rutin and coumarin

Our current understanding of the pathophysiology of chronic venous disease (CVD) suggests that veno-active drugs (VAD) can provide effective symptom relief. Few studies have conducted head-to-head comparisons of VAD and placebo while also assessing objective measures (such as water plethysmography findings and tibiotarsal joint range of motion) and patient-reported quality of life outcomes.. To compare the effects of different VAD on limb volume reduction, tibiotarsal range of motion, and quality of life.. 136 patients with CVD (CEAP grades 2-5) were randomly allocated into four groups to receive micronized diosmin + hesperidin, aminaphthone, coumarin + troxerutin, or placebo (starch). Patients were administered a questionnaire consisting of a quality of life (QoL) measure designed specifically for persons with CVD, and underwent tibiotarsal joint angle measurement and water plethysmography of the lower extremity before and 30 days after pharmacological intervention. Assessors were blind to the treatment groups.. Nine patients dropped out of the trial. Data collected from the 127 remaining patients was considered for statistical analysis. There were no differences in tibiotarsal joint range of motion. Volume reductions ≥100 mL were more frequent in the diosmin + hesperidin group than in any other group. QoL scores were best in the aminaphthone group, and between-group differences were found on individual analysis of questionnaire items.. Use of VAD was associated with significant improvements in QoL as compared with placebo. VAD may be effective for providing symptom relief in patients with CVD.

Topics: Biomechanical Phenomena; Brazil; Cardiovascular Agents; Chronic Disease; Coumarins; Diosmin; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Foot Joints; Hesperidin; Humans; Hydroxyethylrutoside; Male; para-Aminobenzoates; Plethysmography; Quality of Life; Range of Motion, Articular; Recovery of Function; Surveys and Questionnaires; Time Factors; Treatment Outcome; Venous Insufficiency

The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.

Topics: Administration, Oral; Adolescent; Adult; Anticoagulants; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cotinine; Coumarins; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Gene Frequency; Genotype; Humans; Hydroxyethylrutoside; Male; Middle Aged; Mixed Function Oxygenases; Nicotine; Nicotinic Agonists; Phenotype; Polymethacrylic Acids; Polymorphism, Genetic; Polyvinyls; Thailand; Tobacco Use Cessation Devices; Umbelliferones

Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine.. The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis.. The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior.. No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Topics: Adult; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Chemical and Drug Induced Liver Injury; Coumarins; Cytochrome P-450 CYP2A6; Double-Blind Method; Drug Combinations; Female; Gene Frequency; Genotype; Humans; Hydroxyethylrutoside; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mixed Function Oxygenases; Polymorphism, Genetic; Prospective Studies; Smoking; Venous Insufficiency

Coumarin is reported to elevate liver function tests (LFT) values. In a prospective, placebo-controlled, clinical trial, efficacy and safety of a coumarin-containing combination (SB-LOT) were evaluated in the treatment of chronic venous insufficiency. Here, we report on the drug safety of coumarin with special respect to liver reaction.. 114 patients were treated with SB-LOT (30 mg coumarin and 180 mg troxerutin t.i.d.) and 117 with placebo during a period of 16 weeks. LFT values (ALT, AST, AP and gamma-GT) were monitored at baseline, 4, 6, 8, 12 and 16 weeks of therapy. Adverse drug reactions were assessed regarding causality. Additionally, lymphocyte proliferation test was used to identify allergic reactions. Logistic regression analysis was performed to identify possible risk factors.. No serious adverse drug reactions occurred. Elevations of LFT were assessed as biochemical abnormality. Specific clinical symptoms such as jaundice did not occur. Only 1 patient reported fatigue and exhaustion. Logistic regression estimated a basic risk for elevation of LFT of 4.9% under SB-LOT and 2.1% under placebo. Hepatitis in the history and diseases of the liver were identified as risk factors.. This evaluation contributes to safety data of SB-LOT in man. LFT elevation is transient and the low risk of the SB-LOT therapy to increase LFT value can be limited when risk factors are considered.

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Anticoagulants; Aspartate Aminotransferases; Coumarins; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Female; gamma-Glutamyltransferase; Humans; Hydroxyethylrutoside; Liver; Male; Middle Aged

Prospective, randomized placebo-controlled double-blind study to prove the efficacy of Coumarin/Troxerutine (Venalot Depot) for protection of salivary glands during a head and neck irradiation.. Forty-eight radiotherapy patients (60 Gy) with head and neck cancer were included in this trial. During radiotherapy the salivary glands were located in the core irradiation field. Primary efficacy parameters were sialometry, quantitative salivary gland scintigraphy and clinical evaluation of early effects of radiotherapy (RTOG-score, Table 1). All data were collected at 6 assessments: 1 week pre-radiation (U1), at start (U2), half time (U3) and end (U4) of irradiation, 8 days (U5) and 28 days (U6) after the end of irradiation (Figure 1).. Twenty-three patients (11 verum, 12 placebo) completed the study with all assessments. Sialometrically, all patients were severely (half of radiotherapy) or completely (end of radiotherapy) xerostomatic (Figure 2). In a global efficacy measure according to O'Brien combining scintigraphy and RTOG there was a tendency for a higher efficacy of verum compared to placebo (p = 0.068). After start of irradiation therapy, the RTOG-score showed continuously and significantly lower early radiation effects under verum than under placebo (U3 vs U6: p < 0.05, area under curve: p = 0.032; Table 2, Figure 3). The scintigraphically determined excretion fraction was slightly less impaired in the verum group compared to the placebo treatment (p = 0.12. Figure 4). There was no difference in drug safety between placebo and verum for adverse events, changes in the activity of liver enzymes and for global impression of tolerability.. The results give support for an advantageous effect of Venalot Depot in the treatment of radiogenic sialadenitis and mucositis. In even a small number of evaluable patients, early clinical effects of irradiation (RTOG-score) were less pronounced in the active treatment group than in the placebo group, but the sample size was too low to prove statistically also the benefit of coumarin/troxerutine with the scintigraphic method. Sialometry seems not suitable for the assessment of early radiation effects.

Topics: Adult; Aged; Coumarins; Double-Blind Method; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Hydroxyethylrutoside; Male; Middle Aged; Mouth Mucosa; Prospective Studies; Radiation Injuries; Radiation-Protective Agents; Radiotherapy; Salivation; Treatment Outcome; Xerostomia

Using previously presented data, from an open multi-centered trial, the Medians and Third Quartiles were calculated for the overall edema reductions the "average" patient received from an "average" therapist using Complex Physical Therapy (CPT) on 628 lymphedematous limbs. These data provide therapists and patients a general guideline as to the minimal reductions which can be expected in three quarters of patients from average therapists, using CPT with or without the administration of benzo-pyrones. Benzo-pyrones were considered separately: oral (given for three months before and for 11 months after the course of CPT) and topical (during and after CPT). Depending on which measure of edema and its alterations were used, these reductions increased those from CPT alone from 130% to 200% and, after one year, between 150% to 300%. Whereas the effects of oral and topical benzo-pyrones were not statistically different, their combined usage was more effective than use of either alone.

Topics: Administration, Oral; Administration, Topical; Anticoagulants; Arm; Combined Modality Therapy; Coumarins; Humans; Hydroxyethylrutoside; Leg; Lymphedema; Physical Therapy Modalities; Treatment Outcome

Pyranocoumarins are compounds with an important pharmacological profile, such as anti-inflammatory, antioxidant, cytotoxic, antiviral, antibacterial, and hypoglycemic effects. These molecules have a widespread presence as secondary metabolites in medicinal plants used to treat Diabetes Mellitus (DM). The aim of this work was to evaluate antidiabetic activity in Streptozotocin (STZ)-induced diabetic rats and the antioxidant effects of 3',4'-Di-O-acetyl-cis-khellactone (DOAcK), as well as its toxic potential. We obtained DOAcK with an enantiomeric excess of 70% by chemical synthesis. Our results showed that this compound exerts an important antidiabetic effect: blood glucose decreased in groups treated with DOAcK by 60.9% at dose of 15mg/kg (p<0.05) compared with the diabetic control group, and demonstrated a statistically significant increase in weight gain (45.7±9.7 in the group treated with DOAcK vs. -23.0±33.1 in the group with diabetes). In a biochemical profile, DOAcK did not modify lipid metabolism and did not cause damage at the renal level. DOAcK administration increased the activities of Catalase (CAT), Glutathione Peroxidase (GPx), and Super Oxide Dismutase (SOD) to levels near those of the healthy group. Histopathological analysis exhibited morphology similar to that of the healthy group and the group treated with DOAcK. DOAcK is not mutagenic by Ames test for Salmonella typhimurium strains TA98, TA100, or TA102, and is not genotoxic by Micronucleus assay; median lethal dose (LD50) >2000mg/kg and, at this dose, no signs of toxicity or death were reported after 14days of observation. These results indicate that DOAcK can improve glucose metabolism, which may be due to the increased antioxidant activity of CAT, GPx and SOD. In addition, DOAcK is not toxic in the studies tested.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Coumarins; Diabetes Mellitus, Experimental; Glutathione; Glutathione Peroxidase; Hypoglycemic Agents; Insulin; Islets of Langerhans; Liver; Mutagenicity Tests; Oxidative Stress; Rats; Salmonella typhimurium; Streptozocin; Superoxide Dismutase

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.

Topics: Alanine Transaminase; Animals; Anticoagulants; Bile; Chemical and Drug Induced Liver Injury; Coumarins; Glutamate Dehydrogenase; Hydroxyethylrutoside; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Melilotus; Phytotherapy; Plant Extracts; Protective Agents; Rats; Rats, Wistar