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PubMed1988

Use of sorption promoters to increase systemic absorption of coumarin from transdermal drug delivery systems.

In previous communications it was shown that coumarin is transdermally well absorbed. Increasing the application area for a coumarin ointment from 5 cm2 to 30 cm2, the absolute bioavailability increases from 8.6% to 66%. Using a transdermal drug delivery system (TDDS) based on an elastomer matrix, the absolute bioavailability was 21.9%. By selecting a proper sorption promoter (Labrafil), the absolute bioavailability increased to 71%. No correlation was found between tlag, flux or amount permeated obtained from ex vivo flux measurements, and the in vivo parameters Cmax and AUC. Whereas the bioavailability of a large area application of coumarin ointment is practically the same as with a small TDDS, the latter one is preferred to maintain a therapeutic concentration over a 24 h or 48 h period.

Administration, Cutaneous↗
PubMed1986

[Hepatic and duodenal biotransformation in Japanese quail (Coturnix coturnix): activities of 7-ethoxycoumarin O-deethylase and coumarin 7-hydroxylase].

In vitro cytochrome P-450-dependent monooxygenase activity was studied in hepatic and duodenal microsomes from the Japanese quail (Coturnix coturnix) with two substrates, 7-ethoxycoumarin and coumarin. The rate of formation of 7-hydroxycoumarin--as the main metabolic product--was followed by fluorometry. 7-Ethoxycoumarin O-de-ethylase activity (7-ECOD) was shown in liver and duodenum, but coumarin 7-hydroxylase (Cou 7-OH) was found only in liver. The requirement for some cofactors (NADPH), the inhibitory action of CO, optimal pH and temperature, kinetic constants (Km, Vm, and the spectral dissociation constant, Ks) were determined in all cases. Specific activities were found in the range 1-4 nmole/mg/min, 0.1-1 nmole/mg/min, and 0.5-3 nmole/mg/min for hepatic and duodenal 7-ECOD and hepatic Cou 7-OH, respectively. The coumarin 7-hydroxylase activity showed some striking features, inhibition by excess of substrate and high inhibition by alcohols.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Combined treatment of advanced malignant melanoma with coumarin and cimetidine.

An immunostimulant therapy with coumarin and cimetidine was evaluated in 17 patients with advanced malignant melanoma. Induction therapy with coumarin 100 mg daily was given for 8 weeks, after which cimetidine 1000 mg daily was added. No patients had been previously treated with cytotoxic drugs. All patients had good performance status. Sixteen patients experienced progressive disease, and only one patient showed no change lasting for 30 weeks. It is concluded that treatment with this schedule of coumarin and cimetidine is without effect in advanced malignant melanoma.

Adult↗
PubMed1977

[Test of combination of the agents coumarin and troxerutin for embryotoxic and teratogenic side-effects in Göttingen miniature pigs (author's transl)].

Göttingen miniature pigs were used to test a combination of the active principles coumarin and troxerutin (Venalot) for teratogenic and embryotoxiic side-effects. The experimental group consisted of 17 mother pigs with 95 fetuses, the control group of 6 untreated sows with 45 fetuses. The combination of coumarin and troxerutin was administered orally at a level of the 100-fold therapeutic dose (i.e. 25 mg coumarin + 150 mg troxertutin/kg/day) from day 6 to day 30 of gestation. The pathological and histological examinations of the uteri and fetuses revealed no indications of any embryotoxic or teratogenic damage caused by the tested combinations. Morphological and clinico-chemical investigations did also not result in any findings definitely attributable to the medication.

Animals↗
PubMed1977

[Different enzyme liberation in the liver of rats and mice by a combination of coumarin and rutin sulphate sodium salt (author's transl)].

In Wistar rats, combined treatment with ethanol or carbon tetrachloride and a mixture of coumarin and sodium salt of rutin sulphate (Venalot injectable solution) causes slight increases of some liver-specific enzymes in plasma. This effect was not observed in DBA/2 4-mice whose metabolism of coumarin is widely analogous to that of man. The LD50 for coumarin in those mice was twice that in rats. These results are discussed in the light of different metabolic pathways of coumartin in both species.

Alanine Transaminase↗
PubMed1979

[Effect of coumarin on the livers of DBA/2J and CH3/HeJ mice].

32 weeks chronic feeding of DBA/2J- as well as CH3/HeJ-mice with 0.5 and 1.0% coumarin, respectively, in the diet, caused minimal increases of glutamate-oxalatetransaminase, gamma-glutamyltransferase and sorbitdehydrogenase activities in the serum only, when approximately 2 g coumarin/kg daily were administered. Neither macroscopic nor microscopic examination of liver tissue revealed any pathological alterations caused by coumarin. Correspondingly the animals were unaffected in their behaviour and growth during the coumarin loading.

Alanine Transaminase↗
PubMedDate not supplied

o-Hydroxyphenylethanol, a novel lactone ring-opened metabolite of coumarin.

A novel metabolite of coumarin was isolated by high pressure liquid chromatography from in vitro incubations with a rat liver 10,000g postmitochondrial supernatant fraction. Mass spectral analysis and co-chromatography with authentic reference compound was utilized to identify the lactone ring-opened metabolite as o-hydroxyphenylethanol. Formation of this metabolite required both the microsomal and cytosolic fractions and the maximum rate of production was observed in the presence of both NADPH and NADH. Analysis of urine from rats administered [14C]coumarin established that o-hydroxyphenylethanol was formed in vivo and the amount excreted was about 15% of that of o-hydroxyphenylacetic acid, the major urinary metabolite. Precursor-product relationship studies indicated that o-hydroxyphenylethanol was readily converted to o-hydroxyphenylacetic acid both in vivo and in vitro while the reverse reaction was not observed. The relationships of these results to the currently accepted pathway(s) leading to ring-opened coumarin products are discussed.

Animals↗
PubMed1983

Use of activated partial thromboplastin time to monitor coumarin anticoagulation.

The activated partial thromboplastin time after heparin removal (aPTT/HR) is an anionexchange procedure that permits the unobstructed monitoring of the progress of coumarin anticoagulation by removing interfering heparin. An all-intrinsic-pathway anticoagulant surveillance scheme based upon the aPTT/HR has been proposed and provisionally tested. The adoption of the new scheme will depend upon the identification of partial thromboplastins that are as predictable and reliable as the tissue thromboplastins in modern one-stage prothrombin times. In this study, the commercial APTT Reagent and Simplastin performed with equal sensitivity and specificity when evaluated by means of prothrombin group factor assays on coumarintreated subject plasmas. It is concluded that this commercial partial thromboplastin (1) is capable of being used for the purpose of following heparin, heparin plus coumarin, and coumarin anticoagulation; (2) is potentially able to identify more of the inherited and acquired derangements that can lead to anticoagulation-associated hemorrhage; and (3) is a universally available alternative to the traditional anticoagulant monitoring approach.

Blood Coagulation Tests↗
PubMedDate not supplied

Antipyretic and pharmacokinetic evaluation of coumarin in the rabbit after endotoxin administration.

The antipyretic effect of coumarin (C) and the drug disposition of C and its metabolites, 7-hydroxycoumarin, 7-HOC, and 7-hydroxycoumarin glucuronide, 7-HOCG, upon endotoxin challenge were studied in an animal model. A parallel design was used with 6 rabbits each in the following groups: control, coumarin 1 mg/kg I.V., endotoxin 0.125 mg/kg I.V., and coumarin 1 mg/kg I.V. plus endotoxin 0.125 mg/kg I.V. C reduces the elevated temperature significantly during the first half hour with the mean temperature difference versus time curve being lower than that for the endotoxin challenged group. Although not significant there is a trend for increased elimination half-life and apparent volume of distribution for C. The apparent volume of distribution for 7-HOC and 7-HOCG increased significantly, and the elimination half-life of 7-HOCG increased significantly.

Animals↗
PubMed1981

Coumarin or warfarin treatment of mice does not increase the microbicidal or tumoricidal capacities of macrophages.

Benzopyrones have been shown to affect several functions of macrophages. We examined the effects of two benzopyrones, coumarin and warfarin, on the capacity of mouse macrophages to inhibit microorganisms and tumour target cells. Mice were treated with daily i.v. doses of either drug. Then the mice were challenged with lethal doses of Toxoplasma gondii or peritoneal macrophages from these mice were challenged in vitro with T. gondii or tumour target cells Survival of coumarin or warfarin-treated mice challenged with T. gondii was similar to that of control mice. Multiplication of T gondii and growth of tumour target cells were similar in preparations of macrophages from coumarin-treated, warfarin-treated, or control mice and were inhibited in preparations of activated macrophages from Corynebacterium parvum-treated mice that served as positive controls. Under our experimental conditions, benzopyrones did not activate mouse macrophages.

Animals↗
PubMed1994

Molecular and cellular pharmacology of novel photoactive psoralen and coumarin conjugates of pyrrole- and imidazole-containing analogues of netropsin.

The molecular and cellular pharmacology of novel sequence-directed photoactive agents, in which either psoralen or coumarin is conjugated to minor groove-binding AT-selective pyrrole-, or more GC-selective imidazole-containing analogues of netropsin, is described. The compounds were relatively non-toxic in the dark and showed marked photoinduced cytotoxicities when irradiated at 366 nm UV. The psoralen-containing pyrrole (1) and imidazole (2) compounds gave the largest photoinduced effect, were more active than 8-methoxypsoralen (8-MP) itself by 333- and 22-fold, respectively, and were more potent than the corresponding coumarin-containing analogues 3 and 4. Following irradiation, 1 and 2 were > 300- and > 10-fold more efficient at producing interstrand cross-links in naked DNA, respectively, than 8-MP. 1 was at least 10-fold more efficient at producing cross-links in cells than 2, reflecting the difference in their IC50 values. No cross-links were observed with the coumarin analogues, but these compounds were more potent than 8-MP. AT and GC sequence recognition was confirmed by DNA footprinting, and sites of covalent modification mapped by a polymerase stop assay. All compounds produced blocks at thymine base sites following irradiation. 1 was more efficient than 8-MP and produced a different pattern of covalent modification, whereas 2 was more selective than either 1 or 8-MP. A 1H-NMR study on a 1:1 complex of 2 with the hexamer (5'-dA1T2G3C4A5T6-3')2 indicated that the imidazole carboxamide moieties of 2 reside in the minor groove of the sequence 5'-GCAT-3' of the hexamer with the C-terminus located on the 3'-TA site, and the psoralen group intercalated between the 5'-A1T2-3' base pairs.

Base Sequence↗
PubMed1977

Tissue levels of (3(-14)C) coumarin in the rat: distribution and excretion.

The benzo-pyrones (including coumarin) are a very effective therapy for mild thermal oedema and cases of acute and chronic lymphoedema. In this preliminary report the distribution of a single injected dose of coumarin was followed in normal tissues of rats for 100 hours. Comparisons are to be made later with drug levels in thermally injured and lymphoedematous tissues. The resluts show 7-4% of the injected dose to remain in the tissues after 100 h. During this time 30-9% was excreted in the faeces and approximately 47% excreted in the urine. At any given time most of the dose was present in the gut, muscular tissues, skin and liver. For the gut tissues this was 33%, for the muscular tissues 28%, for the skin 18% and for the liver 16%. The highest concentrations per gram of tissue were however in the kidney and liver, representing the two organs of metabolism and excretion of the coumarin.

Animals↗
PubMed1993

[Effects of total coumarins, essential oil and water extracts of Cnidium monnieri on plasma prostaglandin and cyclic nucleotide in the rats of kidney-yang insufficiency].

Effects of total coumarins, essential oil and water extracts of Cnidium monnieri on plasma prostaglandin (PGE2 and PGF2 alpha) and cyclic nucleotide levels in rats of Kidney-Yang insufficiency were studied. 55 rats were divided randomly into 5 groups, Group I was administered orally with saline (normal group), group II was injected with intraperitonally hydrocortison acetate to induce Kidney-Yang insufficiency (control group), group III, group IV and group V (experimental groups) were injected with hydrocortison acetate, the same as group II, and administered orally with the total coumarins, essential oil and water extracts of Fructus Cnidii respectively. The levels of plasma PGE2, PG2 alpha and plasma cAMP, cGMP were measured. In group II, in comparing with those of group I, the levels of plasma PGE2, and PGF2 alpha decreased significantly (P < 0.01), and the value of cAMP/cGMP also lowered obviously (P < 0.01) due to the significant reduction of cAMP and insignificant change of cGMP. In group III and group V, the above-mentioned indices changed significantly (P < 0.01 or 0.05) compared with those of group II, and after treatment it normalized basically in comparing with those of group I. In group IV, those indices didn't change regularly and apparently as group III and group V did, compared with group II, and could not normalize satisfactorily. It is suggested that the coumarins in the fruit of Cnidium monnieri are probably the effective ingredients to invigorate Kidney and strengthen Yang, while the efficacy of essential oil remained unconfirmed.

Animals↗
PubMed1993

Effects of coumarin derivatives on superoxide anion generation.

A number of simple coumarins with different patterns of substitution were tested on activated polymorphonuclear leukocyte superoxide generation and superoxide scavenging using the reduction of nitroblue tetrazolium. The most effective compound was fraxetin, which showed a better potency as an inhibitor of superoxide radical generation than as a scavenger. From the structure-activity study it can be deduced the importance of an ortho-dihydroxyl function, especially at the position 7, 8. Blockade of active hydroxyl groups by methylation or glycosylation decreases the activity. None of the coumarins were cytotoxic on leukocytes as assessed by lactic dehydrogenase activity release. Inhibition of superoxide generation in activated neutrophils may play a role in the vasoprotective effects of simple coumarins.

Animals↗
PubMed1977

In vitro effect of duclauxin and derivatives of coumarin on nucleic acid and protein synthesis in Ehrlich's Ascites Carcinoma cells (EAC).

The effect was studied of 32 natural and synthetic derivatives of coumarin, dicoumarin, and 4.4'epoxydicoumarin on the uptake of 14C-labelled precursors in nucleic acid (NA) and protein synthesis by EAC cells in vitro. Of the three tested groups of compounds, the most cytotoxic effect was found in the derivatives of coumarin that inhibited, on the same level, incorporation of the added 14C-adenine, 14C-L-valine and 14C-uridine but not 14C-thymidine. The utilization of the present precursors by EAC cells was not affected by epoxydicoumarins. Derivatives of coumarin and dicoumarin inhibited only NA synthesis in in vitro proliferating EAC cells. Of the evaluated compounds, chiefly duclauxin specifically decreased proliferation of EAC cells in vitro.

Animals↗
PubMed1996

Lack of pharmacokinetic interaction between dextromethorphan, coumarin and mephenytoin in man after simultaneous administration.

The possible interference of simultaneously given dextromethorphan (10 mg dextromethorphan-HBr-H2O), coumarin (10 mg), and mephenytoin (100 mg (R/S)-mephenytoin) on oxidative routes of drug metabolism performed by different cytochrome P450 enzymes and the possibility to detect all of the three substances and their metabolites in urine were investigated in 12 healthy subjects. The concentrations of parent drugs and main metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorphan as calculated using hydroxylation index (HI) for mephenytoin and as seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their metabolites or of coumarin and mephenytoin with their metabolites in urine is possible. The combined HPLC separation of all parent compounds and metabolites, however, is not useful because of the necessity to treat the urine samples in very different ways. An overlapping of retention times of the substances in HPLC does not occur. With it a simultaneous administration of all three drugs is possible. A following collection of urine over a period of 8-12 h serves for characterizing activities of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activities of these cytochromes is easily definable without the disturbing influence of intraindividual variation of drug oxidation with time.

Administration, Oral↗
PubMed1998

French pharmacovigilance survey evaluating the hepatic toxicity of coumarin.

Synthetic coumarin (benzopyrone) was launched in France in 1988 for the adjuvant therapy of lymphoedema of the upper limb following radiosurgical treatment of breast cancer. Further to the reporting of hepatic reactions, a national survey has been carried out. The survey dealt with 22 cases reported to the pharmacovigilance regional centres and 20 to Knoll France company (five duplicate cases) up to June 1996. Thirty-four cases corresponding to an elevation of ALT over 2N and/or alkaline phosphatase over 1.5N (criteria chosen for selection in this survey) had been taken into account. Among these cases, a causal relationship was considered likely or probable for 15 of them. Two positive rechallenges were reported. The hepatic reactions observed between 2 to 6 months of treatment in two-thirds of the cases (average dose: 90 mg/day; i.e. recommended dose) was essentially cytolytic in 85% of the cases, with jaundice in 14 cases and hyperbilirubinaemia reported in five other cases. In 23 cases (68%), the increase of ALT exceeded 10N. Of the patients 41% were hospitalized. Severe liver failure with encephalopathy justified liver transplantation once and likely led to encephalopathy and fatal evolution in two other cases. The evolution was favourable in the other cases. The drug was prescribed for other uses than the registered indication in more than 50% of these cases. No risk factors could be identified in the survey. This survey provides a strong signal for potential hepatotoxicity of coumarin (likely due to the production of a reactive metabolite in some patients exhibiting a coumarin 7-hydroxylation deficiency).

Journal Article↗
PubMed1999

Putrescine Influences Growth and Production of Coumarins in Hairy Root Cultures of Witloof Chicory (Cichorium intybus L. cv. Lucknow Local).

The effect of putrescine (Put) on the growth and production of two coumarins, esculin and esculetin, in hairy roots of chicory (Cichorium intybus L. cv. Lucknow local) was examined. To study the role of Put on growth and production of coumarins, polyamine inhibitors, namely alpha-dl-difluromethylornithine and alpha-dl-difluromethylarginine were used at 1 mM concentration. Put treatment at 1.5 mM produced a 1.9-fold increase in the growth of hairy roots, as well as the production of esculin and esculetin. The treatments with polyamine (PA) inhibitors resulted in much lower growth and production of coumarins compared with both 1.5-mM Put treatment and the control. Both free and conjugated PAs were studied over the whole culture period, and conjugates of all three PAs, namely Put, spermidine, and spermine, were higher than free PAs throughout the culture period. The treatments with PA inhibitors showed lower levels of endogenous PAs compared with Put-treated samples. The treatment with 1.5 mM Put showed maximum accumulation of endogenous conjugated Put (2,098 +/- 157 nmoles gm(-1) fresh weight). The production of esculin and esculetin was strictly correlated with growth in all treatments. Put at 1.5 mM resulted in greater length of primary root (18.3 +/- 1.4 cm) as compared with the control (11 +/- 0.9 cm) and larger numbers of secondary and tertiary roots.

Journal Article↗