmacokinetic positive interaction to Warfarin, so we must check PT-INR frequently.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Barbiturates; Hematoma; Humans; International Normalized Ratio; Male; Prothrombin Time; Thromboembolism; Ureteral Diseases; Warfarin

A uricosuric agent, bucolome, has been shown to intensify the anticoagulant effect of warfarin. The aims of the present study were to clarify its mechanism(s) and to apply in vitro approaches for predicting this potentially life-threatening in vivo interaction. An in vivo study revealed that Japanese patients given warfarin with bucolome (300 mg/day, n = 21) showed a 1.5-fold greater international normalized ratio than those given warfarin alone (n = 34) despite that the former received a 58% smaller warfarin dose than the latter. Enantioselective assays revealed that bucolome increased plasma unbound fractions of (S)- and (R)-warfarin by 2-fold (p <.01), reduced unbound oral clearances of (S)- and (R)-warfarin by 84 (p <.01) and 26% (p <.05), respectively, and inhibited the unbound formation clearance for (S)-warfarin 7-hydroxylation by 89% (p <.01). In contrast, bucolome elicited no appreciable changes in the plasma unbound (S)-warfarin concentration versus the international normalized ratio relationship. In vitro studies with recombinant human cytochrome P-450 2C9 and liver microsomes showed that bucolome was a potent mixed-type inhibitor for (S)-warfarin 7-hydroxylation, with K(i) of 8.2 and 20.2 microM, respectively. An in vitro model incorporating maximum unbound bucolome concentration in the liver estimated as a sum of hepatic artery and portal vein concentrations and in vitro K(i) made an acceptable prediction for bucolome-induced reductions in in vivo total (bound + unbound) oral clearance, unbound oral clearance, and unbound formation clearance for (S)-warfarin. In conclusion, the augmented anticoagulant effect of warfarin by bucolome due to the metabolic inhibition for pharmacologically more potent (S)-warfarin may be predictable from in vitro data.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Barbiturates; Blood Proteins; Drug Interactions; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding; Stereoisomerism; Warfarin