Bishydroxycoumarin (dicumarol) therapy in myocardial infarction; results of bishydroxycoumarin therapy as it is practiced in a private hospital.
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Warfarin sodium was compared with bishydroxycoumarin (Dicumarol) in 16 patients on long-term anticoagulant therapy. When the patients were changed from bishydroxycoumarin to warfarin sodium there was no improvement in control of their prothrombin times. It was found that 5 mg. of warfarin had slightly less effect than 50 mg. of bishydroxycoumarin. It was concluded that the drugs were equally effective in long-term anticoagulant therapy. The metabolism of the ingested drug was more important than absorption in determining the control of the patients' prothrombin times.
Three highly reproducible experiments on drug interaction in normal human volunteers provided anomalous results: chronic halofenate administration shortened plasma antipyrine and bishydroxycoumarin half-lives but prolonged plasma warfarin half-lives. This dissociation in the effect produced by a chronically administered drug on the metabolism of test drugs has not previously been reported in man. Chronic halofenate administration to rats, mice and dogs stimulated several hepatic microsomal drug-metabolizing systems, including those responsible for bishydroxycoumarin warfarin hydroxylation.
1. The effect of intravenous sodium salicylate on the biliary excretion of 14C-bishydroxycoumarin ((14)C-BHC) was studied in rats.2. Salicylate (88.9 mg/kg) increased the biliary excretion of (14)C-radioactivity from a control value of 12.3 +/- 2.7% to 29.3 +/- 2.5% of the administered dose in 6 h after injection.3. During the 6 h period, 11% of the dose of radioactivity underwent biliary recycling in the salicylate-treated rats compared to only 6% in the absence of salicylate.4. About 15.3% of the radioactivity excreted in the bile of rats given BHC alone was detected as unchanged BHC, 8.6% was present as BHC-conjugate, conjugates of BHC metabolites accounted for 30.9%, and the remainder consisted of unidentified metabolites.5. Salicylate treatment did not significantly alter the excretory pattern of unchanged BHC and its metabolites.
Eight goats, 2 nontreated controls and 6 treated, were used to study the pharmacodynamics and pharmacokinetics of bishydroxycoumarin. In 5 of the 6 treated goats, there was a significant relationship between prothrombin times and drug concentrations. Activated clotting times did not change with time in either the controls or the treated goats. Five of 6 treated goats reached a plateau of drug concentration after 24 to 36 hours. Lag times for onset of pharmacologic effect ranged from 12 to 24 hours. The one goat (No. 3) that did not respond in concert with the other 5 was extremely nervous and became anorectic during the period of indoor confinement.
Interactions between treatments with coumaphos, bishydroxycoumarin (an anticoagulane), trichlorfon (an organophosphorous compound), and phenobarbital sodium (an inducer of microsomal enzymes) were investigated in sheep. A daily dose of 2 mg of coumaphos/kg of body weight for 6 days did not affect the plasma enzymes or the antiprothrombinemic effect of bishydroxy-coumarin in wethers. The treatment of ewes with an intravenous (IV) injection of trichlorfon, insufficient to produce significant inhibition of erythrocyte acetylcholinesterase (AChE) activity, appeared to produce additive effects with those produced by subsequent treatment with 4 mg of coumaphos/kg/day. In ewes given 40 mg of phenobarbital sodium/kg for 5 days intraperitoneally (IP), the anticholinesterase effect of 4 mg of coumaphos/kg was significantly reduced and signs of toxicity were not present. Treatment with daily doses of 2 mg of coumaphos/kg for 6 days did not modify the anticholinesterase effect of a 2nd series of treatments given 6 weeks later.
The influence of oral administration of heptabarbital on the gastrointestinal absorption of bishydroxycoumarin (BHC) was investigated in rats. Pretreatment of the animals with 20 mg/kg heptabarbital twice dialy for three days prior to the administration of 50 mg/kg BHC resulted in a 40% decrease from controls in the area under the BHC plasma concentration time curve (AUC). Preliminary studies indicated that a similar decrease in gastrointestinal absorption of BHC could be seen following a single oral dose of heptabarbital administered concomitantly with the anticoagulant.
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