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PubMed1992

Phase II evaluation of coumarin (1,2-benzopyrone) in metastatic prostatic carcinoma.

The unavailability of effective treatment of metastatic hormone refractory prostatic carcinoma warrants trials of new and promising treatments. Coumarin is an investigational new drug that has produced objective tumor regression in some patients with metastatic renal cell carcinoma and malignant melanoma. Coumarin has shown activity against prostatic carcinoma in the Dunning R-3327 rat prostatic adenocarcinoma model. Forty-eight patients with metastatic hormone naive (5 stage D1 and 10 stage D2) or hormone refractory (33 stage D3) prostatic carcinoma of average age 67.6 years (range 46-86) and ECOG performance status of 2 or better were given 3 grams coumarin daily by mouth and evaluated monthly for toxicity and response by rigid criteria in a multicenter trial. Toxicity was limited to asymptomatic SGOT elevations in 3 patients and nausea and vomiting in 4 patients that required cessation of therapy in 2. Eligibility and protocol violations removed 6 additional patients from response evaluation. There were no complete responses. Partial responses (3 of 40 patients, 8%) occurred in 2 patients with bidimentionally measurable disease and 1 patient with disease evaluable by bone scan and elevated prostate specific antigen and prostatic acid phosphatase. The remaining patients progressed after 1 to 12 (average 4.4) months. Coumarin is a relatively nontoxic drug that may warrant further trials in a subset of patients with prostatic carcinoma.

Adult↗
PubMed1995

Characterization of the resonance energy transfer couple coumarin-BODIPY and its possible applications in protein-lipid research.

In our search for suitable resonance energy transfer (RET) couples for studying protein-lipid interactions, the promising couple coumarin-BODIPY was found and characterized. We characterized the RET from the donor coumarin to two different dipyrrometheneboron difluoride (BODIPY)-labeled phospholipid analogs both experimentally and theoretically. Calculations using the spectral overlap revealed a Förster energy transfer radius (RO) of 50 +/- 2 A and 40 +/- 2 A for the coumarin-(beta-BODIPY FL C12-HPC) and the coumarin-(beta-BODIPY 530/550 C12-HPC) couple respectively. Experimentally this was estimated to be 49.0-51.5 A and 38.5-42.5 A respectively. The use of this couple for studying protein-lipid interactions is exemplified by measurements on a bacterial precursor protein.

Bacterial Proteins↗
PubMed1994

Interindividual variability of coumarin 7-hydroxylation in a Turkish population.

One hundred healthy Turkish volunteers (70 male, 30 female) aged from 19 to 56 years were given 5 mg coumarin p.o. after an overnight fast. Urine samples were collected before and 2, 4 and 8 h after drug administration. The extent and rate of formation of 7-OH-coumarin (7OHC) was determined by the urinary excretion of the metabolite as measured with the fluorometric method. On average, 80% of 7OHC formed was excreted in 2 h. The total amount of 7OHC formed was 59.8% (21.5%) (mean and SD, n = 100, range 17-100%) of the given dose. The percentage of 7OHC excreted during the first 2 h compared with the 7OHC excretion at 8 h was a constant and stable individual characteristic for the rate of the formation of 7OHC ('2 h coumarin test'). Although four individuals had relatively slow coumarin test values (34-40%), no clear-cut polymorphism in the rate of 7OHC formation was found. However, 7OHC formation was lower in males and in cigarette smokers.

Adult↗
PubMed1994

Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers.

The effect of grapefruit juice on the urinary excretion of 7-hydroxycoumarin after oral administration of 10 mg coumarin, as an index of cytochrome P450 dependent coumarin metabolism, has been investigated in an open, randomised cross over study in 13 healthy volunteers (7 female, 6 male). The percentage of 7-hydroxycoumarin found in urine was significantly decreased up to 8 h after simultaneous intake of 300 ml grapefruit juice. If the same volume of juice was swallowed 30 min prior to the administration of coumarin, 7-hydroxycoumarin excretion was delayed by up to 6 h. MRTexcr. of coumarin was 70% extended by coadministration of grapefruit juice. It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways. The mechanism of cytochrome P450 inhibition by these flavonoids is still poorly understood.

Adult↗
PubMed1994

Coumarin modulates the cell-cycle progression of an MTV-EJras cell line.

The effects of coumarin (1,2-benzopyrone) on ras oncogene expression during the cell cycle of an MTV-EJras cell line was determined by flow cytometry. ras oncogene expression in cells was induced by dexamethasone and increased fivefold during G1/G0 phase and threefold in S phase. Dexamethasone also increased the percentage of cells in S phase from 21% to 31%, compared to phosphate-buffered-saline-treated control cells (P < 0.01). Coumarin decreased the percentage of dexamethasone-treated cells in S phase from 31% to 19%, with a concomitant increase in the percentage of cells in G1/G0 compared to control levels. Coumarin also reduced ras expression (mean fluorescence) by 40% in G1/G0 phase and 30% in S phase. We conclude that coumarin significantly reduces the cell-cycle progression of MTV-EJras cells and decreases ras expression in both G1 and S phases. These findings suggest a novel approach to the selective control of proliferation of malignant cells.

Animals↗
PubMed1994

Coumarin (1,2-benzopyrone) for the treatment of prostatic carcinoma.

The unavailability of effective treatment for metastatic hormone-refractory and clinically localized but pathologically unfavorable prostatic carcinoma warrants trial of new and promising treatments. Preliminary studies in patients with metastatic disease have shown (a) subjective but no objective responses to 100 mg coumarin and cimetidine daily; (b) objective responses in 3 of 40 patients treated with 3 g coumarin daily, all of whom had normal performance status and 1 of whom remains with three resolved bone metastases and stable prostate-specific antigen levels after 4 years; (c) toxicity only in bedridden patients. We recently initiated two multi-center trials of 1 g coumarin daily. Metastatic prostatic carcinoma patients of normal performance status were treated in a phase II trial. Patients who had been treated by radical prostatectomy, but had surgical margin, seminal vesicle or lymph node involvement or detectable prostate-specific antigen after radical prostatectomy, were randomized to coumarin or placebo.

Aged↗
PubMed1984

Possible coumarin-like mechanism of action for cephalosporins.

In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K1 was injected to investigate whether this was followed by an increase in vitamin K1 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K1-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K1-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K1-epoxide plasma concentrations following injection of 10 mg vitamin K1, whereas in normal subjects only traces of K1-epoxide could be detected (less than 0.030 micrograms/ml). The K1-epoxide concentrations found in our three patients treated with cephalosporins were 0.12, 0.16 and 0.19 micrograms/ml, respectively. This indicates that latamoxef or cefazedone might reduce clotting factor synthesis by a coumarin-like mechanism of action in these patients. Although the effect of cephalosporins in enhancing vitamin K1-epoxide plasma concentrations is less than that of coumarins, it might cause severe hypoprothrombinaemia in the presence of latent vitamin K deficiency.

Aged↗
PubMed1977

(3-14C) coumarin distribution in rat tissues after the injection of a single dose.

Experimentally it has been shown that coumarin is a very effective therapy in the treatment of high protein oedemas. This study reports on the distribution of a single dose of 3-14C-coumarin in rats. Blood levels of coumarin were always much lower than those of the tissues at similar times. The half life of 3-14C-coumarin and its labelled metabolites was found to be about 43 hours. This ties in fairly well with the optimum frequencies of the administration of the drug which was found to be 24 hours. At this time, skin and muscle levels (the tissues most effected in lymphoedema and in thermal oedema) were maximal.

Animals↗
PubMed1986

The effect of coumarin (5,6 benzo-alpha-pyrone) on elicited members of the mononuclear system in dogs with chronic secondary lymphedema.

The effect of coumarin is investigated on the morphological features of members of the mononuclear phagocytic system (MPS) attaching to subcutaneously (s.c.) implanted coverslips in "normal" and chronically lymphedematous tissues. In untreated "normal" tissues there was no attachment suggesting that the presence of lymphedema elsewhere influences MPS activity. Coumarin restored attachment proportions to those found in normal tissues of dogs with no lymphedema. In lymphedema, coumarin significantly increased the proportion of macrophages which were round with less than ten pseudopods (new recruits) and the proportion with distinct pseudopods combined with more than ten vacuoles (active elicited members of the MPS). Coumarin resulted in a significant decline in the proportion of macrophages which were round and with more than ten apparently lipid-containing vacuoles, suggesting a facilitation of their removal to other sites.

Animals↗
PubMedDate not supplied

Viper venoms and coumarin-induced prothrombin. A comparison of several one-stage methods employing three different venoms as thromboplastins.

Three venoms obtained from three vipers, namely Echis carinatus, Notechis scutatus scutatus and Oxyuranus scutellatus, have been used as thromboplastin in a one-stage assay of coumarin-induced prothrombin. Regardless of the venom used, prothrombin resulted to be low in coumarin-treated patients. The mean values obtained were 27.2, 33.6, and 24.2%, respectively. These values were comparable to those obtained by means of the classical one-stage method (24.8%). A good correlation was observed among the different methods. However, the levels observed using the Notechis scutatus scutatus venom method were slightly higher as compared to those obtained by means of the other viper venoms and by means of the classical one-stage method. The three viper venoms used seem unable to activate coumarin-induced prothrombin. The levels obtained were in fact, in each instance, definitely lower than those observed immunologically. Methods which employ these viper venoms may be used in the evaluation of prothrombin in coumarin-treated patients.

Animals↗
PubMed2004

Solid phase synthesis of 3-(4-hydroxyphenyl)coumarin: preliminary experiments for combinatorial synthesis of substituted 3-phenylcoumarin derivatives.

Coumarin and its derivatives occur widely in nature. Many attempts were made for synthesis of various coumarin derivatives because of their interesting biological activities. In this study, solid phase synthetic approach of 3-(4-hydroxyphenyl)coumarin was achieved for combinatorial synthesis of substituted 3-phenylcoumarin analogues. Starting from 4-hydroxyphenylacetic acid methyl ester, release of 3-(4-hydroxypnehyl)coumarin from polymer support was accomplished.

Combinatorial Chemistry Techniques↗
PubMed2005

Main comedications associated with major bleeding during anticoagulant therapy with coumarins.

OBJECTIVE: To study the main comedications associated with major bleeding during anticoagulant therapy with coumarins in a non-selected population under everyday circumstances. METHODS: The study population for this retrospective cohort study included all new users of phenprocoumon or acenocoumarol aged 40-80 years, during the period 1992-2000 in the PHARMO Record Linkage System. All patients were followed until the last dispensing of phenprocoumon or acenocoumarol, the first bleeding complication requiring hospitalization, death, or the end of the study period. The number of days on coumarins alone and the number of days on coumarins in combination with several potentially interactive drugs during follow-up were determined for each patient. RESULTS: The inclusion criteria of this study were met by 19,935 new users of phenprocoumon or acenocoumarol. During follow-up, 552 patients were hospitalized for bleeding. Of all potentially interactive drugs started during anticoagulant therapy by at least 50 patients and with at least five bleedings, antibacterial drugs were associated with a four to seven times increased risk of bleeding. Among non-steroidal anti-inflammatory drugs, naproxen had the highest relative risk. Antithrombotic salicylates and tramadol were associated with a three times increased risk of bleeding. CONCLUSION: Antibacterial drugs, non-steroidal anti-inflammatory drugs, antithrombotic salicylates and tramadol were the main potentially interactive drugs associated with major bleeding during anticoagulant therapy with coumarins under everyday circumstances.

Acenocoumarol↗
PubMed2006

Resonance energy transfer in new fullerene-coumarin diads.

The fluorescence properties of new [60] and [70] fullerene-coumarin diads are studied. These diads were synthesized by covalently linking a coumarin dye to a fullerene (C60 or C70) by a cyclopropanation reaction. The absorption and fluorescence spectra, quantum yields and lifetimes of the diads are reported. The fluorescence quenching of the coumarin moiety by the fullerene was observed in all diads, indicating the occurrence of resonance energy transfer between the coumarin and fullerene moieties.

Coumarins↗
PubMed1992

Interactions of a series of coumarins with reactive oxygen species. Scavenging of superoxide, hypochlorous acid and hydroxyl radicals.

Sixteen plant-derived or synthetic coumarins with various hydroxyl and other substitutions were tested for their ability to inhibit lipid peroxidation and to scavenge hydroxyl radicals, superoxide radicals and hypochlorous acid. Seven unsubstituted or monosubstituted coumarins were essentially inactive in all tests except for ability to scavenge OH with rate constants approximately greater than 1 x 10(9) M-1. sec-1. Of the remaining nine, six containing dihydroxy substitutions were effective inhibitors of Fe3+-ascorbate-dependent microsomal lipid peroxidation (IC50 less than 20 microM), with ortho-dihydroxy + one additional substitution optimal (IC50 less than 10 microM). ortho-Dihydroxylated coumarins were pro-oxidant (enhanced OH generation) in the Fe3+-EDTA-H2O2 deoxyribose system but decreased OH' generation in the Fe3+-ascorbate-H2O2 deoxyribose system, indicating that these compounds can both chelate iron ions and also readily donate electrons for redox cycling of Fe3+. The meta-dihydroxycoumarin did not show this behaviour, but was an effective scavenger of hypochlorous acid, a property shared by only one other compound. Several other coumarins with one or more hydroxyl substituents were also capable of effectively removing superoxide anions (IC50 3.7-72 microM), although some could not be quantified due to direct rapid reduction of cytochrome c. We conclude that several compounds, notably 5,7-dihydroxy-4-methylcoumarin, possess beneficial biochemical profiles of interest in relation to pathophysiological processes dependent upon reactive oxygen species.

Animals↗
PubMed1993

Sensitive high-performance liquid chromatographic method for the determination of coumarin in plasma.

A high-performance liquid chromatographic method was developed for the determination of coumarin in plasma at low concentrations. The method involves a single-step extraction of the alkalinized sample with hexane and subsequent evaporation of the organic phase in the presence of hydrochloric acid to collect and concentrate the coumarin. Analysis of the acidic phase was performed on a C8 column and coumarin was detected by measuring the UV absorbance at 275 nm. The limit of detection was 0.3 microgram l-1. The assay was used to study the evolution of concentrations of coumarin in one volunteer after oral administration of a single 10-mg dose.

Calibration↗
PubMed1992

Transient absorption spectra and quenching of coumarin excited states by nucleic acid bases.

Triplet-triplet absorption spectra of coumarin show different profiles and maxima in ethanol from those in water, which are very similar to those reported in benzene. Long-lived transient species other than triplet states were generated as initial photoproducts between coumarins and nucleic acid bases. The excited singlet and triplet states of coumarins were quenched by nucleic acid bases. Adenine base quenched the excited singlet state of coumarins more efficiently than thymine base. However, photocycloadducts of furocoumarins are formed predominantly with thymine, and not with adenine. Moreover, it is reported that the poly[dA-dT].poly[dA-dT] sequence region is the most favourable site for the photocycloaddition reaction of furocoumarins. The results imply that adenine contributes to singlet-state photocycloaddition reaction of furocoumarins with thymine, probably through an adenine-furocoumarin-thymine termolecular interaction.

Adenine↗
PubMed2005

Synthesis and in vivo analgesic and anti-inflammatory activity of some bi heterocyclic coumarin derivatives.

Sets of coumarinyl ethers having chromone, benzofuranyl and 4-hydroxy coumarins (4, 5, 6) were prepared and tested for analgesic and antiinflammatory activity. The 4-(4'-acetyl-3'-hydroxy-phenoxymethyl)-coumarin 3 were synthesised by the reaction of 4-bromo methyl coumarin with 2, 4-dihydroxy acetophenones, were found to less active. Further compound 3 having the ortho hydroxy moiety was cyclised to chromones 4 and benzofurans 5 were found to enhance the analgesic and anti-inflammatory activity. The cyclisation to 4-hydroxy coumarin 6 was found to be reducing the anti-inflammatory and analgesic activity in this series. These newly synthesized compounds were found to produce less toxicity and less ulcerogenic effects.

Analgesics↗
PubMed2006

New zirconium (IV) complexes of coumarins with cytotoxic activity.

Complexes of zirconium (IV) with some bis-coumarin ligands have been synthesized. The zirconium (IV) complexes with bis-coumarins were characterized by different physicochemical methods-elemental analysis, IR-, and (1)H-NMR-spectroscopies and mass spectral data. The spectral data of zirconium (IV) complexes were interpreted on the basis of comparison with the spectra of the free ligands. The results of the ligands and their complexes, based on spectral data are informative and useful for suggestion of the metal-ligand binding mode. Cytotoxic screening by MTT assay was carried out. In the present study we performed comparative evaluation of the cytotoxic effects of the three newly synthesized zirconium complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia LAMA-84. The preliminary cytotoxicity screening program revealed that the investigated zirconium complexes induced 50% inhibition of the cell viability of HL-60 and LAMA-84 cells at micromolar concentrations and thus could be considered as biologically active. Independently of the tumor test system evaluated the complex of bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane proved superior to the remaining agents with respect to the IC(50) values obtained. The complexes of both the other coumarins evaluated proved to be less potent than the corresponding free ligands, as evidenced by the IC(50) values obtained. Thus the zirconium complexes with coumarin ligands represent a novel class of antiproliferative agents, which deserve further attention in search of anticancer lead compounds.

Antineoplastic Agents↗