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PubMed1993

Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes.

Coumarin is 7-hydroxylated by the P450 isoform Cyp2a-5 in mice and CYP2A6 in humans. Various drugs, endogenous substances, plant substances and carcinogens, altogether about 90 chemicals, were evaluated as possible inhibitors of coumarin 7-hydroxylase (COH) activity in mouse microsomes. The effects of selected compounds on COH activity in human liver microsomes were also tested. The furanocoumarin derivatives methoxsalen (8-methoxypsoralen) and psoralen proved to be the most potent inhibitors of mouse COH activity (IC50 values 1.0 and 3.1 microM, respectively). The furanocoumarins bergapten (5-methoxypsoralen), isopimpinellin (5,8-dimethoxypsoralen), imperatorin and sphondin also effectively inhibited mouse COH activity (IC50 values 19-40 microM). Methoxsalen, isopimpinellin and metyrapone were also inhibitors in mice in vivo. Methoxsalen was a potent inhibitor of COH activity also in human liver microsomes, (IC50 value 5.4 microM), whereas bergapten, isopimpinellin and imperatorin had no effect. The imidazole antimycotic miconazole was a potent but non-specific inhibitor of COH activity. Several known substrates and inhibitors of members in the CYP1A, CYP2B, CYP2C, CYP2D and CYP3A subfamilies were poor inhibitors of COH activity. These results suggest that (i) the coumarin-type compounds in particular interact with the active sites of Cyp2a-5 and CYP2A6, and (ii) the active sites of Cyp2a-5 and CYP2A6 are structurally different, since a number of compounds inhibited mouse, but not human COH activity.

Animals↗
PubMed2006

Oral anticoagulant treatment with coumarin derivatives does not influence plasma homocysteine concentration.

BACKGROUND: High circulating levels of homocysteine are a risk factor for arterial and venous thrombosis. This association has been established in numerous case-control studies. In some of these studies, patients were treated with anticoagulants at the time of venapuncture. It is not clear whether homocysteine concentrations are influenced by anticoagulants. If anticoagulation does, indeed, have an effect on homocysteine levels, it might underestimate or overestimate the possible association of homocysteine levels and vascular disease. METHODS: In this study we used two different groups to investigate the effect of coumarin derivatives on homocysteine concentrations. Homocysteine levels were measured in 40 patients who were on the waiting list for orthopedic surgery and who were expected to receive prophylactic anticoagulant therapy after the operation. Measurements were taken before the operation, as well as during and after coumarin therapy. Homocysteine concentrations were also measured in a second study group consisting of 12 healthy volunteers who were treated with oral anticoagulants. RESULTS: Mean homocysteine concentrations increased by 6% (95% CI 2-10%) during the treatment with coumarin derivatives. This corresponds to a 1 mumol/L increase in homocysteine concentration. After the anticoagulant treatment period, the concentrations decreased again. We determined that this slight increase does not influence the interpretation of epidemiological studies. We also observed no significant effect of anticoagulants on homocysteine concentration after 13 weeks of treatment of healthy volunteers (decrease of 3.6%, or approximately 0.6 micromol/L; 95% CI -17.5-8.5%). CONCLUSION: We conclude that anticoagulation does not influence homocysteine concentrations to any significant degree.

Journal Article↗
PubMed2006

Antifungal activity of some coumarins obtained from species of Pterocaulon (Asteraceae).

Fractionation of antifungal hexane extracts of the aerial parts of three Pterocaulon spp., Pterocaulon alopecuroides, Pterocaulon balansae and Pterocaulon polystachyum (Asteraceae) from South Brazil traditionally used to treat animal mycoses, afforded the coumarins 5-methoxy-6,7-methylenedioxycoumarin, 7-(2',3'-epoxy-3'-methylbutyloxy)-6-methoxycoumarin, 6,7-methylenedioxycoumarin (ayapin), along with a mixture of 6-hydroxy-7-(3'-methylbutyl-2'-en-oxy)-coumarin (prenyletin) and 6-methoxy-7-(3'-methylbutyl-2'-en-oxy)-coumarin (prenyletin-methyl-ether). Among the different components of the active extracts, only the mixture of prenyletin and prenyletin-methyl-ether isolated from Pterocaulon polystachyum showed activity against Cryptococcus neoformans, Microsporum gypseum, Trichophyton rubrum and Trichophyton mentagrophytes. Nevertheless their MIC values were higher than the MIC of the original extracts, suggesting that the mixture but not only one compound would be the responsible for the activity detected in these Pterocaulon species.

Antifungal Agents↗
PubMed2006

Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.

INTRODUCTION: Prothrombin complex concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. MATERIALS AND METHODS: In the acute model, rats received 2.5 mg.kg(-1) phenprocoumon, and reversal of anticoagulation by 4.88 mL.kg(-1) saline, 100 microg.kg(-1) rFVIIa (NovoSeven) or 50 U.kg(-1) PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), prothrombin time (PT) and tail tip bleeding. RESULTS: Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT (p<0.01), fully normalized blood loss (p<0.01) and shortened bleeding time (p=0.008), while rFVIIa was without significant effect on these endpoints. CONCLUSIONS: In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.

Animals↗
PubMed1996

Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of alpha-chymotrypsin: significance of the "aromatic" nature of the novel ester-type coumarin for strong inhibitory activity.

A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with "aromatic" esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of alpha-chymotrypsin yet reported (kinact/KI = 760,000 M-1 S-1 at pH 7.5 and 25 degrees C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective alpha-chymotrypsin inhibitors.

Animals↗
PubMed2001

[Recurrent coumarin necrosis in type II protein S deficiency].

Coumarin necrosis is a rare but clinical very important complication of therapy with coumarin derivatives. We report a patient with congenital protein S deficiency type II, who developed coumarin necrosis during stabilization of phenprocoumon. Diagnostic problems and therapeutic alternatives are discussed considering the recent literature.

Adult↗
PubMed1999

Synthesis and evaluation of the physicochemical properties of esterase-sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers.

In an attempt to improve the membrane permeabilities of opioid peptides, we have synthesized cyclic prodrugs of [Leu5]-enkephalin and DADLE using a coumarinic acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid- and phenylpropionic acid-based cyclic prodrugs followed similar strategies. Key intermediates were the compounds with the C-terminal amino acids of opioid peptides (L-Leu, [Leu5]-enkephalin; D-Leu, DADLE) attached to the phenol hydroxyl group and the remaining amino acids of the peptide linked via the N-terminal amino acid (L-Tyr) attached to the carboxylic acid groups of the prodrug moieties (coumarinic acid or propionic acid). Cyclization of these linear precursors gave the cyclic prodrugs in 30-50% yields. These cyclic prodrugs exhibited excellent transcellular permeation characteristics across Caco-2 cell monolayers, an in vitro model of the intestinal mucosa. To correlate the cellular permeabilities of these cyclic prodrugs with their physicochemical properties, we calculated their Stokes-Einstein molecular radii from their diffusion coefficients which were determined by NMR and we determined their membrane interaction potentials using immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs exhibited molecular radii similar to those of the parent compounds, [Leu5]-enkephalin and DADLE. However, these cyclic prodrugs were shown to have much higher membrane interaction potentials than their corresponding opioid peptides. Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently due to the alteration of their lipophilicity and hydrogen bonding potential, but not their molecular sizes.

Amino Acid Sequence↗
PubMed1988

[Tetralogy of Fallot following coumarin administration in early pregnancy--an embryopathy?].

A case report of a 35-year old woman is presented who continued a coumarin therapy unconscious of an early pregnancy up to day 61. At term she delivered a baby with tetralogy of Fallot, up to now not mentioned in the symptom complex of malformations due to a coumarin therapy. In the case presented the typical symptoms of a warfarin embryopathy including a chondrodysplasia punctata and other morphological changes were lacking. Although some cases of cardiac malformations have been reported in literature following coumarin therapy in early pregnancy, a causal connection could not be confirmed.

4-Hydroxycoumarins↗
PubMedDate not supplied

Release characteristics of polymethacrylate nanospheres containing coumarin-6.

Sustained release nanospheres were prepared from the polymethacrylates Eudragit S(100) and E(100) containing a water insoluble dye by a salting-out method. Coumarin-6 was used as a model for insoluble analgesics to ascertain uptake and release properties dependent on polymer characteristics and pH. Morphology and particle size were characterized by scanning electron microscopy (SEM). Particles were smooth, spherical and uniform with diameters ranging from 0.6-0.8 micro m. Yield was 38% and 86% for E(100) and S(100), respectively, and encapsulation of coumarin-6 efficiency was 58% and 75%, respectively. Coumarin-6 was stable within the polymer matrix at temperatures from -20 degrees C to 45 degrees C for 4 months. Release was most efficient from S(100) polymers in phosphate buffer at pH 7.4 and 8.0 reaching a maximum; 5 hours prior to samples at pH 7.0 and 9.0. Release was biphasic and concentration as a function of the square root of time produced linear data suggesting a Higuchi type diffusion from a polymer matrix. Release from E(100) was 65% lower than that from S(100) and was not solely dependent upon the ionization of polymer but most likely due to a combination of factors including buffer ionization.

Analgesics↗
PubMed1971

Effects of Seselin and Coumarin on Growth, Indoleacetic Acid Oxidase, and Peroxidase, with Special Reference to Cucumber (Cucumis sativa L.) Radicles.

Seselin, a natural coumarin derivative isolated from citrus roots, inhibited radicle growth in seedlings of cucumber (Cucumis sativa), lettuce (Lactuca sativum), radish (Raphanus sativus), and wheat (Triticum aestivum) grown in the dark. Coumarin similarly inhibited radicle growth of cucumber seedlings. Growth retardation of the cucumber radicles was accompanied by an increased activity of peroxidase and indole-3-acetic acid oxidase. Both compounds antagonized indole-3-acetic acid-induced growth of wheat coleoptiles, whereas coumarin was much less effective than seselin in antagonizing gibberellic acid-induced release of reducing sugars from barley endosperm. It is suggested that seselin plays an important role in the regulation of root growth, and that it is the indole-3-acetic acid oxidase cofactor previously detected in citrus roots.

Journal Article↗
PubMed2004

The risk of overanticoagulation in patients with heart failure on coumarin anticoagulants.

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small-scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non-selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) > or = 6.0, the last INR assessment, death, loss to follow-up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR > or = 6.0. The risk of overanticoagulation was 1.66 [95% confidence interval (CI): 1.33-2.07] for cases of prevalent heart failure and 1.91 (95%CI: 1.31-2.79) for incidental cases. The decrease in dose requirements in patients with incidental heart failure showed a significant trend from the fifth INR measurement preceding the date of incidental heart failure to the third measurement after this date. Heart failure is an independent risk factor for overanticoagulation. Therefore, patients with heart failure should be closely monitored to prevent potential bleeding complications.

Acenocoumarol↗
PubMed2003

Thin layer chromatography-application in qualitative analysis on presence of coumarins and flavonoids in plant material.

Drugs, natural medicinal plant, animals and mineral materials, have a large and various application in official pharmacy and medicine. Carriers of multilateral pharmacological effects that those drugs shown, are chemically define as active components that are present in them. Methods of qualitative and quantitative analysis are used for the chemical investigation of components that drugs contain. Method of thin layer chromatography has been shown as very reliable. According to the chemical investigation of single drugs, it is possible to define a group of compound or single compound comparing them with standards. Relating to the usage of method of thin layer chromatography, it has been carried out investigation on presence of coumarins and flavonoids in domestic plant material that have wide everyday usage. Coumarins and flavonoids from the point of view of chemical belonging are phenol derivatives with important pharmacological effects. Applying method of thin layer chromatography, it is detected presence of coumarins and flavonoids substances in plant material that has been tested. Anethi graveolens fructus et folium (fruit and leaf of dill), Anethum graveolens L., Apiaceae, Avenae sativae fructus (fruit of oats), Avena sativa L., Poaceae and Asperulae odoratae herba (sweet woodruff), Asperula odorata L., Rubiaceae. Chromatograms are developed in systems cyclohexane-ethylacetat (13:7) and toluene-ether (1:1) saturated with 10% acetic acid, and visualisation by observing on UV lamp (254 and 366 nm), spraying with reagents KOH (10% ethanol solution) and diphenylboryloxyethylamine (1% methanol solution).

Journal Article↗
PubMed1999

[Secondary prevention after deep venous thrombosis. Low molecular weight heparin versus coumarin].

In numerous clinical trials low molecular weight heparins (LMWHs) have proven to be highly efficacious and safe in preventing thromboembolic complications. There is also a strong evidence that for the prevention of recurrence after deep venous thrombosis LMWHs lead to results comparable to those of dose-adjusted coumarin: in a monocentric randomized prospective study 200 patients after conservatively or surgically treated deep vein thrombosis received either a fixed dose of LMWH (5000 U anti-Xa; Fragmin P forte) s.c. or dose-adjusted coumarin (Marcumar) p.o. during a period of 3-6 months. During a follow-up of 12 months there was no significant difference between both groups regarding recurrence of deep vein thrombosis but three major bleeding complications in the coumarin-group (none in the LMWH-group) occurred.

Adult↗
PubMed2003

[Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for coumarin poisoning in a dog].

Coumarin poisoning in dogs is not unusual and is in most cases caused by warfarin, a coumarin derivative which is used as a rodenticide. Competitive inhibition of vitamin K with an incomplete synthesis of the coagulation factors II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3-year old male West Highland White Terrier with a reduced general condition and dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3 mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT with uncharacteristic thrombin time (TT); factor II, VII and X activities were reduced while factor V activity was normal, all of which are characteristic for coumarin poisoning. HPLC did not reveal the presence of warfarin but of phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This observation has not been described for dogs to date.

Animals↗
PubMed1991

Coumarin-induced skin necrosis.

Coumarin skin necrosis is a rare and usually unpredictable complication of coumarin therapy, occasionally leading to death. Onset is usually between the third and sixth day of coumarin therapy. The patient most commonly complains of pain in a region of abundant subcutaneous fat, with progression to erythema, petechiae, and gangrenous necrosis. Thrombosis of the dermal and the subcutaneous veins is demonstrated pathologically. We describe a case and review the pathogenesis, treatment, and prevention of this lesion.

Aged↗
PubMed1989

[Self-mutilation with a coumarin derivative].

The experiment of a self-injury by permanent intoxication with the coumarin derivative Warfarin is described. Various isolated haemostatic defects as differential-diagnostically demarcated causes for the leading symptom decrease of the value of the thromboplastin time which concern the effect of coumarin are mentioned. It is referred to the coagulation-analytic and chemical-toxic methods of proof of coumarins.

Adult↗
PubMed1996

[Studies of antitumor and chemopreventive agents against neoplasm: synthesis of coumarin 3-glyoxal derivatives and relationship between structure and antimutagenic activity].

It has been shown that alpha-glyoxal and its derivatives possess antivirus and antitumor activities. Eighteen new coumarin 3-glyoxal derivatives were synthesized in our laboratory. The fragmentation pattern of MS and the characteristic signals of 1HNMR of these compounds have also been studied. In pharmacological test in vitro most of these analogues showed antimutagenic activities, among them, compound 9 exhibited very strong antimutagenic activity and eight compounds showed strong effects. The struture-activity relationship and the possible active substructure responsible for the activity of these compounds were discussed. As expected, coumarin 3-glyoxals showed higher antimutagenic activities than their 3-acetyl coumarin counterparts. We also found that alkylation or esterification of 7-hydroxy were favorable to their activities.

Antimutagenic Agents↗
PubMed1963

Glucosides of coumarinic and o-coumaric acids in the tonka bean.

The beta-glucosides of coumarinic and o-coumaric acids were detected in extracts of cotyledons, exocarps, and seedling leaves of the tonka bean. The existence of these compounds and the presence of a beta-glucosidase having specificity for coumarinyl glucoside suggest that the tonka bean synthesizes coumarin by a pathway similar to the one found in sweetclover.

Cellulases↗