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PubMed1991

Effects of tricyclic drug on induced circular dichroism spectra of dicumarol bound to alpha 1-acid glycoprotein.

Effects of both tricyclic and non-tricyclic drugs on the extrinsic Cotton effects of dicumarol bound to human alpha 1-acid glycoprotein (AGP) have been investigated. Basic tricyclic drugs caused the reversal of the signs of the induced Cotton effects of the circular dichroism (CD) spectra of the dicumarol-AGP system while the basic drugs not possessing tricyclic rings and acidic drugs decreased the observed ellipticities without changing the signs of its CD spectra. There was no reversal of the CD signs of the drugs not containing two hydroxycoumarin rings bound to AGP by basic tricyclic drugs. Raising of pH and temperature, and the addition of guanidine hydrochloride decreased the observed ellipticities of the CD spectra of the dicumarol-AGP system without showing any change in the signs of the Cotton effects. The mutual displacement data showed that protriptyline increased its own binding and that of dicumarol with AGP. The results of CD titration and equilibrium dialysis experiments suggest that dicumarol-AGP and dicumarol-AGP-protriptyline form a 1:1 binary complex and a 1:1:1 ternary complex, respectively.

Antidepressive Agents, Tricyclic↗
PubMed2004

Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor.

The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate (Mn(3+)) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor dicumarol into the right rat substantia nigra. The behavioral effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of Mn(3+) and Mn(3+) plus dicumarol produced significant impairment in motor behavior compared with control animals. However, the effect seen in the Mn(3+) plus dicumarol injected group was significantly more severe than that observed in the Mn(3+) alone injected group. In motor activity and rearing behavior, the simultaneous injection of Mn(3+) plus dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance conditioning although without affecting the motor behavior. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral Mn(3+) and Mn(3+) plus dicumarol injections exhibited a significant reduction in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity of Mn(3+) in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could play a neuroprotective role in the nigrostriatal DA systems.

Animals↗
PubMed2004

Effects of the DT-diaphorase inhibitor dicumarol on striatal monoamine levels in L-DOPA and L-deprenyl pre-treated rats.

It has been proposed that DT-diaphorase plays a strategic role as a neuroprotective enzyme for monoamine neurons, perhaps together with monoamine oxidase (MAO). Thus, we investigated the long-term effects produced by DT-diaphorase inhibition with dicumarol injected unilaterally into the medial forebrain bundle (MFB) on monoamine and metabolite levels, alone, or following dopamine loading with 3,4-dihydroxyphenyl-L-alanine (L-DOPA) or MAO inhibition with L-deprenyl. Monoamine levels were assayed in aliquots from tissue samples from right and left striatum, including both dorsal and ventral regions. Dicumarol alone produced increases in 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), but not in dopamine and metabolite levels when assayed two weeks later. However, following preloading with L-DOPA (3 x 25 mg/kg s.c. 7, 4 and 1 h before surgery), a long-lasting bilateral increase in dopamine and metabolite levels was observed after dicumarol. No effect was observed on dopamine, 5-HT and metabolite levels after L-deprenyl (3 x 10 mg/kg, s.c.) alone, but the levels were unilaterally increased when L-deprenyl was followed by dicumarol. The same result was produced when both L-deprenyl and dicumarol were injected simultaneously into the same brain region. In conclusion, the present study shows that intracerebral inhibition of DT-diaphorase produces long-term changes in 5-HT, but also in dopamine metabolism when DT-diaphorase inhibition is combined with MAO inhibition by systemic or intracerebral treatment with L-deprenyl. It is suggested that both MAO and DT-diaphorase have to be inhibited for inducing long-term changes in monoamine metabolism. Thus, DT-diaphorase is an enzyme to be taken into account when L-DOPA is used to treat Parkinson's disease, or when an MAO-inhibitor is used to treat depression.

Animals↗
PubMed1981

Occurrence and range of dicumarol concentrations in sweet clover.

The dicumarol concentration in 272 cured sweet clover samples from 4 counties in North Dakota was determined. Dicumarol concentrations ranged from 0 to 164.7 mg/kg of sweet clover, with 64.6% of the 272 samples containing less than 10 mg/kg. Round bales were significantly (P less than 0.05) higher in dicumarol concentration (mean of 22.9 +/- 3.10 mg/kg) than were stacks or silage (means of 1.8 +/- -6.3 mg/kg and 0.6 +/- 2.1 mg/kg, respectively). The outer section of core samples taken from round bales contained significantly (P less than 0.0021) higher concentrations of dicumarol than did the inner section of the core, with means of 30.8 mg/kg and 16.6 mg/kg, respectively. A significant (P less than 0.0001) correlation existed between crude protein and dicumarol values (r = 0.44).

Animal Feed↗
PubMed1975

Determination of dicumarol metabolites in bile of rats.

After intravenous administration of dicumarol-14C to rats, the bile excreted over the next 24 hr contained from 32 to 46% of the administered radioactivity. At least three primary metabolites and a small amount of unchanged dicumarol were present in the bile. Over 91% of the primary metabolites was converted to dicumarol and 7-hydroxydicumarol by hydrolysis with beta-glucuronidase. Some primary metabolites were hydrolyzed simply by acidification to pH 3 or by treatment under the acidic conditions utilized in the enzymatic hydrolysis. The three primary metabolites contain carboxylic acid groups, as indicated by their electrophoretic mobility-pH profiles, and some are simple glucuronides of dicumarol and 7-hydroxydicumarol. The possibility that others are derivatives of these compounds in which a coumarin lactone ring is opened cannot be ruled out. When the metabolites released by either acidification or enzymatic hydrolysis were chromatographed in n-butanol-3 M ammonia, artifacts were produced, presumably as a result of decomposition of 7-hydroxydicumarol. The question is raised whether a previously reported metabolite (B055) is an artifact.

Animals↗
PubMed1977

Comparative pharmacokinetics of coumarin anticoagulants XXXI: Effect of plasma protein binding on distribution kinetics of dicumarol in rats.

The purpose of this investigation was to determine, with respect to dicumarol, the effect of plasma protein binding on the pharmacokinetic parameters used conventionally to describe the distribution kinetics of a drug on the basis of the time course of its plasma concentration. After rapid intravenous injection, plasma dicumarol concentrations in adult male Sprague-Dawley rats declined triexponentially, with the terminal exponential phase starting at about 4 hr. The free fraction f, of dicumarol in the serum of individual animals ranged from 0.000150 to 0.000790. The parameters of the equation Ct = Pe-pit + Ae-alphat + Be-betat for plasma concentration Ct at time t were obtained by nonlinear least-squares computer fitting of the experimental data and varied appreciably between animals. Of these parameters, only beta showed a significant correlation with f. These observations indicate that the distribution kinetics of this very extensively plasma protein-bound drug, as reflected by the time course of its plasma concentration after intravenous injection, are apparently not affected by intersubject differences in plasma protein binding. There is a remarkable similarity in the valves of P, A, B, pi, and alpha for dicumarol and warfarin, even though the serum free fraction of these drugs differs considerably.

Animals↗
PubMed1979

Comparative pharmacokinetics of coumarin anticoagulants. XLII: Effect of phenobarbital on systemic availability of orally administered dicumarol in rats with ligated bile ducts.

The purpose of this investigation was to determine if the previously demonstrated inhibitory effect of phenobarbital treatment on the systemic availability of orally administered dicumarol in rats is related to the known effect of phenobarbital on bile output. It was found that phenobarbital had no apparent effect on the systemic availability of an aqueous dicumarol suspension in rats with ligated bile ducts. Compared to results obtained previously on normal rats, bile duct-ligated rats absorbed and eliminated dicumarol much more slowly and absorbed much less of the anticoagulant. On the other hand, the relative inductive effect of phenobarbital treatment on dicumarol elimination was similar in normal and in bile duct-ligated animals. The latter exhibited substantial serum transaminase elevations, indicative of liver damage presumably secondary to cholestasis. These results demonstrate that a drug-drug interaction can depend markedly on the pathophysiological status of the animals.

Animals↗
PubMed1986

Studies on drug-milk freeze-dried formulations. I: Bioavailability of sulfamethizole and dicumarol formulations.

In this study, solid dispersion formulations of dicumarol (3,3'-methylenebis[4-hydroxycoumarin]) and sulfamethizole (N'-(5-methyl-1,3, 4-thiadiazol-2-yl)sulfanilamide) in defatted milk were prepared by freeze-drying. X-ray crystallographic data showed that both drugs were dispersed in the formulations in an amorphous state. Bioequivalency comparisons between freeze-dried formulations, after regeneration with water, and control capsules containing the pure drug substances were studied in four male volunteers. Determination of the plasma dicumarol levels indicated superiority of the dicumarol-milk formulation. Statistically significant differences were found between area under the curve, maximum plasma concentration, and apparent elimination rates. Analysis of the urine sulfamethizole data revealed that the two formulations exhibit statistically equivalent rates and extents of excretion of unchanged sulfamethizole. The binding of both drugs to casein and their solubility in the presence of casein were measured in vitro. The presence of casein caused an increase in the solubility of dicumarol, while it had no effect on the solubility of sulfamethizole. Normal protein binding cannot be responsible for the effects noted. Extrapolation of the in vitro data to the in vivo situation was attempted. Drug-milk freeze-dried formulations are promising for the enhancement of the bioavailability of sparingly water soluble drugs.

Adult↗
PubMed1992

Inhibitory effect of dicumarol on the excitability of the sarcolemma of skeletal muscle.

Dicumarol (7.5 x 10(-6) M -7.5 x 10(-5) M) inhibited the twitches and the simultaneously recorded electromyogram of the indirectly stimulated rat diaphragm preparation. The directly stimulated curarized preparation was inhibited in a similar way. Accordingly, the excitability of the sarcolemma was inhibited by dicumarol. The inhibitory effect was irreversible upon washing. Intracellular microelectrode recordings disclosed that the inhibitory effect was accompanied by a depolarization, and the inhibition was potentiated in high K+ (9.5 mM) solution. In addition, the ability of the preparations to produce a depolarization contracture with KCl (100 mM) was inhibited by dicumarol. Therefore, a part of the inhibitory effect might be caused by the depolarization. On the other hand, subthreshold direct stimulation disclosed that the inhibitory effect might be due to an increase of the threshold. However, a lack of synergistic interaction with lidocaine (0.2 mM) showed that this effect of dicumarol was probably not a membrane stabilizing or local anaesthetic effect.

Anesthetics, Local↗
PubMed1975

Management of thrombo-embolism after aortic valve replacement with the Björk-Shiley tilting disc valve. Medicamental prevention with dicumarol in comparison with dipyridamole - acetylsalicylic acid. Surgical treatment of prosthetic thrombosis.

Dicumarol anticoagulation poved very effective in the prevention of thromboembolic complications after aortic valve replacement with the Björk-Shiley tilting disc valve. We have, however, encountered six late deaths because of massive cerebral hemorrhage, which represent 3% of the patients who were maintained on dicumarol medication at that time. This unacceptable mortality prompted us to introduce two programmes, one without anticoagulation and another one with dipyridamole-acetylsalicylic acid. Furthermore, dicumarol was terminated in patients with haemorrhagic episodes, instable anticoagulation, pregnancy, and in those reguiring surgery. The results were disappointing, however, and the majority of the patients involved were therefore put on dicumarol medication. Eleven of the 64 consecutive patients taking dipyridamole - acetylsalicylic acid had thrombo-embolic episodes during a mean follow-up period of 9 months...

Adult↗
PubMed1975

Effect of bilirubin on the distribution, elimination and anticoagulant action of dicumarol in Gunn rats-1-2 (38547).

Jaundiced Gunn rats were found to have a significantly larger apparent volume of distribution and higher rate constant for elimination of dicumarol than their nonjaundiced littermates. Anticoagulant effect-log plasma dicumarol concentration lines were parallel in the two groups of animals, with the line for the jaundiced rats shifted to a lower concentration range. In vitro studies showed that bilirubin can displace dicumarol from serum protein binding sites. There are indications of a genetic influence on the distribution and anticoagulant effect of dicumarol in Gunn rats.

Animals↗
PubMed1992

Enhancement of xanthine dehydrogenase mediated mitomycin C metabolism by dicumarol.

These studies examined the effect of dicumarol on xanthine dehydrogenase (XDH), an enzyme recently shown to bioreduce mitomycin C. Dicumarol, which has previously been shown to inhibit xanthine oxidase (XO), inhibited both XDH and XO mediated conversion of xanthine to uric acid but potentiated the metabolism of mitomycin C by XDH and XO. Formation of 2,7-diaminomitosene following mitomycin C bioactivation by XDH was increased 3-fold aerobically and 4-fold hypoxically when 20 microM dicumarol was included in the reaction mixture. XO mediated metabolism of mitomycin C hypoxically was increased approximately 50% by the inclusion of dicumarol.

Animals↗
PubMed1993

Dicumarol content in alcoholic herb elixirs: one of the factors at risk induced IVKD-I.

Nine medicinal plants known to be the ingredients of the traditional herbal medicinal elixir, and seven popular commercial alcoholic herb elixirs were investigated for the content of dicumarol by using high pressure liquid chromatography (HPLC) and thin layer chromatography (TLC) methods. Umbelliferae (Conioselinum Univittatum) were the only medicinal plants found to contain dicumarol 0.04 mg/dl. Dicumarol content was also found in three out of seven brands of commercial alcoholic herb elixirs with the concentration of 0.58, 1.86 and 6.00 mg/dl. These findings indicated that the traditional herbal medicinal elixirs containing dicumarol in varying amount may play a role in inducing bleeding diathesis in breast-fed infants of mothers known to consume the elixir.

Alcoholic Beverages↗
PubMed1976

Spectrophotometric assays for warfarin sodium and dicumarol. Use in rapid detection of patients suspected of drug intoxication or surreptitious noningestion.

The usefulness of assays for the rapid identification and determination of quantitative plasma levels of warfarin sodium and dicumarol is documented by the case histories of five patients: a man who accidentally took dicumarol for several weeks and developed an acute condition within the abdomen, a man who ingested 500 mg of warfarin sodium in a suicide attempt, a malingering nurse who surreptitiously took dicumarol, a nurse with warfarin intoxication who did not follow dosage prescription because of fear of developing thrombosis, and a woman with calf vein thrombosis who did not ingest the administered warfin sodium becausing of fear of developing bleeding. In every patient, the diagnosis of surreptitious ingestion or noningestion was suspected on the basis of the coagulation profile pattern. Confirmation of the disorder by the spectrophotometric assay enable the clinician to choose the appropriate course of action with speed and purpose.

Accidents, Home↗
PubMed1976

Effects of lipids on bioavailability of sulfisoxazole acetyl, dicumarol, and griseofulvin in rats.

The effects of hexadecane, oleyl alcohol, polysorbate 80, trioctanoin, and triolein on the bioavailability of sulfisoxazole N1-acetyl, dicumarol, and griseofulvin were investigated. Compared to administration of the drugs in water, the rate of absorption of the drugs was either decreased or not changed by the lipids. The extent of absorption of sulfisoxazole acetyl and dicumarol was significantly increased by polysorbate 80 and triolein and not affected by hexadecane or oleyl alcohol. Tricotanoin increased the extent of abosrption of sulfisoxazole acetyl but had no effect on the absorption of dicumarol. Compared to the aqueous vehicle, the extent of absorption of greiseofulvin was decreased by hexadecane, oleyl alcohol, and triolein, increased by polysorbate 80, and not affected by trioctanoin. The extent of absorption of sulfisoxazole acetyl was not affected by the amount of triolein in which it was administered nor by emulsification of triolein prior to administration.

Animals↗
PubMed1977

Chelates of dicumarol I: Preparation and structure identification of magnesium chelate.

A magnesium chelate of dicumarol was prepared by reacting a suspension of dicumarol and magnesium oxide in 50% water-methanol. GLC, thermogravimetric, and elemental analyses showed that this compound has a 2:1 ligand-metal stoichiometry with 2 moles of water associated with the complex. Although the chelate does not melt, two endothermic peaks at 205 and 274 degrees were observed in the thermogram, in contrast to a single endothermic peak corresponding to a melting point of 288 degrees for dicumarol. IR spectroscopy indicated that the magnesium is bonded between the carbonyl at C-2 and the oxygen at C-4' (or vice versa).

Carbon↗
PubMed1997

Measurement of dicumarol-sensitive NADPH: (menadione-cytochrome c) oxidoreductase activity results in an artifactual assay of DT-diaphorase in cell sonicates.

Purified DT-diaphorase can be assayed as either dicumarol-inhibitable NAD(P)H:menadione oxidoreductase or dicumarol-inhibitable NAD(P)H:dichlorophenolindophenol reductase. Both of these methods have been utilized to assay DT-diaphorase activity in tissue and cell homogenates. When DT-diaphorase activity was measured as dicumarol-inhibitable NADPH:dichlorophenolindophenol reductase in sonicates of two cell lines previously shown to not have any measurable activity of this enzyme, no enzymatic activity was detected. However, when the water-soluble bisulfite addition product of menadione was used as the electron acceptor, an artifactual activity for DT-diaphorase was detected in these cell lines. When another cell line was assayed utilizing menadione bisulfite, an apparent activity of about three times that found with dichlorophenolindophenol was measured, and thus, may overestimate DT-diaphorase activity in cells having activity. When menadione was used in place of menadione bisulfite, an artifactual DT-diaphorase activity was also detected, but was about one-half that obtained with menadione bisulfite. Polarographic determinations of the midpoint potentials for menadione and menadione bisulfite indicated that the latter compound was easier to reduce and may account for the greater apparent DT-diaphorase activity measured with this compound.

2,6-Dichloroindophenol↗
PubMed1992

Inhibitors of the plasma membrane redox system of Zea mays L. roots. The vitamin K antagonists dicumarol and warfarin.

The action of the 4-hydroxycoumarins dicumarol and warfarin, antagonists of probable vitamin K type components of the plasma membrane electron-transport system, on plasma membrane redox activity of intact maize roots was compared. Both effectors inhibited electron transfer to extracellular hexacyanoferrate III. While the effect of the strongly lipophilic dicumarol on the electron-transport system was irreversible by rinsing, the inhibition caused by the hydrophilic warfarin could be reverted completely by exchange of the incubation medium. We take these results as possible evidence for the integration of dicumarol into the plasma membrane. The action of warfarin may be confined to enzymic sites freely accessible from the aqueous apoplasmic solution.

Cell Membrane↗