Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson's Disease.

The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate ß sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated ß sheet aggregate (ß23), and prevented ß23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

Safety and Effectiveness of Bipolar Transurethral Resection of the Prostate in Patients Under Ongoing Oral Anticoagulation with Coumarins or Antiplatelet Drug Therapy Compared to Patients Without Anticoagulation/Antiplatelet Therapy.

Objective: To determine whether transurethral resection of the prostate (TURP) is safe and effective in patients under ongoing therapeutic oral anticoagulation (OAC) or antiplatelet drug (APD) therapy. Patients and Methods: We analyzed data on 276 consecutive TURP patients under ongoing APD therapy with acetylsalicylic acid (n = 130) or clopidogrel (n = 16) or ongoing OAC with phenprocoumon (n = 57), without stopping or bridging the medication, compared to 73 TURP patients without APD/OAC. Results: Outcomes of patients under acetylsalicylic acid were comparable to the controls. Under ongoing OAC therapy TURP patients tended to need slightly longer bladder irrigation (median 24 hours vs 22 hours, p = 0.06), needed longer transurethral catheterization (median 42 hours vs 24 hours, p = 0.031), were threefold more likely to have postoperative urinary retention (18% vs 6%, p = 0.04), had slightly longer hospital stays (median 4 days vs 3 days, p = 0.008), and tended to need more blood transfusions (9% vs 1%, p = 0.09), compared to controls. TURP patients under ongoing APD therapy with clopidogrel needed slightly longer bladder irrigation (median 24 hours vs 22 hours, p = 0.006), received more blood transfusions (19% vs 1%, p = 0.017), and had more rehospitalizations (19% vs 3%, p = 0.039). The significant functional improvement 1, 3, and 12 months after TURP was similar in all groups. Conclusions: Ongoing APD therapy with acetylsalicylic acid does not significantly impact TURP outcomes in terms of bleeding complications. Patients under ongoing therapeutic OAC with phenprocoumon or APD with clopidogrel can safely undergo TURP with an increased risk of bleeding complications, blood transfusions, and longer hospitalization.

Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema.

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.

Molecular Pathway of Psoralidin-Induced Apoptosis in HepG2 Cell Line.

OBJECTIVE: To test the role of psoralidin in human liver cancer HepG2 cells in vitro. METHODS: Cell viability was assessed by methylthiazolyldiphenyl-tetrazolum bromide assay and apoptotic cells were labeled by annexin V then sorted by flow cytometry. Protein expressions of caspase-3, caspase-8, caspase-9, Bax, Bid, Bcl-2, Bcl-xL and p53 were examined by western blot while activity of caspase-3, -8 and -9 were also determined. RESULTS: Psoralidin reduces cell viability greatly in a time dependent manner (64%, 40%, 21%, 12% at 2, 6, 24 and 48 h treatment with 64 µmol/L psoralidin respectively) and up-regulates activities of caspase-3, -8 and -9 in a concentration dependent manner (between 4 to 64 µmol/L). Psoralidin also increases the expression of pro-apoptosis genes Bax, Bid and p53 while decreases the expression of pro-survival genes Bcl-2 and Bcl-xL, both in a concentration dependent manner between 4 and 64 µmol/L (P<0.05 at 16 and 64 µmol/L). Caspase-3 inhibitor (Ac-DEVD-CHO at concentrations between 10 to 20 µmol/L), p53 inhibitor (pifithrin-α at 5 µmol/L) and cyclosporin A can attenuate the apoptotic effect of psoralidin. CONCLUSION: The cytotoxic role of psoralidin might work through both intrinsic and extrinsic apoptotic pathway.

Gastroprotective efficacy and safety evaluation of scoparone derivatives on experimentally induced gastric lesions in rodents.

This study investigated the gastroprotective efficacy of synthesized scoparone derivatives on experimentally induced gastritis and their toxicological safety. Six scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/ethanol- and indomethacin-induced gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy)-methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy)-methylenedioxycoumarin were found to be equipotent or less potent that of rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the scoparone's phenyl ring significantly improves gastroprotective activity, whereas the presence of a dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective scoparone derivatives-5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin-were examined for their acute toxicity in mice as well as their effect on cytochrome P450 (CYP) enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to CYP3A4 and CYP2C9 enzyme activity. These results indicate that compared to other scoparone derivatives, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on drug-metabolizing enzymes.

[Cinnamon rolls are not associated with admission for toxic or alcoholic hepatitis in a Danish liver referral centre].

INTRODUCTION: Cinnamon contains cumarin, which may be toxic to the liver. EU-regulations standardardize the amount of cinnamon in pastry including cinnamon rolls. The aim of the study was to investigate if cinnamon intake from pastry was associated with toxic or alcoholic hepatitis. RESULTS: We registered 58 patients with toxic hepatitis, 38 (66%) women and 20 (34%) men with a median age of 51 (range: 32-80) and 53 (range: 18-78) years, respectively. A total of 22 patients had primarily cholestasis and 36 had hepatitis biochemically. The duration of toxic liver disease from admission to normalization of liver enzymes was similar in the two groups (3.5 ± 3.5 vs 3.6 ± 3.5 months). Toxic hepatitis was most often caused by drugs e.g. NSAID (n = 15; 26%), antibiotics (n = 9; 16%), alternative medicine (n = 7; 12%) and Antabuse (n = 5; 9%). We registered eight patients admitted with severe alcoholic hepatitis, five men and three women, median age of 60 (range: 34-67) years. Alcoholic hepatitis was associated with high alcohol intake. None of the patients with toxic or alcoholic hepatitis reported of excessive intake of cinnamon rolls and there was no evidence of cinnamon added to alcohol of alternative medicine products. CONCLUSION: Intake of cinnamon from cinnamon rolls is not associated with admission for toxic or alcoholic hepatitis. However, for the diagnosis of toxic liver diseases including alcohol it is very important to have patient information regarding any new drugs, alternative medicine and alcohol intake. Further, other causes of liver diseases should be excluded. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

The pros and cons of plant estrogens for menopause.

Concerns pertaining to the risk of estrogen exposure through HT have prompted an increase in the use of natural alternatives. Phytoestrogens may provide postmenopausal women with a practical alternative and many women have already begun to utilize phytoestrogen supplements. However, research regarding the efficacy of phytoestrogens as a hormone therapy alternative has been previously pessimistic or questionable at best. This review scrutinizes the most current research regarding the efficacy of three types of phytoestrogens, isoflavones, lignans and coumestans, and their specific effect on the reduction of climacteric symptoms, specifically vasomotor symptoms, vaginal atrophy, insomnia and osteoporosis. A discussion of the research pertaining to the relative safety of each phytoestrogen in terms of breast and endometrial health is also included. Overall, current research demonstrates that phytoestrogens are effective in reducing the intensity of hot flushes, and some phytoestrogen combinations result in a decreased frequency. Certain phytoestrogens have also been shown to decrease vaginal atrophy, improve sleep and cognition, and positively affect bone health. Even though initial research was generally unconvincing, the more recent evidence reviewed here is rather positive. In terms of safety and reports of adverse reactions, trials have not shown an increase in breast cancer risk or increase in endometrial hyperplasia following phytoestrogen use, but trials explicitly designed to find neoplasia have not been reported. Moreover, unlike hormone therapy, lignans may not increase clotting risk in postmenopausal women, thus supplements may serve as a treatment option for patients who have contraindications to hormone therapy. Phytoestrogens may provide a safe and partially effective alternative to HT. However, because research regarding phytoestrogens is relatively new, pharmaco-vigilence is still required, as these products are not yet FDA-approved. This article is part of a Special Issue entitled 'Phytoestrogens'.

Suppression of BSEP and MRP2 in mouse liver by miroestrol and deoxymiroestrol isolated from Pueraria candollei.

Miroestrol and deoxymiroestrol are highly active phytoestrogens isolated from the tuberous root of Pueraria candollei var. mirifica (Leguminosae). Modulatory effects of miroestrol and deoxymiroestrol on the mRNAs of BSEP and MRP2 genes involved in bile salt transportation, in C57BL/6 mice were investigated. In contrast to estradiol, miroestrol and deoxymiroestrol suppressed the expression of BSEP and MRP2 mRNA in both male and female mice. The results suggest for the first time that the use of miroestrol and deoxymiroestrol-containing products as alternative medicines or health supplements should be concerned according to their effects on key genes that regulate the bile salt export pump, which could result in the risk of hepatotoxicity and intrahepatic cholestasis.

Severe liver dysfunction possibly caused by the combination of interferon beta-1b therapy and melilot (sweet clover) supplement.

WHAT IS KNOWN AND OBJECTIVE: We report a case of severe liver dysfunction exacerbated after interferon beta (IFNB)-1b injection in a patient with multiple sclerosis (MS) who had been taking a melilot (sweet clover) supplement. Although IFNB-1b therapy for MS can cause mild liver dysfunction, severe hepatotoxicity attributable to supplement use has been reported. CASE SUMMARY: A 23-year-old Japanese woman taking a melilot supplement containing coumarin at 10 mg/day for 3 years was admitted to our hospital to receive IFNB-1b therapy for MS. Fourteen days after subcutaneous injection of IFNB-1b every other day, her aspartate transaminase (AST) and alanine aminotransferase (ALT) levels were elevated at 235 and 681 IU/L, respectively. After the discontinuation of IFNB-1b therapy and supplement intake, AST and ALT returned to normal levels. Later, she started receiving an intramuscular injection of IFNB-1a weekly without supplement intake. She was able to continue IFNB-1a therapy this time, showing a slight elevation of AST level at 61 IU/L. WHAT IS NEW AND CONCLUSION: The combination of IFNB-1b therapy and melilot supplement intake may cause severe liver dysfunction in patients with MS. Given the doubtful value of the supplement, we suggest that it should be avoided by patients receiving interferon therapy.

In-vivo antioxidant and immunomodulatory activity of mesuol isolated from Mesua ferrea L. seed oil.

Mesua ferrea L. (Nagkesar) is traditionally being used for antiseptic, anti-inflammatory, antiasthmatic and antiallergic activities. It is an ingredient of ayurvedic formulations like Brahma Rasayana and Chyavanprash which are being used to improve immunity. The present study was performed to evaluate immunomodulatory activity of mesuol isolated from M. ferrea seed oil in experimental animals. In humoral immune response model, mesuol evoked a significant dose dependent increase in antibody titer values in cyclophosphamide (50 mg/kg, i.p., 9th and 16th day) induced immunosuppression which was sensitized with sheep red blood cells (SRBC) on the 7th and 14th day of experiment. In cellular immune response model, an increase in paw volume was recorded on the 23rd day in cyclophosphamide-induced immunosuppressed rats treated with SRBC (0.03 ml 2% v/v, s.c.) on the 21st day. Mesuol restored the hematological profile in cyclophosphamide induced myelosuppression model. Mesuol potentiated percentage neutrophil adhesion in neutrophil adhesion test in rats and phagocytosis in carbon clearance assay. The study indicated immunomodulatory activity of mesuol.

Ceylon cinnamon does not affect postprandial plasma glucose or insulin in subjects with impaired glucose tolerance.

Previous studies on healthy subjects have shown that the intake of 6 g Cinnamomum cassia reduces postprandial glucose and that the intake of 3 g C. cassia reduces insulin response, without affecting postprandial glucose concentrations. Coumarin, which may damage the liver, is present in C. cassia, but not in Cinnamomum zeylanicum. The aim of the present study was to study the effect of C. zeylanicum on postprandial concentrations of plasma glucose, insulin, glycaemic index (GI) and insulinaemic index (GII) in subjects with impaired glucose tolerance (IGT). A total of ten subjects with IGT were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with placebo or C. zeylanicum capsules. Finger-prick capillary blood samples were taken for glucose measurements and venous blood for insulin measurements, before and at 15, 30, 45, 60, 90, 120, 150 and 180 min after the start of the OGTT. The ingestion of 6 g C. zeylanicum had no significant effect on glucose level, insulin response, GI or GII. Ingestion of C. zeylanicum does not affect postprandial plasma glucose or insulin levels in human subjects. The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects with poor glycaemic control would then be lost.

Efeito de dinamizações de Arnica montana L. no metabolismo de chambá (Justicia pectoralis Jacq. ) / Effect of dynamizations of Arnica montana in metabolism of chambá (Justicia pectoralis Jacq. )

Este estudo objetivou avaliar a resposta do crescimento e do metabolismo secundário de Justicia pectoralis, expresso em produção de cumarina, a crescentes dinamizações de A. montana. O experimento foi conduzido na Universidade Federal de Viçosa. O delineamento estatístico foi inteiramente casualizado, com seis repetições e cinco tratamentos, totalizando 30 parcelas experimentais, sendo cada parcela constituída de uma planta por vaso. Os tratamentos foram as dinamizações 3CH, 30CH, 60CH, 100CH e 200CH do preparado homeopático A. montana. Os tratamentos foram aplicados às plantas via pulverização, em intervalos semanais, iniciando logo após o plantio. Após quatro meses do plantio as plantas foram colhidas. As características de crescimento avaliadas foram matérias fresca e seca de folhas e caules, matérias fresca e seca de inflorescências e matérias fresca e seca total. No estudo fitoquímico foi avaliada a produção da cumarina (1-2 benzopirona). Não houve resposta nas variáveis de crescimento aos tratamentos. As dinamizações de A. montana causaram alterações no metabolismo secundário das plantas. Os conteúdos de cumarina das plantas com A. montana 3CH e 30CH foram próximos e mais baixos, aumentando progressivamente a partir de 60CH, chegando ao máximo em 100CH, seguido de redução em 200CH. A preparação homeopática A. montana causa alterações no metabolismo secundário de chambá, sendo as repostas dependentes da dinamização.

Were evaluated the responses to dynamizations of Arnica montana in the growth and in the secondary metabolism of Justicia pectoralis expressed as coumarin production. The studies were carried out at the Universidade Federal de Viçosa. The statistical design was completely randomized, with six replicates and five treatments, 30 experimental plots, one plant per pot. The treatments were dynamizations 3CH, 30CH, 60CH, 100CH and 200CH homeopathic preparation of A. montana. The application the treatments begun are planting seedlings, the aerial part being sprayed, at weekly intervals. After four months of planting, the plants were harvested. The evaluated growth characteristics were: fresh and dry matter of leaves and stems, fresh and dry matter of inflorecenses, and fresh and dry matter total. In the phytochemistry study, the production of the coumarin 1,2-benzopyrone was evaluated. Were no responses of growth characteristics. The dynamizations of A. montana caused changes in secondary metabolism of plants. The coumarin production with A. montana plants 3CH and 30CH were lower, increasing progressively from 60CH, and coming to increased in 100CH, followed by a large reduction in the 200CH. The homeopathic preparation A. montana cause change in secondary metabolism of chambá, and the responses depend on dynamizations.

Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: evidence for the involvement of monoaminergic systems.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants.

BACKGROUND: Vitamin K's effects extend beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis. Vitamin K is required for the gamma-carboxylation of osteocalcin. Likewise, this gamma-carboxylation also occurs in the liver for several coagulation proteins. This mechanism is interrupted by coumarin-based anticoagulants in both the liver and bone. METHODS: A thorough review of the literature on vitamin K, osteocalcin and their role in bone metabolism and osteoporosis, as well as the potential bone effects of anticoagulant therapy was conducted. CONCLUSIONS: Epidemiological studies and clinical trials consistently indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk. Typical dietary intakes of vitamin K are below the levels associated with better BMD and reduced fracture risk; thus issues of increasing dietary intakes, supplementation, and/or fortification arise. To effectively address these issues, large-scale, intervention trials of vitamin K are needed. The effects of coumarin-based anticoagulants on bone health are more ambiguous, with retrospective studies suggesting that long-term therapy adversely affects vertebral BMD and fracture risk. Anticoagulants that do not affect vitamin K metabolism are now available and make clinical trials feasible to answer the question of whether coumarins adversely affect bone. The research suggests that at a minimum, clinicians should carefully assess anticoagulated patients for osteoporosis risk, monitor BMD, and refer them to dietitians for dietary and supplement advice on bone health. Further research is needed to make more efficacious decisions about vitamin K intake, anticoagulant therapy, and bone health.

Clematis vitalba L. aerial part exhibits potent anti-inflammatory, antinociceptive and antipyretic effects.

Extracts obtained from the dried aerial parts of Clematis species are used as folk remedy worldwide for the treatment of various inflammatory ailments such as rheumatism and to reduce fever. In order to test the effectiveness of extracts, fractions and subfractions from dried Clematis vitalba L. (Ranunculaceae) aerial parts were studied on mice. Extracts are shown to have a potent effect on carrageenan-induced hind paw edema and acetic acid-induced increased vascular permeability models. Through bioassay-guided fractionation procedures a new C-glycosylflavon, 4'-O-coumaroyl-isovitexine (vitalboside) was isolated as the main active ingredient of the aerial parts. Vitalboside showed a potent and dose-dependent (in 75 and 150 mg/kg does, per os) in vivo anti-inflammatory activity against acute (carrageenan-, serotonin- and PGE(2)-induced hind paw edema model, castor oil-induced diarrhea), subacute (subcutaneous air-pouch) and chronic (Freund's complete adjuvant-induced arthritis) models of inflammation. The same compound was also isolated as the main antinociceptive principle which was assessed by using the models based on the inhibition of p-benzoquinone-induced writhings, as well as antipyretic activity against Freund's complete adjuvant-induced increased body temperature. Acute and subchronic toxicity studies were also performed.

Troxerutin protects the isolated perfused rat liver from a possible lipid peroxidation by coumarin.

For more than 40 years coumarin has been successfully used in the therapy of chronic venous insufficiency (CVI). The occurrence of liver injuries is rather rare and happens predominantly when doses are administered which are significantly higher than necessary for therapeutical use. Such effects caused by high coumarin concentrations are reproducible in in vivo experiments in mice or rats and HepG2-cells. In order to characterize the mechanism of liver injuries, the isolated perfused rat liver has been chosen as model. Since liver injuries are quite rare, if coumarin is used in co-medication with troxerutin, a possible protective influence of this flavonoid has been investigated. In concentrations higher than 4 mmol/l, coumarin alone is effective in the isolated perfused rat liver. Then the release of the enzymes alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increases and there is a measurable reduction of perfusion flow, oxygen consumption and rate of bile secretion. Additionally, the concentrations of hepatic adenosine triphosphate (ATP) and oxidized and total glutathione (GSSG/GSH) decrease. In the livers of fasting animals, coumarin doubles the concentration of hepatic malondialdehyde (MDA). This effect cannot be detected if troxerutin is added. In general, troxerutin reduces the concentration of all coumarin-metabolites in the perfusate and bile and changes the ratio of the main metabolites, coumarin: 3-hydroxycoumarin: 7-hydroxycoumarin. An analysis of the metabolic steps also shows that the amount of coumarin eliminated via faeces does not stem from absorbed coumarin, because the amount of orally applied coumarin detectable in the bile is less than 1%. The study demonstrates that troxerutin has hepatoprotective properties and thus protects the liver from a possible lipid peroxidation caused by coumarin. However, it is necessary to point out that these adverse effects caused by coumarin can be detected only in very high concentrations considerably above the regular therapeutical dosage. This allows the conclusion that troxerutin is a beneficial cofactor in coumarin preparations used for the therapy of chronic venous insufficiency.