rutin and troxerutin

Ginkor Fort® (Tonipharm, Recordati Group; GB-T-H combined treatment) comprises ginkgo biloba extract, troxerutin and heptaminol chlorhydrate. It is a venotonic and vasculoprotective agent that strengthens veins, increases vessel resistance, and reduces permeability. Thanks to these synergistic actions, it is indicated for the treatment of signs and symptoms of venous insufficiency (VI) and signs related to the hemorrhoidal crisis. This review recapitulates the rationale for using venotonics to manage VI and discusses available evidence on the use of GB-T-H combined treatment to manage VI and hemorrhoidal crisis.. Papers were retrieved by a PubMed search using different keywords. No language or publication date restrictions were used. Documents from the Authors' literature collection were also considered. Papers were selected for inclusion according to their relevance to the topic.. Preclinical and clinical studies showed that the GB-T-H combined treatment acts on both the acute phase symptoms and the pathogenetic mechanisms of the VI, through the prevention of the hypoxia-induced activation of endothelial cells, the reduction of the capillary tone and the hemostatic activity. This leads to the long-term slowing of the disease progression, suggesting that the GB-T-H combined treatment can manage the acute clinical manifestations and as a prevention measure with prolonged use in both VI and hemorrhoidal crises. In the available study, the GB-T-H combined treatment showed excellent tolerability.. Available literature evidence and extensive clinical experience support the use of the GB-T-H combined treatment as an effective and safe option for treating and preventing the clinical manifestation of VI and hemorrhoidal crisis.

Topics: Endothelial Cells; Ginkgo biloba; Heptaminol; Humans; Hydroxyethylrutoside; Phytotherapy; Plant Extracts; Venous Insufficiency

Troxerutin (TRX), a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of TRX against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. TRX has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). TRX also reduces acetylcholinesterase activity and upregulates phosphoinositide 3- kinase/Akt signaling pathway in Alzheimer's disease models. Natural products such as TRX may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.

Topics: Acetylcholinesterase; Antioxidants; Chronic Disease; Humans; Hydroxyethylrutoside; NF-E2-Related Factor 2; Oxidative Stress

Rutoside (rutin; quercetin rutinoside) is a glycoside found in various plant products, including apples, citrus fruits and cranberries. Hydroxyethylrutosides (HR) are semisynthetic derivatives sold as standardized products for the treatment of chronic venous insufficiency (CVI). Commercially available products include Relvène(®) (France), Venoruton(®) (Switzerland) and Paroven(®) (United Kingdom). However, the evidence for their efficacy is inconclusive. The aim of this systematic review was to evaluate the evidence of efficacy and tolerability of hydroxyethylrutosides for CVI.. We searched electronic databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and publisher databases, conference proceedings and references lists for randomized controlled trials published in English and non-English languages. We also performed hand searches for additional trials. We included all trials that assessed the effectiveness of HR for CVI. Comparisons include HR (with or without compression bandaging) vs. placebo (with or without compression bandaging) or HR vs. compression bandaging alone. Two review authors independently selected studies, extracted data and assessed risks of bias in the included trials.. The search identified 1474 records. Only 15 trials involving 1643 participants met our inclusion criteria. A meta-analysis based on similar studies that compared HR with placebo showed that HR significantly reduced symptoms of pain (SMD -1·07, 95% CI -1·44 to -0·70), symptoms of heavy legs (OR 0·50; 95% CI 0·28-0·91) and cramps (SMD -1·07, 95% CI -1·45 to -0·69). No serious adverse effect due to HR was reported.. The findings showed that HR produced modest improvements in several symptoms of CVI. However, all the included trials were of limited quality, and therefore, better-quality trials are still required to draw firm conclusions on the usefulness of HR for CVI.

Topics: Chronic Disease; Humans; Hydroxyethylrutoside; Phytotherapy; Randomized Controlled Trials as Topic; Rutin; Venous Insufficiency

Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit.. The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9 , MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011).. Only randomised controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded.. Two authors independently extracted the data and analysed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion.. We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation.The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality.Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of  pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05).. The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.

Topics: Calcium Dobesilate; Diosmin; Flavonoids; Hemorrhoids; Hemostatics; Humans; Hydroxyethylrutoside; Ligation; Plant Extracts; Postoperative Care; Randomized Controlled Trials as Topic; Vasoconstrictor Agents

The aim of this article was first to review the complex pathophysiological mechanisms responsible for symptoms and signs of primary chronic venous disease (CVD) that allow the identification of targets for pharmacological treatment. The results of CVD treatment with venoactive drugs (VADs) were emphasised and presented in the form of recommendations. The last section raises key questions to be answered to improve protocols for good clinical trials and to draw up future guidelines on these agents.. The literature has been reviewed here using PubMed and Embase.. Venous hypertension appears to underlie all clinical manifestations of primary CVD. Inflammation is key in wall remodelling, valve failure and subsequent venous hypertension. Changes in the haemodynamics of veins are transmitted to the microcirculation, resulting in capillary alteration leading to oedema, skin changes and eventually venous ulceration. Venous symptoms may be the result of interplays between pro-inflammatory mediators and nerve fibres located in the venous wall. Therefore, venous inflammation constitutes a promising therapeutic target for pharmacological intervention, and some available VADs could attenuate various elements of venous inflammation. Based on recent studies, reviews and guidelines, tentative recommendations for the use of VADs were proposed and strong recommendations were given to two of them (micronised purified flavonoid fraction and oxerutins).. VADs should be accorded a better role in the management of CVD. However, larger and more definitive clinical trials are needed to improve the existing recommendations.

Topics: Anticoagulants; Blood Viscosity; Capillaries; Capillary Permeability; Capillary Resistance; Chronic Disease; Diosmin; Edema; Humans; Hydroxyethylrutoside; Inflammation; Lymphatic System; Pain; Skin Diseases; Vasodilator Agents; Veins; Venous Insufficiency

Topics: Animals; Antioxidants; Brain; Cholesterol; Cognition Disorders; Humans; Hydroxyethylrutoside; Insulin Resistance; Mice

A range of surgical, endovenous, physical and medical treatments are available for patients with chronic venous disease. The aim of this review was to evaluate the evidence for pharmacological agents used for the treatment of chronic venous disease.. A literature search was performed using Pubmed, Embase, Cochrane and Google Scholar databases. The initial search terms 'varicose vein', 'venous ulcer', 'venous disease' and 'lipodermatosclerosis' were used to identify relevant clinical studies of pharmacotherapy in patients with chronic venous disease (C4-C6).. A huge range of naturally occurring and synthetic drugs have been studied in patients with chronic venous disease. For patients with C4 venous disease, micronized purified flavonoid fraction (MPFF), oxerutin, rutosides and calcium dobesilate may reduce venous symptoms and oedema. MPFF and pentoxifylline have been shown to improve venous ulcer healing when used in addition to multilayer compression bandaging. The clinical benefits of other medications remain unproven. Reliability of meta-analyses was limited by study heterogeneity, small sample sizes and lack of long-term follow-up.. In prospective randomized studies, MPFF (Daflon(®)), other flavonoid derivatives and pentoxifylline have demonstrated clinical benefits in patients with C4-C6 venous disease. Pharmacotherapy should be part of a range of treatment options in the modern management of patients with chronic venous disorders.

Topics: Calcium Dobesilate; Cardiology; Chronic Disease; Compression Bandages; Drug Therapy; Flavonoids; Humans; Hydroxyethylrutoside; Hypertension; Pentoxifylline; Randomized Controlled Trials as Topic; Rutin; Treatment Outcome; Vascular Diseases; Venous Insufficiency

Varicose veins and the complications of venous disease are thought to affect over a quarter of the adult population and the management of these conditions are a major cause of health service expense. Advances in the understanding of venous pathophysiology have highlighted numerous potential targets for pharmacotherapy. This review considers the evidence for pharmacological agents used for the treatment of chronic venous disease. A literature search using Pubmed, Embase and Cinahl databases was performed. The initial search terms 'varicose vein', 'venous ulcer' and 'venous disease' were used with appropriate search limits to identify prospective studies of pharmacotherapy in venous disease. A wide range of venoactive and non-venoactive drugs have been studied in patients with venous disease. The use of micronized purified flavonoid fraction (Daflon) can reduce symptoms of pain, heaviness and oedema in patients with venous reflux and a recent meta-analysis concluded that Daflon improves healing in patients with venous ulceration treated with compression. Pentoxifylline may be a useful adjunct to compression therapy for patients with venous ulceration. Oxerutins and calcium dobesilate may be of benefit in reducing oedema and rutosides may help to relieve the symptoms of varicose veins in pregnancy. The clinical benefits of other medications remain unproven. Although numerous pharmacological agents have been proposed and studied, Daflon has demonstrated the greatest clinical benefits in patients with venous disease. Further research is needed to define the role of venoactive drugs in clinical care and improve our understanding of the pathophysiology of venous disease to help identify new therapeutic avenues.

Topics: Animals; Anticoagulants; Chronic Disease; Clinical Trials as Topic; Diosmin; Hemostatics; Humans; Hydroxyethylrutoside; Vascular Diseases; Vasoconstrictor Agents; Veins

Lymphoedema is the accumulation of excess fluid in the body caused by obstruction of the lymphatic drainage mechanisms. It can be caused by a number of factors, including congenital predisposition, parasitic infection or surgery. Lymphoedema is chronic and progressive and affects a significant proportion of the population. The standard treatment regimes include compression hosiery, skin care and exercise. The use of drugs in treatment, particularly benzo-pyrones, has gained favour over the last ten years. Benzo-pyrones, originally developed for use in vascular medicine, are prescribed to reduce vascular permeability and thus the amount of fluid forming in the subcutaneous tissues. Advocates for this treatment method believe that, as a result of reducing filtration, the drugs have some beneficial effect on pain and discomfort in the swollen areas. Proponents also claim that these drugs increase macrophage activity, encouraging the lysis of protein, which in turn reduces the formation of fibrotic tissue in the lymphoedematous limb.. To assess the effectiveness of benzo-pyrones compared to placebo or to different benzo-pyrones in reducing limb volume, pain and discomfort in lymphoedematous limbs. To assess the effect of benzo-pyrones on the quality of affected tissues and on the patient's quality of life and, finally, to establish the incidence of adverse effects. We searched the Cochrane Breast Cancer Group register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4,2003), MEDLINE, EMBASE, CINAHL, UnCover, PASCAL, SIGLE, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and The International Society of Lymphology congress proceedings.. Types of studies considered for review were randomised controlled trials testing Paroven, coumarin, Venastat, Cyclo 3 Fort or Daflon versus placebo (with both groups having or not having standard physical treatment. Eligibility for inclusion was confirmed by two blinded reviewers who screened the papers independently using a checklist of criteria relating to the randomisation and blinding of the trial. Both reviewers extracted data from the eligible studies using a data extraction form.. Overall, 15 trials were included that evaluated the role of benzo-pyrones. Three trials of oxerutin were found. Each tested the drug over 6 months using the same dose of drug against placebo. Two were crossover trials and one a parallel group trial with a total number of 127 participants and data available for only 81 of them. There were insufficient data provided in any of the trials to calculate the per cent reduction or increase in baseline excess limb volume. Standard deviations or confidence intervals and the numbers in the groups at the different stages of the trial were missing for all the data in two of the reports and for much of the data in the third, making any attempt at meta-analysis impossible. One trial testing Cyclo 3 Fort (approved name) over 3 months was found and involved 57 patients but provided insufficient data to allow a proper analysis of its findings. A single trial of Daflon (approved name) was found, lasting 6 months and involving 104 participants; once again there was insufficient information provided in the report to reach a conclusion about the effectiveness of the drug. Three trials of coumarin combined with troxerutin were found and tested two different doses of the drug against each other with no placebo, however, numbers of participants in the trial groups and baseline data were not provided. Eight trials of coumarin were identified. Two of the reports were confirmed as reporting the same trial and a further trial potentially also referred to the same trial but this was unconfirmed. A further two papers appeared to refer to the same trial but this was not confirmed. Three trials involved the same researcher. Five studies were conducted in India or China and they added anti-filarial dia or China and they added anti-filarial drugs to the interventions tested. The numbers of participants withdrawn and the numbers included in the analyses in all these trials were not extractable; the reporting of outcome measures in most of the trials was not clear. Loprinzi's 1999 trial in the USA reported the conduct of the trial and its findings with more detail, however, its conclusions were very much at odds with the findings of the other trials, finding that no difference was observed between those on the active preparation (coumarin) and placebo in any of the outcomes under investigation. This trial also reported a case of hepato-toxicity in a patient receiving the active preparation.. Meta-analysis was not performed due to the poor quality of the trials. It is not possible to draw conclusions about the effectiveness of Benzopyrones in reducing limb volume, pain, or discomfort in lymphoedematous limbs from these trials.

Topics: Anticoagulants; Benzopyrans; Coumarins; Diosmin; Extremities; Humans; Hydroxyethylrutoside; Lymphedema; Plant Extracts; Randomized Controlled Trials as Topic

The benzo-pyrones reduce all high-protein oedemas, including lymphoedema and elephantiasis, by increasing the numbers of macrophages and their normal proteolysis. Thus they remove the excess protein, and thereby the oedema which is caused by it. They also remove the stimulus it provides for chronic inflammation and fibrosis, and its action as a culture medium for bacteria. Coumarin (5,6 benzo-[alpha]-pyrone, 56 BaP) and oxerutins (HR, O(beta-hydroxy-ethyl)-rutosides) have been used in many clinical trials on a variety of high-protein oedemas. Four such trials are summarised here: on lymphoedema and elephantiasis (from many causes in Australia, and filaritic in India and China). The drugs reduced these much more slowly than adequate physical therapy, but they did reduce them. About half the excess volume was removed over six months in the Australian trials. In India and China similar rates were achieved with lymphoedema, but elephantiasis reduced at a slower rate. The benzo-pyrones convert a slowly worsening condition into a slowly improving one. No compression garments are necessary. In addition, the drugs considerably reduce the number of attacks of secondary acute infection, reduce the deformities of elephantiasis and considerably improve the patients' comfort and mobility. They may be taken orally, or applied topically, have very low toxicities and only few, minor side-effects. They are useful in many other forms of high-protein oedema, and improve the results of physical therapy for lymphoedema.

Topics: Administration, Cutaneous; Administration, Oral; Anticoagulants; Arm; Australia; China; Combined Modality Therapy; Coumarins; Double-Blind Method; Elephantiasis; Humans; Hydroxyethylrutoside; India; Leg; Lymphedema; Multicenter Studies as Topic; Physical Therapy Modalities; Randomized Controlled Trials as Topic; Time Factors

Topics: Anticoagulants; Chronic Disease; Humans; Hydroxyethylrutoside; Venous Insufficiency

We evaluated the efficacy of new flavonoids mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) to reduce bleeding from I-III degrees hemorrhoidal disease in the short and medium time.. One hundred fifty-four consecutive patients with hemorrhoidal disease recruited in four colorectal units were enrolled to the study. Exclusion criteria were allergy to the flavonoids, inflammatory bowel disease, obstructed defecation syndrome, pregnancy and puerperium, associated anal disease or hemorrhoidal thrombosis, proctologic surgical procedures within 1 year before recruitment, contemporary cancer or HIV, previous pelvic radiotherapy, patients receiving oral anticoagulant therapy, or contemporary administration of other therapy for hemorrhoids. Patients with inability to understand the study or mental disorders were also excluded.. Seventy-eight were randomized to receive the mixture of diosmin, troxerutin, rutin, hesperidin, and quercetin (study group, SG), and 76 a mixture of diosmin in combination with hesperidin, diosmetin, isoroifolin, and linarin in purified micronized fraction (control group, CG). Bleeding, number of pathological piles, and Golligher's grade were assessed at each scheduled visit and compared using the Chi-square test. During the study period, bleeding improved after 1 and 6 months both in the SG (79.5 and 70.5%) and in the CG (80.2 and 75%) without significant differences between two groups. Satisfaction degree after 6 months was greater in the patients of the SG (4.05) towards the CG (3.25): this result was statistical significant (p 0.003).. Use of flavonoids mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) is a safe and effective mean of managing bleeding from hemorrhoidal disease and minimal adverse events are reported.

Topics: Adult; Aged; Diosmin; Double-Blind Method; Drug Combinations; Female; Gastrointestinal Hemorrhage; Hemorrhoids; Hesperidin; Humans; Hydroxyethylrutoside; Italy; Male; Middle Aged; Prospective Studies; Quercetin; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Objective We aimed to evaluate the efficiency of O-(beta-Hydroxyethyl)-rutosides (Oxerutin) in reducing the incidence of venous system disease among patients with calf muscle pump dysfunction secondary to immobilization due to lower-limb fractures. Methods A total of 60 patients with lower-limb fractures and immobilized in plaster casts were included in this study randomized into control (n = 30; mean: 30.37 ± 6.03 years; 73.3% males; no treatment) and experiment (n = 30; mean: 31.67 ± 4.76 years; 66.6% males; Oxerutin, 500 mg po q12hr) treatment groups. Doppler ultrasound was performed to evaluate the effect of oxerutin on the alterations in the venous circulation. Results Patients in the control group were determined to be more commonly affected from the below-knee immobilization in terms of venous dysfunction in the great saphenous vein in the below-knee region when compared with the patients in the oxerutin treatment group (46.7 vs. 13.3%, respectively; p = 0.011). Incidence of reflux in the small saphenous vein was more common in the control group during the healing period when compared with the experiment group (40.0 vs. 10.0%, respectively; p = 0.017). None of the patients developed venous thrombosis. Conclusions In conclusion, the impairment of the lower extremity muscle pump should be considered as an important risk factor for venous disease, and should be evaluated. O-(beta-Hydroxyethyl)-rutosides during 6-8 week cast immobilization for a lower limb fracture may be an effective prophylactic regimen in reducing the incidence of reflux in the below-knee superficial veins.

Topics: Adult; Female; Follow-Up Studies; Fracture Fixation; Humans; Hydroxyethylrutoside; Incidence; Leg Injuries; Male; Postoperative Complications; Prospective Studies; Saphenous Vein; Ultrasonography, Doppler, Color; Venous Insufficiency

To evaluate the effectiveness and safety of Longxue Tongluo capsule on patients of atherosclerotic thrombotic cerebral infarction convalescence with blood-stasis syndrome, a double-blind, randomized controlled, multi-center clinical trial was conducted. A total of 160 eligible patients were randomly divided into treatment group and control group, with 80 patients in each group, and all of them were orally given Troxerutin pill(three pills each time, three times daily). Longxue Tongluo capsule was applied in the treatment group, while placebo was applied in the control group(two capsules each time, three times daily) for 4 weeks. Main outcomes were measured by ITT analysis. The neurological function deficits scale showed a decrease of 5.17±2.60 in the treatment group, while 4.31±2.31 in the control group, with significant differences between the two groups(P<0.05); the reduction rate in the treatment group (37.2±15.8)% was significantly higher than that in the control group (29.9±15.3)%(P<0.05). In terms of the comprehensive curative effect by ITT, the effective rates in the treatment and control group were 31.6% and 13.5%, respectively(P<0.05). With respect to the efficacy of traditional Chinese medicine syndrome by ITT, the total effective rate of the treatment group was significantly higher than the control group 88.2% vs 68.9%, P<0.05. Three cases of adverse events occurred in this study, including 1 case of diarrhea in treatment group and 2 cases of skin itch and upper respiratory infection in control group. In conclusion, Longxue Tongluo capsule is effective and safe in the treatment of patients of atherosclerotic thrombotic cerebral infarction convalescence with blood-stasis syndrome, and can effectively alleviate the patients' nerve function defect degree and invalidism, with a good effect on blood stasis syndrome.

Topics: Cerebral Infarction; Double-Blind Method; Drugs, Chinese Herbal; Humans; Hydroxyethylrutoside; Phytotherapy; Treatment Outcome

The role of a mixture of phlebotonics in the treatment of acute hemorrhoid crisis is investigated to test their efficacy.. One hundred and thirty-four consecutive patients with an acute hemorrhoidal crisis recruited in five colorectal units entered the study. Sixty-six of them were randomized to receive a mixture of diosmin, troxerutin and hesperidin (group A), and 68 a placebo (group B). The main symptoms, the use of oral painkillers and the Bristol scale score were recorded at each scheduled visit and compared using both Student's t test for independent samples and the ANOVA models for repeated measures. The presence of edema, prolapse and thrombosis were also recorded and compared using the Chi-square test. Furthermore, the trend of proportions during the time of the evaluations was assessed by the Chi-square test for linear trend.. Pain, bleeding and the proportion of patients who reported persistence of edema and thrombosis decreased significantly after 12 days of treatment in group A. After 6 days, the number of paracetamol tablets taken by patients in group A was significantly lower than the amount of flavonoid mixture.. The use of a mixture of diosmin, troxerutin and hesperidin is a safe and effective mean of managing symptoms of acute hemorrhoidal disease. Furthermore, in patients receiving treatment, there was faster control and lower persistence of edema and thrombosis.

Topics: Acute Disease; Adult; Aged; Analgesics; Anticoagulants; Chi-Square Distribution; Diosmin; Drug Combinations; Edema; Epidemiologic Research Design; Female; Hemorrhoids; Hesperidin; Humans; Hydroxyethylrutoside; Male; Middle Aged; Pain Measurement; Prospective Studies; Rectal Prolapse; Research Design; Thrombosis; Young Adult

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

Chronic venous insufficiency (CVI) is an important cause of discomfort and inability to work. Hydroxyethylrutosides (Venoruton); 0-[beta-hydroxyethyl]-rutosides) has been used for decades for the treatment of CVI. Studies have reported symptomatic relief and a decreased capillary filtration after the administration of the oral preparations. Calcium dobesilate is a synthetic venoactive drug acting on several levels. It inhibits capillary permeability; it has antioxidant properties; and it inhibits the synthesis of prostaglandins and thromboxanes, reducing platelet and erythrocyte aggregation, as well as blood viscosity. The aim of this study is to determine whether the combination of both drugs is more effective in decreasing patients' complaints.. One hundred and fifty patients with primary venous insufficiency were randomized into three groups: Group A receiving calcium dobesilate only, Group B receiving oxerutin only and Group C receiving both calcium dobesilate and oxerutin. Patients were evaluated with a questionnaire before and four weeks after treatment regarding following parameters: itching, fatigue, heaviness, numbness, cramp, swelling and sensitiveness. Patients rated their symptoms from 0 to 4 (0: absent; 1: mild; 2: moderate; 3: severe; 4: very severe).. Complaints, which were scored by patients before and after treatment, decreased. Among the single-drug groups, itching score decreased more in Group B, whereas scores of fatigue, heaviness, numbness, cramp and swelling decreased more in Group A. But the difference was not significant, statistically. But all complaints decreased significantly in Group C. Difference of scores after treatment revealed no statistical significance in Group A and B, but scores of Group C produced a significant difference when compared with Group A and B.. Results demonstrate that a combination of calcium dobesilate and oxerutin shows a better improvement of complaints. These observations have to be confirmed in larger series with objective tests. Changes of quality of life after a combination therapy might also be of interest.

Topics: Adult; Anticoagulants; Calcium Dobesilate; Chronic Disease; Drug Synergism; Drug Therapy, Combination; Female; Hemostatics; Humans; Hydroxyethylrutoside; Male; Middle Aged; Quality of Life; Surveys and Questionnaires; Treatment Outcome; Venous Insufficiency

This study evaluated the clinical efficacy of Venoruton (O-(beta-hydroxyethyl)-rutosides) (HR) (Novartis Consumer Healthcare) in subjects with severe chronic venous insufficiency (CVI).. Patients were included in an average 8-month follow-up registry. At the end of the study 3 spontaneous groups emerged: a group treated with HR 2 g/day, a second group with HR 1 g/day and elastic stockings, and another group with stockings only. The age range was between 45 and 55. The 3 resulting groups were comparable clinically and for age/sex distribution. There were no differences in ambulatory venous pressure (AVP) at inclusion; microcirculatory and clinical evaluations were comparable.. At 8 months there was a decrease in skin resting flux in all groups. Better results (P<0.05) were obtained in the group using the higher dosage and the associated treatment. Stockings alone were less effective (P<0.05). There was significant decrease (P<0.05) in capillary filtration (RAS) in all groups with an advantage in the combination group (P<0.021). HR alone was more effective (P<0.05) than compression alone. There was an improvement in the symptomatic score in all groups with better results (P<0.5) in the combined group; HR alone was more effective (P<0.025) than compression alone. The clinical severity score was reduced (P<0.05) in all groups with better results in the combined group. HR alone was more effective (P<0.05) than compression alone. The venous disability score indicated that HR alone was more effective (P<0.025) than compression. No side effects or tolerability problems were observed with HR. Compliance of HR was also very good. A cost comparison was made considering a comparable control groups (cost of best standard management=100%). Cost in group A was 44% of standard costs; cost in group B (HR+stockings) was 48% of standard costs, and cost in group C (stockings only) was 67% (P<0.05).. The study confirms the long-term efficacy of HR in CVI patients. Controlling signs/symptoms and edema in CVI with HR also prevents the most severe complications of CVI.

Topics: Adult; Aged; Blood Pressure Monitoring, Ambulatory; Chronic Disease; Cost-Benefit Analysis; Female; Humans; Hydroxyethylrutoside; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Registries; Stockings, Compression; Venous Insufficiency

A fixed combination of aescin and troxerutin has been developed for treating inner ear perfusion problems of different aetiology. The efficacy of this combination is tested versus pentoxyfyllin in a randomized clinical study as group comparison with 34 patients for each group. The improvement of hearing after 40-44 days of treatment is determined as end point of treatment. Hearing was measured by threshold, whereby a difference of more than 10dB is judged as a significant improvement. After the treatment with the combination of aescin and troxerutin hearing is significantly improved, in 23 of 34 patients the threshold is changed more than 10dB, which is checked by sign-test with p<0.05. With pentoxyfyllin hearing is also improved, although to a lesser degree. Both drugs are well tolerated, major adverse drug effects are not observed with either treatment.

Topics: Administration, Oral; Aesculus; Aged; Anticoagulants; Case-Control Studies; Drug Combinations; Escin; Female; Hearing; Hearing Disorders; Hearing Tests; Humans; Hydroxyethylrutoside; Male; Middle Aged; Pentoxifylline; Phytotherapy; Plant Extracts; Treatment Outcome; Vasoconstrictor Agents

Damage to endothelial cells is common in vascular disorders and in reactions associated with transplantation. An elevated number of circulating endothelial cells indicates the extent of endothelial damage in a variety of disorders. In chronic venous insufficiency (CVI), the number of endothelial cells is abnormally increased, and this can be considered an important indication of endothelial damage. A group of 23 subjects with two levels of CVI (severe and very severe with previous ulcerations) with an increased endothelial cell count (seen by microscopy) was studied and treated for 4 weeks with oral Venoruton (0-[beta-hydroxyethyl]-rutosides) (1 g/day) to evaluate the effects of treatment on the circulating endothelial cells in blood taken from a peripheral leg vein. The controls comprised two groups with comparable age and sex distribution, one of healthy individuals and one of CVI subjects. After 4 weeks, a significant decrease was noted in endothelial cells both in subjects with CVI and in those with very severe CVI with previous ulcerations. This study suggests that endothelial cells may play a significant role in venous disease, being both an indication of severe disease and a further problem in itself. The use of Venoruton appears to decrease the number of circulating endothelial cells. This suggests an important role of this compound in protecting the endothelium and offers new potentially important therapeutic options that are not limited only to venous disease.

Topics: Blood Circulation; Cell Count; Chronic Disease; Endothelial Cells; Endothelium, Vascular; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Vasoconstrictor Agents; Venous Insufficiency

A simple, rapid, sensitive and specific liquid chromatography/tandem mass spectrometry method was developed and validated to quantify troxerutin in human plasma. The analyte and rutin, used as the internal standard, were analyzed on a Phenomenex Synergi Fusion RP column interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. Acetonitrile/water (20:80 v/v) was used as the isocratic mobile phase, with 0.1% formic acid in water. A simple sample preparation method of protein precipitation with perchloric acid was employed. The assay was linear over the concentration range 31.25-4000 pg/mL. Correlation coefficients generated by linear regression with a 1/x(2) weighting factor ranged from 0.9991 to 0.9996. The intra- and inter-day precision over the entire concentration range were less than 12.28%. The method was successfully applied to a pharmacokinetic study after oral administration of a 300 mg troxerutin drop pill to 18 healthy volunteers.

Topics: Adult; Blood Chemical Analysis; Chromatography, Liquid; Humans; Hydroxyethylrutoside; Male; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Therapeutic Equivalency

The aim of this study was to assess the clinical efficacy, compliance and safety of Ginko biloba--Troxerutin-Heptaminol Hce in the treatment of patients with acute hemorrhoidal attacks in Thailand.. In a prospective clinical study on hospital outpatients, the authors studied the effect of Ginko biloba--Troxerutin-Heptaminol Hce for a week in adults (18-70 years old) with acute hemorrhoidal attacks.. Twenty-two patients, with a mean age of 41.7 years were included in the study. The male to female ratio was 1 : 1.2. Most patients (77%) had grade 1 and 2 hemorrhoids with an average duration of attacks of 3 days. On intention to treat analysis, bleeding, pain, tenesmus and discharge were significantly improved. Treatment was well accepted and safe.. In the short-term, Ginko biloba--Troxerutin-Heptaminol Hce is effective, acceptable and safe in the treatment of patients with acute hemorrhoidal attacks.

Topics: Acute Disease; Adolescent; Adult; Aged; Drug Therapy, Combination; Female; Follow-Up Studies; Ginkgo biloba; Hemorrhoids; Heptaminol; Humans; Hydroxyethylrutoside; Male; Middle Aged; Pain Measurement; Phytotherapy; Prospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome

The rutosides are naturally occurring flavonoids that have documented effects on capillary permeability and edema. The purpose of this study was to assess the effect of troxerutin, one of the rutosides, on the symptoms of the common cold. Ninety-four volunteers with common cold symptoms were recruited for participation in the study. Volunteers were randomized to either active treatment (n=49) with troxerutin (50 mg) and Zn gluconate (25 mg) or control treatment (n=45) with 10 mg Zn gluconate. Symptoms were assessed by subjective symptom score prior to treatment and then daily for the next 4 days. The total symptom score over the 4 days of study treatment was 27.7+/-2.0 (mean+/-SEM) and 33.0+/-2.6 in the active and control groups, respectively (p=0.10, unpaired t-test). The total daily symptom score on day 1 was reduced by 11% compared to baseline in the active group and by 1% in the control group (p=0.03). Evaluation of the effect of treatment on individual symptoms revealed a significant effect on rhinorrhea. The total rhinorrhea score over the course of the study was 3.7+/-0.4 in the active group compared to 5.1+/-0.5 in the control group (p=0.025, unpaired t-test). Daily rhinorrhea scores were significantly lower in the active group on study days 1 and 3. Based on this preliminary study, the possibility that the rutosides might provide a safe and effective treatment for rhinorrhea in the common cold deserves systematic evaluation.

Topics: Administration, Oral; Adult; Common Cold; Double-Blind Method; Female; Gluconates; Humans; Hydroxyethylrutoside; Male; Patient Compliance; Zinc

This study evaluated the protective effects of Venoruton on the development of flight edema in normal subjects travelling in economy in long-haul flights (8-9 hours). Edema is a relevant aspect of long-haul flights affecting both venous patients and normal subjects. Edema and flight microangiopathy were studied in a group of 164 subjects randomized (after informed consent) into two groups to evaluate prophylaxis in 8- to 9-hour flights. The treatment group received Venoruton (hydroxyethyl rutosides) 1 g twice daily for 3 days (2 days before the flight and the day of the flight). The control group received comparable placebo. Edema was evaluated with a composite edema score based on the edema tester, on the measurements of ankle circumference, volume measurements, subjective swelling, and on a discomfort score. Items 1, 4, and 5 are based on an analogue scale line (1 to 10) directly defined by the subjects before and after the flights. Of the included subjects, 151 completed the study. Dropouts were due to poor compliance, travelling, or connection problems. Age and gender distribution were comparable in the two groups as were risk factor distributions. The level of edema at inclusion was comparable in the two groups of subjects. After the flight there was an average score of 6.7 (SD 1.7) in the control group, while in the Venoruton group the score was on average 3 (SD 1.1) (p < 0.05). In the control group 77% of the subjects had an evident increase in ankle circumference and volume, which was clearly visible at inspection and associated with discomfort. In the Venoruton group, edema was clearly present only in 8% of subjects (associated with discomfort rated between 3 and 6 on the analogue scale line) and it was mild, not associated with symptoms. Therefore the control of flight edema with Venoruton was clear both considering parametric data (circumference and volume) and non-parametric (analogue scale lines) measurements. The combined evaluation of the edema score is significantly favorable for subjects under prophylaxis with Venoruton.

Topics: Administration, Oral; Aerospace Medicine; Aircraft; Edema; Humans; Hydroxyethylrutoside; Phytotherapy; Reference Values; Venous Thrombosis

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

The aim of this study was the evaluation of the effects of Venoruton (HR) on the prevention and control of flight microangiopathy and edema in subjects with varicose veins flying for more than 7 hours. A group of 80 patients with varicose veins, edema, and initial skin alterations due to chronic venous hypertension were included. Measurements of skin laser Doppler (LDF) resting flux (RF), PO2 and rate of ankle swelling (RAS), were made before and after the flights (within 2 hours before the flights and within 2 hours after the flights). The length of the flights was between 7 and 9 hours; all seats were in coach class. The two groups (treatment and control) were comparable for age and sex distribution. The variation (decrease) in PO2 was significant in both groups. In subjects treated with HR the decrease in PO2 was smaller (p < 0.05). The decrease in LDF-RF was significant in both groups with a higher flux at the end of the flight in the treated subjects (p < 0.05). The venoarteriolar response was decreased at the end of the flights. The decrease was less evident in the treatment group (p < 0.05). The increase in RAS was significant in the control group while it was limited in the HR group. In conclusion, HR is useful for reducing the increased capillary filtration and in controlling edema in patients with chronic venous disease in long-haul flights. HR is effective to control flight microangiopathy associated with edema.

Topics: Adult; Aerospace Medicine; Ankle; Edema; Female; Humans; Hydroxyethylrutoside; Hypertension; Male; Microcirculation; Oxygen; Partial Pressure; Skin; Time Factors; Treatment Outcome; Ultrasonography; Varicose Veins; Vasoconstrictor Agents; Venous Insufficiency

The aim of this study was to demonstrate whether and how HR (Venoruton(1000), Paroven, 0-[beta-hydroxyethyl]-rutosides) and Daflon (diosmin, 500 mg) were comparatively effective in improving the microcirculation in venous hypertension and microangiopathy.. A group of 90 patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a Venoruton and a Daflon (DF) group: patients in the Venoruton group received oral HR (2 g/day for 8 weeks); those in the Daflon group received three 500-mg tablets daily every 8 hours. The two groups were comparable for age and sex distribution. The mean age was 41 years (SD +/- 11) in the Venoruton group (46 patients) and 41.3 (SD +/- 12) in the DF group (44 patients).. There were no differences in microcirculatory parameters between the Venoruton and DF treatment groups at inclusion. There was no significant change between inclusion and measurements at 8 weeks in the DF group. In comparison, a significant decrease (P < .05) in RF (resting skin flux) and RAS (rate of ankle swelling) was observed in the Venoruton group (P < .001). The decrease in capillary filtration was associated with improvement in signs and symptoms (measured by an analogue scale line) (P < .05). Symptomatic improvement was clinically and statistically significant and important only in the Venoruton group. No side effects and no drop-outs were observed.. Venous microangiopathy was improved by the treatment with Venoruton. The comparison with Daflon indicates that HR is comparatively more effective both on microcirculatory parameters and on signs and symptoms.

Topics: Adult; Chi-Square Distribution; Chronic Disease; Diosmin; Female; Humans; Hydroxyethylrutoside; Hypertension; Male; Middle Aged; Prospective Studies; Statistics, Nonparametric; Venous Insufficiency

Venoruton is a standardised mixture of O-(beta-hydroxyethyl) rutosides (HR) used for the relief of oedema and related symptoms in patients with chronic venous insufficiency. OBJECTIVES. The primary objective was to evaluate the pharmacokinetic parameters, in particular the rate and extent of absorption (bioavailability) of two markers of Venoruton: mono-3'-HR and mono-4'-HR derivatives [glucuroconjugated forms (HG)], analysed in their deconjugated form as O-(beta-hydroxyethyl)-quercetin (HQ): mono-3'-HQ and mono-4'-HQ, and to investigate dose proportionality. A secondary objective was to evaluate the general safety of the different dosages.. In this open, single-dose, randomised, four-way, crossover study, 16 healthy volunteers received four different oral doses of Venoruton powder (0.5, 1, 2 or 4 g). Eighteen blood samples were obtained between 10 min pre-dose and 120 h post-dose.. Peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) of mono-3'-HQ were or tended to be proportional to the dose between 1 g and 4 g. The dose proportionality could be extended to the 0.5-g dose, although C(max) and AUC were not always estimable at that dose level (due to the low number of data points above the limit of quantification). For mono-4'-HQ, the increase of C(max) and AUC was also or tended to be proportional to the dose over the whole tested range (0.5-4 g). Time to peak concentration of both Venoruton derivatives remained unaffected by the administered dose. The elimination half-life of both molecules was very similar with the three highest doses. It was shorter with the 0.5-g dose but was not accurately estimated (or even not estimable in some subjects) due to the low number of points above the limit of quantification.. The bioavailability of both Venoruton derivatives (mono-3'-HQ and mono-4'-HQ) tended to be proportional to the dose. The rate of appearance and the elimination half-life of both molecules were not modified with the administered dose. The different doses of the study medication were safe and well tolerated. Mono-3'-HQ and mono-4'-HQ are therefore new bioanalytic and pharmacokinetic markers for Venoruton.

Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Powders

The aim of this study was to demonstrate whether HR (Paroven-Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving the microcirculation in venous hypertension and microangiopathy. Sixty patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a treatment group and a placebo group. Patients in the treatment group received oral HR (2 g/day for 8 weeks); those in the placebo group received a comparable placebo.. The two groups were comparable for age and sex distribution. The mean age was 45 years (SD 9) in the treatment group (31 patients) and 45.5 (SD 10) in the placebo group (29 patients). There were no differences between the placebo and treatment groups at inclusion. There was no change between inclusion and measurements at 8 weeks in the placebo group. A significant decrease (P < 0.05) in flux at rest and rate of ankle swelling was observed in the treatment group. The decrease in capillary filtration was associated with improvement in signs and symptoms (P < 0.05). The difference in flux, sign and symptoms, and filtration was clinically important at 8 weeks in the treatment group when compared with the placebo group. No adverse effects were observed.. Venous microangiopathy was improved by HR treatment.

Topics: Adult; Edema; Female; Humans; Hydroxyethylrutoside; Hypertension; Male; Microcirculation; Middle Aged; Placebos; Prospective Studies; Skin Ulcer; Treatment Outcome; Vascular Diseases; Vasoconstrictor Agents; Venous Insufficiency

This study was planned to demonstrate in a prospective, placebo-controlled, randomized study, whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), is effective in improving the microcirculation in subjects with diabetic microangiopathy and neuropathy. Patients with severe diabetic microangiopathy, neuropathy and edema, patients with microangiopathy, without neuropathy, and 20 healthy subjects were included. Microangiopathy was defined by laser Doppler flowmetry and capillary filtration (rate of ankle swelling (RAS)). Inclusion criteria were: increase in resting flux (RF) and RAS, a decrease in venoarteriolar response (VAR), and alterations in flux increase with temperature. The 2 groups of patients and the control group were randomized in a treatment sub-group which received HR (1 g, twice daily for 6 months); those in the placebo group received similar treatment.. Groups were comparable; there were no drop-outs. There were no differences in the treatment and placebo groups at inclusion. Treatment was well tolerated; no adverse effects were reported. No variations were observed in healthy subjects at 6 months. In both groups of patients, significant decreases (P < 0.05) in RF and RAS were observed in the active treatment groups. The decrease in RAS was associated with a decrease in edema (P < 0.05) in both treatment groups. The decrease in RF and the increase in VAR were associated with a proportional decrease in RAS (P < 0.05). In patients without neuropathy, the variations in RF, VAR, and RAS were larger (P < 0.05) at 6 months. The variations in healthy subjects were limited and not significant.. The decrease in capillary filtration and edema with HR is associated with symptomatic improvement. The action on edema is beneficial for the evolution of neuropathy. The effects of HR on flux, RAS, and edema are important in early stages of microangiopathy to avoid progression to clinical stages.

Topics: Adult; Diabetic Angiopathies; Diabetic Neuropathies; Edema; Female; Humans; Hydroxyethylrutoside; Hypertension; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Placebos; Skin Ulcer; Treatment Outcome; Vasoconstrictor Agents

This study evaluated the effects of HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides) on the prevention and control of flight microangiopathy, and particularly on edema, in subjects with varicose veins flying for more than 7 hours. Forty patients with varicose veins, edema, and initial skin alterations due to chronic venous hypertension were included. Measurements of skin laser Doppler flowmetry resting flux, Po(2) and rate of ankle swelling, were made before and after the flights (within 4 hours before the flights and within 2 hours after the flights). The length of the flights was between 7 and 9 hours; all seats were in coach class. The 2 groups were comparable for distribution. The variation of Po(2) was significant in both groups. However, in subjects treated with HR, the decrease in Po(2) was smaller (P < 0.05). The decrease in laser Doppler flowmetry resting flux was also significant in both groups, with a higher flux at the end of the control period in the treated subjects (P < 0.05). The venoarteriolar response progressively decreased at 7 and 9 hours. The decrease was less evident in the treatment group (P < 0.05). The rate of ankle swelling was progressively increased in the control group; the increase was not significant in the HR group. In long-haul flights, HR is useful for reducing the increased capillary filtration and in controlling edema in patients with venous hypertension and is effective in controlling perfusion disorders and microangiopathy, particularly swelling and edema, due to flights.

Topics: Adult; Aerospace Medicine; Aircraft; Ankle; Edema; Female; Humans; Hydroxyethylrutoside; Laser-Doppler Flowmetry; Male; Microcirculation; Prospective Studies; Travel; Varicose Veins; Vasoconstrictor Agents

The variation of capillary filtration rate (CFR) and ankle edema (AE) were evaluated in three groups of patients with venous hypertension with ambulatory venous pressure > 42 mmHg and in healthy subjects before and after treatment for four weeks with HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (30 patients) was treated with HR 500 mg tid; group B (30 patients) was treated with 1 g tid; group C (30 patients) was treated with placebo; group D (10 healthy subjects) was treated with HR 1 g/day in a randomised study. CFR was assessed by venous occlusion plethysmography. Subjective symptoms of venous hypertension were assessed by an analogue scale line considering four symptoms: swelling sensation, restless lower extremity, pain and cramps, and tiredness.. There were no significant differences for sex and age distribution among the groups; no significant differences were found for ambulatory venous pressure and refilling time and parameters of venous hypertension among groups. There was a significant difference between normal subjects and patients. There were no drop-outs and observed intolerance. In group A, there was a significant decrease of CFR (P < 0.01) after treatment. In group B (2 g/day), the decrease was greater than that in group A (P < 0.05). In group C (placebo) there was no significant difference before or after treatment. The variations in analogue score was higher with the higher dosage. The score of group A fell from 7.8 (SD 1.3) to 4 (1). Group B's score fell from 7.9 (2) to 3.1 (1.2). In group C (placebo) there was no change. The decrease in the score in the groups of patients was correlated with the variation in edema and CFR.. HR is effective in venous edema and hypertension. Its effects are dose-related.

Topics: Adult; Dose-Response Relationship, Drug; Edema; Female; Humans; Hydroxyethylrutoside; Hypertension; Male; Microcirculation; Middle Aged; Placebos; Plethysmography; Treatment Outcome; Vasoconstrictor Agents; Venous Insufficiency

The aim of this study was to demonstrate whether HR (Paroven, Venoruton; 0-(beta-hydroxyethyl)-rutosides), was effective in improving levels of plasma free radicals (PFRs) in patients with chronic venous insufficiency (CVI) and venous microangiopathy. Patients were randomized into the treatment group, which received oral HR (1g sachets, twice daily, for 4 weeks), and a placebo group, which received comparable placebo. Below-knee Sigvaris stockings were used during the study. PFRs were measured with the D-Rom test at the finger and at a vein of the leg in an area of CVI. The mean age of included subjects was 46 years (SD 11) in the treatment group (20 patients; 6 females) and 46.4 (SD 8) in the placebo group (20 patients; 7 females). There were no differences between placebo and treatment groups at inclusion in age and sex distribution and in parameters indicating venous hypertension. The decrease of PFRs levels in the treatment group was significant, both at the finger and in the distal blood taken in areas of CVI. There there were no significant changes in the control group. In areas of venous hypertension, PFRs values were on average higher than at the finger (systemic) level (P < 0.05). In parallel with the progressive decrease in PFRs associated with treatment, the analogue score was significantly decreased at 2 (P < 0.05) and 4 weeks (P < 0.02) in the HR group. No changes were observed in the placebo group. No adverse effects were observed. In conclusion, HR treatment is effective in decreasing both the systemic and local values of PFRs and therefore may have a positive effect on the evolution of CVI.

Topics: Adult; Female; Free Radicals; Humans; Hydroxyethylrutoside; Hypertension; Male; Middle Aged; Placebos; Prospective Studies; Skin Ulcer; Treatment Outcome; Varicose Veins; Vascular Diseases; Venous Insufficiency

To study the efficacy of coumarin/troxerutine for the protection of salivary glands and mucosa during irradiation.. Prospective, randomized, placebo-controlled, double-blind trial.. University hospital, Germany.. 48 patients who had radiotherapy to the head and neck.. Salivary gland scintigraphy and acute side-effects of radiotherapy (Radiation Therapy Oncology Group (RTOG) score).. 23 patients (11 experimental, 12 placebo) completed the study. The global efficacy measure combining scintigraphy and RTOG score favoured the experimental arm (P=0.07). The RTOG score showed significantly fewer acute side-effects of radiation in the experimental arm (P<0.05).. The results suggest that coumarin/troxerutine have a favourable effect in the treatment of radiogenic sialadenitis and mucositis.

Topics: Adult; Aged; Coumarins; Cranial Irradiation; Double-Blind Method; Drug Combinations; Female; Head and Neck Neoplasms; Humans; Hydroxyethylrutoside; Male; Middle Aged; Mouth Mucosa; Prospective Studies; Radiation Injuries; Radiation-Protective Agents; Radionuclide Imaging; Radiopharmaceuticals; Salivary Glands; Sialadenitis; Sodium Pertechnetate Tc 99m; Treatment Outcome; Xerostomia

Flavonoids, such as troxerutin, have been shown to be safe and effective agents for the treatment of chronic venous insufficiency. The fixed combination between troxerutin 150 mg and carbazochrome 1.5 mg (Fleboside ampoules) was previously shown to have a good efficacy and safety profile in non-surgical patients with acute uncomplicated hemorrhoids. The purpose of this randomized, double-blind, placebo-controlled study was to investigate the efficacy and tolerability of the active combination in the treatment of post-hemorrhoidectomy patients. 30 patients were randomized to receive one of two treatments: troxerutin 150 mg and carbazochrome 1.5 mg, or placebo, i.m. 3 ml ampoules twice a day for five consecutive days after the surgical procedure, starting from the day of surgery. Efficacy parameters were assessed as follows: at baseline (T1), after the first administration (T2; day of surgery), the second day after the surgical procedure (T3), and the fifth day after the surgical procedure (T4); hemorrhoidal symptoms based on a visual analogue scale (VAS): pain, discharge, bleeding, inflammation, and pruritus; analgesic intake, if any; time to restore a physiological defecation; edema evaluation (based on a four-point scale: 0 = absent; 1 = mild; 2 = moderate; 3 = severe); camera pictures taken at T1 and T4 (in selected patients); and blood coagulation tests. Analysis between treatment groups revealed a highly significant difference at T3 and T4 for the total VAS score (p = 0.007 and p = 0.001, respectively) in favor of the active combination treatment. A statistically significant difference was also observed for bleeding and pruritus at T3 and for these two parameters and both inflammation and edema at T4 (p < 0.001) in favor of the active combination group. No adverse events were reported. Neither the active combination nor placebo affected blood coagulation tests. We conclude that intramuscular administration of the fixed combination of troxerutin 150 mg and carbazochrome 1.5 mg is effective, well tolerated and superior to placebo in improving hemorrhoidal and post-surgical symptoms during the five days following surgery.

Topics: Adrenochrome; Adult; Chi-Square Distribution; Double-Blind Method; Drug Combinations; Female; Hemorrhoids; Humans; Hydroxyethylrutoside; Injections, Intramuscular; Male; Middle Aged; Postoperative Complications; Statistics, Nonparametric; Treatment Outcome; Vasoconstrictor Agents

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

The aim of this study was to investigate, if the the combined treatment of compression stockings and drug treatment with oxerutins (O-(beta-hydroxyethyl)-rutosides, Venoruton) provides additional benefit for patients with chronic venous insufficiency (CVI) compared to compression treatment alone. Oxerutins belong to the group of oedema protective agents and possess anti-exudative and membrane protective activity. A total of 133 female patients with CVI grade II participated in this double-blind, randomised, multi-centre, parallel-group study with two treatment groups. The whole study lasted for 19 weeks, and consisted of a one week placebo run-in phase, 12 weeks treatment phase, followed by a 6 weeks treatment-free follow-up period. All patients received a basis compression therapy that consisted of standard compression stockings. In order to standardise initial fitting of stockings in this multi-centre setting, stockings were fitted after one week of standard diuretics starting at baseline and then stockings were worn for the following 11 weeks. Patients were randomised to receive oxerutins (2 x 500 mg daily) or matching placebo. Leg volumes (water displacement) and associated subjective symptoms (visula analogue scale) were measured during a placebo run-in period at enrolment (week - 1) and half a week later (week - 1/2), at baseline week 0), at 4, 8, 12 weeks on treatment, and again after a 3- and 6-weeks treatment-free follow-up. The primary efficacy criterion, the area under the baseline from week 0 to week 18 (AUB0-18) of leg volume changes, as measurement of the global change of leg oedema during the study, resulted in a superior reduction of -5589 ml.d for the combined treatment with oxerutins compared to -2101 ml.d for placebo (p = 0.012). The mean change of leg volume compared to baseline after 12 weeks of treatment was -63.9 ml for stockings and oxerutins, and -32.9 ml for the patients who received stockings and placebo (p < 0.05). Oxerutins showed a prolonged effect in the follow-up phase compared to placebo, with mean AUB values for week 12 to week 18 of -1769 ml.d versus -133 ml.d (p < 0.01). The study demonstrated that the combined therapy of compression stockings and drug treatment with oxerutins is significantly superior in reducing leg oedema resulting from chronic venous insufficiency compared to compression treatment alone.

Topics: Aged; Bandages; Chronic Disease; Combined Modality Therapy; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Leg; Microcirculation; Middle Aged; Vasoconstrictor Agents; Venous Insufficiency

Oxerutins (O-(beta-hydroxyethyl)rutosides, HR, Venoruton) and horse chestnut extract (HCE) are active principles of first priority for the pharmacological treatment of chronic venous insufficiency (CVI). The efficacies of both compounds were shown in numerous, double-blind, randomized, placebo controlled clinical trials. Besides the direct comparison of the two compounds the aim of the study was to investigate the initial dose/maintenance dose concept for HR. 137 female, postmenopausal patients with CVI II finished the study according to protocol. Following one week placebo run-in the patients were treated either with 1000 mg/d HR, 600 mg/d HCE or 1000 mg/d for 4 weeks and than with 500 mg/d HR within the initial dose/maintainance dose concept for 12 weeks and observed for further 6 weeks. A main confirmative criterion was the volume reduction of the leg. Subjective criteria were descriptively evaluated. HR (1000 mg/d) was proven to be equivalent or better, reducing the leg volume (AUB0-18) by -5273 +/- 11418 ml.d compared to -3187 +/- 10842 ml.d under HR (1000 mg/d and 500 mg/d), and -3004 +/- 7429 ml.d under HCE-treatment. Both compounds exhibit a substantial carry-over effect. The maintenance posology of HR is able to stabilize the therapeutic obtained under initial dose conditions.

Topics: Aged; Bandages; Chronic Disease; Combined Modality Therapy; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Leg; Microcirculation; Middle Aged; Plant Extracts; Plants, Medicinal; Vasoconstrictor Agents; Venous Insufficiency

Oxerutins (O-(beta-hydroxyethyl)-rutosides, HR, Venoruton) are available in different releasing galenical formulations for the treatment of chronic venous insufficiency (CVI). In order to investigate the biopharmaceutical relevance of the releasing properties of the galenical forms the therapeutic efficacy between the commercially available forms was investigated (500 mg sustained release film tablets, 300 mg sustained release film tablets, 300 mg normally releasing capsules) in comparison to an aqueous solution and placebo. In total 100 female patients with CVI grade II participated. The study was carried out following a randomized, placebo controlled design with parallel treatment groups. Following a two-week run-in phase patients were treated for 12 weeks with different posologies of HR (2 x 1/d 500 mg, 3 x 1/d 300 mg, 1 x 1000 mg/d as aqueous solution). Main criterion was the reduction of leg volume following 12 weeks treatment. Subjective criteria were descriptively evaluated. All four HR treatments were significantly superior to placebo (p < 0.0008). The different posologies had no influence on the efficacy. The therapeutic efficacy is independent of the in vitro rate of release. The available forms are regarded as bioequivalent.

Topics: Aged; Biological Availability; Delayed-Action Preparations; Female; Humans; Hydroxyethylrutoside; Leg; Middle Aged; Single-Blind Method; Therapeutic Equivalency; Vasoconstrictor Agents; Venous Insufficiency

The vein wall is nourished by diffusion of blood nutrients from the lumen and from the vasa vasorum. It is likely that drugs take the same ways to reach and diffuse through the vessel wall. Thus the uptake of a drug with affinity for the vein wall should give information on its transport to the tissue. This study aimed to explore troxerutin uptake by the long saphenous vein. Troxerutin is a naturally fluorescent flavonoid which has been known to improve subjective signs of patients with chronic venous insufficiency. Nine patients undergoing surgical treatment of varicosis were enrolled in the study. They received for the last 4 days before surgery either 3,500 mg of troxerutin (n = 4) or 1,000 mg twice daily (n = 2). Three patients as controls did not receive any drug. Two samples from thigh and calf long saphenous vein were harvested in each patients and investigated with a confocal laser scanning microscope developed by our institute measuring the fluorescence emitted by troxerutin after excitation by a 458 nm wavelength laser-beam. The intensity of the overall fluorescence was significantly higher in the treated groups (p < 0,001) and slightly higher in the patient who received 3,500 mg of troxerutin than with the lower dosage. The outer wall region provided the highest fluorescence in the treated group while a significant difference was observed in the fluorescence of the medial region between treated and control group. These results showed a marked affinity of troxerutin for the venous wall. The highest uptake in the outer wall region is likely to result from transport through vasa vasorum, owing to the rheologic properties of the drug. The significant medial fluorescence may account for the venous tone improvement with the drug.

Topics: Endothelium, Vascular; Fluorescence; Humans; Hydroxyethylrutoside; Microscopy, Confocal; Vasoconstrictor Agents; Veins

Abnormal increase of erythrocyte aggregation and reduction of profibrinolytic activity are the two most frequent biological perturbations found in chronic venous insufficiency (CVI). A randomised, controlled, double blind trial was undertaken on 85 patients suffering from grade 1 and 2 CVI, to compare troxerutin with placebo. Two types of biological parameters were measured after 15 days of treatment. Erythrocyte aggregation as evaluated with a Myrenne erythroaggregometer by the indices M (stasis) and M1 (3s-1) progressed favorably in the troxerutin group. The values of M1 at D15 (p < 0.05), and the progression of M (p < 0.001) and M1 (p < 0.01) from D0 to D15, are significantly better in the troxerutin group. Progression of fibrinolytic activity at rest was not significantly different between the 2 groups. Conversely, the progression from D0 to D15 of the values after occlusion of euglobulin lysis time (p < 0.01), tPA (p < 0.01), and PAI activity (p < 0.05) are significantly better in the troxerutin group. The fibrinolysis capacity estimated by euglobulin lysis time (p < 0.01) and tPA (p < 0.05) also progressed favorably in the troxerutin group. These results confirm the anti-erythrocyte aggregation effect of troxerutin, and suggest a favorable effect on blood fibrinolytic activity. They could explain the positive action of this drug on stasis, capillary perfusion and trophic complications of CVL.

Topics: Aged; Anticoagulants; Chronic Disease; Double-Blind Method; Female; Fibrinolysis; Hemorheology; Humans; Hydroxyethylrutoside; Male; Middle Aged; Placebos; Vasoconstrictor Agents; Venous Insufficiency

Hemorheologic factors probably play a role in the pathogenesis and prognosis of retinal vein occlusion. Accordingly, we designed a prospective, randomized, double-masked study to evaluate the effect of troxerutin, a rheologic drug, on retinal vein occlusion. Fifty-three patients were included, 27 with central retinal vein occlusion and 26 with branch retinal vein occlusion. They were randomly assigned for treatment with either troxerutin or a placebo. All subjects were similar in age, gender, associated diseases, hemorheologic values, and clinical severity of the retinal vein occlusion. At the end of follow-up, members of the troxerutin-treated group, as compared with the placebo group, showed significant improvement in visual acuity (P = .03), macular threshold (P = .01), retinal circulation times (P = .04), and macular edema (P = .05). Furthermore, they had diminished progression of ischemia (P = .05) and decreased red blood cell aggregability (P = .006) when compared with the controls. These encouraging preliminary results obtained with a rheologic treatment attest to the pathogenic role of blood viscosity in retinal vein occlusion and suggest that a large-scale randomized study should be conducted.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Drug Evaluation; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Prospective Studies; Retinal Vein Occlusion; Retinal Vessels; Treatment Outcome; Visual Acuity

To evaluate the clinical efficacy and pharmacologic effects of dihydroergotamine and troxerutin on varicose veins.. A double-blind, randomized, placebo-controlled parallel-group study was conducted in 53 patients with primary varicose veins. Patients received either a fixed combination of 3 mg dihydroergotamine and 300 mg troxerutin three times a day or placebo for 3 weeks. Symptomatic improvement was assessed by a self-assessment score, venocontracting effects on a varicose vein were quantified by the venous compliance technique (VCT), and changes in venous dysfunction were measured by digital photoplethysmography (DPPG).. A significant reduction (p < 0.01) of subjective symptoms was observed in both groups. Results from VCT and DPPG after the therapy with dihydroergotamine and troxerutin or placebo were not significantly different (p > 0.05) from pretreatment values. Furthermore, no significant intergroup difference was observed when the before- and after-therapy differences of values of the self-assessment scores (VCT and DPPG) were compared.. In our study, 3 weeks of treatment with a fixed drug combination of 3 mg dihydroergotamine plus 300 mg troxerutin three times a day had no measurable effect compared with placebo on any of the evaluated end points.

Topics: Adult; Dihydroergotamine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Photoplethysmography; Time Factors; Varicose Veins; Vasoconstrictor Agents

Oxerutins (Venoruton) and troxerutin (CAS 7085-55-4) are both mixtures of O-(beta-hydroxyethyl)-rutosides used for the treatment of chronic venous insufficiency. As di-O-(beta-hydroxyethyl)-rutosides and 7-mono-O-(beta-hydroxyethyl)-rutoside were found to be more active with regard to free radical scavenging compared to tri-O-(beta-hydroxyethyl)-rutoside the aim of this study was to compare oxerutins and troxerutin clinically. 12 female, post-menopausal patients with chronic venous insufficiency grade II participated in this double-blind study with random allocation to the treatment groups. They received 900 mg/day oxerutins or troxerutin for 12 weeks and were observed for 4 further weeks without treatment. Leg volumes (water displacement) and subjective symptoms (VAS, visual analogue scale) were evaluated before and following 2, 4, 8, 12 and 16 weeks. Both treatments were active in reducing leg volumes and in ameliorating subjective symptoms (mean volume reduction -167 +/- 157 ml x week). Volume reduction totalled to -261 +/- 154.2 ml x week for oxerutins and -73.2 +/- 97.1 ml x week for troxerutin. The difference is statistically significant (p = 0.04). The findings with subjective symptoms were in good accordance to the objective volume measurement. Oxerutins revealed a remarkable carry over effect.

Topics: Anticoagulants; Chronic Disease; Double-Blind Method; Edema; Female; Humans; Hydroxyethylrutoside; Leg; Middle Aged; Pain; Pain Measurement; Venous Insufficiency

Forty-three patients recruited from general practice with symptom-producing chronic venous insufficiency in the lower limbs participated in a randomized double-blind clinical trial with Venoruton (300 mg x 3) or a placebo for 28 days. Twenty-eight patients were treated with Venoruton and 19 with a placebo. None of the patients received other forms of treatment for chronic venous insufficiency. No differences were observed between the two groups as regards changes in symptoms (swelling, pain, heaviness, restlessness, itching and cramps) the subjective assessment of the discomfort in the extremities or the circumference of the limbs. Venoruton does not appear to have any effect on chronic venous insufficiency in the lower limbs.

Topics: Adult; Aged; Chronic Disease; Female; Humans; Hydroxyethylrutoside; Leg; Male; Middle Aged; Venous Insufficiency

The uptake and localisation of O-(beta-hydroxyethyl)-rutosides (HR) in the venous wall was studied in 8 patients undergoing crossectomy for a varicose long saphenous vein. The fluorescence of cross-sections of the vein wall was measured by laser scanning microscopy, based on the autofluorescence of HR. Four patients (treated group) received 2 x 1.5 g HR IV before surgery, and four (untreated patients) served as controls. Uptake of HR into the veins from treated patients was seen, with a mean fluorescence intensity of 80.9 units compared to 49.4 units in the untreated veins. The increase in fluorescence was clearly demarcated on the endothelial side of the vein wall. It is concluded that HR passes into the vascular wall, where it is localised in the endothelial and sub-endothelial areas.

Topics: Adult; Anticoagulants; Humans; Hydroxyethylrutoside; Lasers; Microscopy, Fluorescence; Middle Aged; Saphenous Vein; Varicose Veins

An experimental clinical study was performed using heparan sulfate in order to ascertain the effects of the drug in the treatment of 2nd or 3rd degree varicose dilatation of the hemorrhoid plexus. Forty female patients, mean age 37 years and suffering from varicose dilatation of the hemorrhoid plexus, were enrolled in the study. The study was carried out in an open comparison with oxerutin using parallel groups with random access. After a run-in period of 3 days, 20 patients commenced treatment with 1 50 mg tablet of heparin sulfate 3 times daily, whereas the other 20 patients were given 1,500 mg oxerutin tablet again 3 times daily. Subsequently, treatment was continued at the following doses: 1 50 mg tablet of heparin sulfate twice a day, and 1,500 mg tablet of oxerutin twice a day, for a duration of two weeks. At pre-established times (before treatment, after 1 week, after 2 weeks), a standard questionnaire was filled in relating to each patient in order to evaluate the efficacy and tolerability of treatment. No adverse or undesirable effects were reported. Each participant was also put on a personalized and computerised diet with the same fibre intake. 55% of patients treated with oxerutin reported persistent moderate or intense pain caused by defecation compared to 45% of the group treated with heparan sulfate. Both drugs induced the remission of skin rash and itching. Compared to the control drug, heparan sulfate was more efficacious in relation to the normalisation of hyperemia and mucoid secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Dose-Response Relationship, Drug; Drug Evaluation; Female; Hemorrhoids; Heparitin Sulfate; Humans; Hydroxyethylrutoside; Random Allocation; Tablets; Varicose Veins

We realized a double-blind randomized study in 26 pregnant with clinical symptoms of lower limbs venous insufficiency. Both groups were similar and received either (n = 12) troxerutine (4 g/day) or placebo (n = 14), during 30 days. Evaluation at J0 and J30 was both clinical and rheological by mean of Myrenne aggregometer. After blood shear rate of 600 s-1, two parameters were determined: M after roughly stopping shear rate, M1 after diminishing to shear rate of 3 s-1. Results exhibited steady values in patients receiving troxerutine while a significant increasing values in patients receiving placebo for the two parameters M and M1. That result in erythrocyte antiaggregating action of troxerutine, hence lowering viscosity action, in venous insufficiency during pregnancy.

Topics: Adult; Anticoagulants; Blood Viscosity; Double-Blind Method; Erythrocyte Aggregation; Female; Hemodynamics; Humans; Hydroxyethylrutoside; Leg; Pregnancy; Pregnancy Complications, Cardiovascular; Vascular Diseases

The success of treatment aimed at improving manifestations of venous insufficiency appears today to be closely linked to a therapeutic impact on blood viscosity and the macrorheological parameters upon which it depends. This double-blind placebo-controlled trial of troxerutine was designed to evaluate changes during treatment in rheological abnormalities in 60 women with vulval varicosities and venous insufficiency of the lower limbs, half in the context of premenstrual syndrome and half in pregnant women from the 4th month on. Initial examination revealed no significant difference between the treated and control groups from a clinical and rheological standpoint in the gynecological and obstetric categories. Analysis of results showed that a high dose of troxerutine was associated with a very marked improvement in symptomatic parameters by the first month of treatment with a significant correlation between clinical criteria and rheological parameters in pregnant women as well as in those with a premenstrual syndrome. These data were confirmed by excellent acceptability as well as subjective assessment by patients after 4 months' treatment at the dosage of 4 g/d.

Topics: Anticoagulants; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Leg; Pregnancy; Pregnancy Complications, Cardiovascular; Premenstrual Syndrome; Varicose Veins; Vascular Diseases; Vulvar Diseases

Topics: Anticoagulants; Capillary Permeability; Humans; Hydroxyethylrutoside; Lymphedema

The value of oxerutins [O-(beta-hydroxyethyl)-rutosides] in the prevention of venous ulcer recurrence was investigated in a double-blind randomized controlled trial of 138 patients with recently healed chronic venous ulcers. Oxerutins in the form of Paroven 500 mg twice daily or identical placebo were given, and all patients were provided with elastic compression stockings. At follow-up 3 months later, patients were assessed for re-ulceration and for tablet and stocking compliance. Oxerutins (n = 69) and placebo (n = 69) groups were well matched for age, sex, duration of previous ulceration and deep vein thrombosis. Cumulative re-ulceration by life-table analysis at 12 and 18 months was 22 and 32 per cent respectively for placebo, and 23 and 34 per cent respectively for oxerutins (P = 0.93). Recurrence was more frequent in patients who complied with both tablets and stockings, suggesting that compliance was influenced by continued symptoms (P = 0.006). This trial failed to demonstrate that oxerutins influenced ulcer recurrence.

Topics: Anticoagulants; Bandages; Double-Blind Method; Humans; Hydroxyethylrutoside; Patient Compliance; Recurrence; Varicose Ulcer

In a double-blind study the effects of troxerutine were assessed in patients with chronic venous insufficiency. The aim of this clinical pharmacological research was to evaluate, after a single oral dose: haemocoagulative and fibrinolytic balance, haemorheological changes and venous function. Correlation between such changes and simultanously assayed plasma drug levels was evaluated. The data obtained seems to give to troxerutine a more enlarged pharmacological characterization, especially regarding its demonstrated profibrinolytic and rheological activities. The maximal pharmacodynamic effects appeared simultaneous with the plasma drug peak.

Topics: Adult; Anticoagulants; Blood Coagulation; Blood Viscosity; Cell Aggregation; Chromatography, High Pressure Liquid; Double-Blind Method; Erythrocyte Deformability; Female; Fibrinolysis; Humans; Hydroxyethylrutoside; Male; Middle Aged; Plethysmography; Spectrophotometry, Ultraviolet; Vascular Diseases

Topics: Anticoagulants; Double-Blind Method; Erythrocyte Deformability; Humans; Hydroxyethylrutoside; Myocardial Infarction

The evaluation of the effects of venoactive drugs and particularly of Venoruton may be performed using microcirculatory parameters. Laserdoppler flowmetry may be used in association with PO2/PCO2 measurements. In this study we combined the microcirculatory evaluation with foot and leg volumetry to evaluate the effects of Venoruton in 15 patients with deep (popliteal vein) incompetence and venous hypertension, treated for 6 weeks. A control group of 20 patients was also evaluated. All these subjects were studied and selected according to ambulatory venous pressure measurements (AVP) and duplex scanning. Measurements were made at the internal perimalleolar region in constant temperature condition (23 degrees C). No variations of AVP or duplex scanning findings were observed after 6 weeks in both treated and untreated patients. Laserdoppler flowmetry showed a significant decrease of the resting flow (which was increased in all patients at the beginning of the study). An increased efficacy of the venoarteriolar response was also recorded together with an increased response of skin flow after increase of temperature in the perimalleolar region in patients treated with Venoruton. This was also associated with an increase of skin PO2 and with a decreased PCO2. In the control group no significant variations of these parameters were observed. Leg volume was also significantly decreased in the patients treated with Venoruton while no changes were observed in controls. In conclusion this study showed the efficacy of Venoruton in improving parameters altered in venous hypertension and the possibility of application of this microcirculatory model to study venoactive drugs used for treating venous hypertension.

Topics: Anticoagulants; Blood Gas Monitoring, Transcutaneous; Clinical Trials as Topic; Female; Humans; Hydroxyethylrutoside; Lasers; Leg; Lymphedema; Male; Microcirculation; Middle Aged; Postphlebitic Syndrome; Random Allocation; Rutin; Venous Insufficiency; Venous Pressure

Superficial vein thrombosis (SVT) is a common complication of varicose veins. Treatment may be surgical by removal of the superficial clots under local anesthetic or medical in association with elastic compression and mobilization. In this study 83 patients with SVT were randomised in treatments groups: A--superficial thrombectomy and elastic compression (EC); B--Ca Heparin (0.5 mgs b.i.b.) + EC; C--Venoruton (1 g, t.i.d.) + EC; D--Venoruton (1 g, t.i.d.) after superficial thrombectomy + EC; E--elastic compression. All treatments were applied for 8 weeks. The evolution of SVT was studied by a system, based on thermography, which analyse by a computerized system the variation of the hyperthermic areas (HA) on thermograms. This was associated with subjective and objective clinical evaluation. Results indicate a decrease of HA in all groups but patients treated with superficial thrombectomy show a significantly (p, 0.05) greater and faster reduction of HA. The reduction of HA produced by Venoruton was also significantly greater (p less than 0.05) than that observed in patients treated by Ca Heparin or elastic compression and it determined also a faster and greater (p less than 0.05) decrease of HA after thrombectomy. These results were confirmed by clinical observations. In conclusion results from this study indicate a positive effect of Venoruton in SVT in determining a faster decrease of hyperthermic areas probably by decreasing local inflammation.

Topics: Adult; Anticoagulants; Bandages; Combined Modality Therapy; Endarterectomy; Female; Heparin; Humans; Hydroxyethylrutoside; Image Processing, Computer-Assisted; Male; Middle Aged; Randomized Controlled Trials as Topic; Rutin; Thermography; Thrombophlebitis

A multi-centre, double blind randomized clinical trial was designed to assess the efficacy and safety of orally administered 0-(beta-hydroxyethyl)-rutosides (HR) capsules in the treatment of 101 patients with post-thrombotic syndrome. Seventeen patients were excluded from the analysis for violation of the study protocol, 41 received HR capsules (1,200 mg/day) and 43 placebo. Mean follow-up scores at the 4th and 8th week show that the HR patients displayed an improved state of tiredness as compared to the placebo's. The mean circumference of the calf for the HR group decreased from 390 (+/- 33) mm at visit one to 382 (+/- 33) mm at visit three, with a mean circumference reduction of 8.7 (+/- 8) mm, compared to a steady placebo circumference of 387 (+/- 31) mm at all 3 visits with a mean circumference reduction of only 2 mm (+/- 9). The estimated treatment effect at week 8 was -6.7 mm, 95% confidence interval (-10.3, -3.0). The mean circumference of the ankle, decreased from 243 (+/- 20) mm to 238 (+/- 20) mm at the 4th week, contrasted with a constant placebo circumference of 241 (+/- 22) mm at both visits. The estimated treatment effect at week 4 was -5.4 mm, 95% confidence interval (-10.2, -0.6). However, at week 8, the estimated treatment effect was only -3.4 mm, 95% confidence interval (-8.6, +1.8). In conclusion, HR capsules may show an improvement in the clinical symptoms and may show a mean circumference reduction of the calf and ankle at the 8th week, in patients with post-thrombotic syndrome.

Topics: Adult; Aged; Anticoagulants; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Multicenter Studies as Topic; Random Allocation; Rutin; Syndrome; Thrombosis

The sudden deafness of vascular origin was treated by Venoruton. 4 patients were observed with positive results as improvement of hearing acuity and disappearance of tinnitus.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Hearing Loss, Sudden; Humans; Hydroxyethylrutoside; Hypertension; Male; Middle Aged; Rutin

A randomised, double-blind, cross-over trial was performed on 26 patients with postmastectomy lymphoedema of the arm, and 14 with lymphoedema of the leg. For 6 months, patients took 0-(beta-hydroxyethyl)-rutosides (oxerutin; "Paroven", "Venoruton", Zyma) in doses of 3 g/day, or the placebos; then they took the reverse. Measurements (volume, circumferences, tonometry and skin temperature) were made monthly. The active drug reduced the volumes of the limbs (p less than 0.05 to 0.01) and their circumferences (p less than 0.05 to 0.001). It increased the softness of the limbs, as shown by the increases in the tonometry values (p less than 0.01 to 0.001). There was a lowering of the elevated skin temperatures (p less than 0.05 to 0.001). Patients reported increased comfort and freedom of movement, a lessening of their bursting pains, heaviness and tension (p less than 0.05 to 0.01), and an increased mobility of their limbs (p less than 0.0001). Most patients (70%) preferred the active drug (p less than 0.0001). An increase in general well-being was reported by 97% of patients when taking the active drug compared with 4% for placebo (p less than 0.0001).

Topics: Arm; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Leg; Lymphedema; Male; Mastectomy; Middle Aged; Postoperative Complications; Random Allocation; Rutin; Skin Temperature

Sixteen chronic schizophrenic subjects were treated for 3 months each with either a benzo-pyrone (Paroven/Venoruton, Zyma) or a placebo in a randomized, double-blind crossover trial. They continued to take their previous drug therapies. Therapeutic effects were measured by the Brief Psychiatric Rating Scale (BPRS), by self-assessment, and by assessment by a relative. Eleven patients completed the trial in relation to BPRS assessment. When on the active substance, as compared with the placebo, they showed a mean improvement of 27% (significant at the 1% level). Ten patients completed the trial in relation to the self and relative's assessments. There were improvements of 16% and 13%, respectively (significant at the 5% levels). Half the patients showed improvements on all the tests. Their improvements were 49%, 31%, and 21%, respectively. There was evidence that the active substance began to have an effect within 2 weeks. No side effects were observed with the active substance.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Rutin; Schizophrenia

In a clinically controlled double-blind study it was demonstrated that tri-(hydroxyethyl)-rutin is not capable of significantly improving blood viscosity or one of its constituent factors. On the basis of data from 58 patients, none of whom was under 43 years old, it was possible to show that the substance tested has no favorable influence on plasma viscosity, erythrocyte deformability and aggregation, or on the concentration of plasma proteins which promote aggregation. Thus, in the very group of patients for whom an improvement in blood flow properties by means of oral administration of tri-(hydroxyethyl)rutin had been hoped for, no therapeutic effect could be demonstrated.

Topics: Adult; Anticoagulants; Arteriosclerosis; Blood Proteins; Blood Viscosity; Clinical Trials as Topic; Diabetic Retinopathy; Double-Blind Method; Erythrocyte Aggregation; Erythrocyte Deformability; Erythrocytes; Female; Humans; Hydroxyethylrutoside; Male; Retinal Diseases; Rutin

Topics: Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Rutin; United Kingdom; Vasodilator Agents; Venous Insufficiency

This study aimed to determine the effects of troxerutin consumption during gestation on reflexive motor behavior in mice offspring. Forty pregnant female mice were allocated into four groups. In the control group, mice received water, while in groups 2-4, female mice p.o. administered troxerutin (50, 100, and 150 mg/kg) at 5, 8, 11, 14, and 17 days of gestation (GD). Following delivery, pups were selected based on their experimental group, and reflexive motor behaviors were determined. Also, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant status (TAS) were determined. Based on the findings, maternal exposure to troxerutin (100 and 150 mg/kg) increased ambulation scores in offspring's compared with control group (P < 0.05). Also, prenatal exposure to troxerutin increased front- and hind-limb suspension scores in newborns compared with control group (P < 0.05). Maternal exposure to troxerutin increased grip strength and negative geotaxis in newborns in comparison with control mice (P < 0.05). Prenatal exposure to troxerutin (100 and 150 mg/kg) decreased hind-limb foot angle and surface righting in pups compared with control group (P < 0.05). Maternal exposure to troxerutin decreased MDA production and increased SOD, GPx, and TAS levels in offspring (P < 0.05). These results suggested that prenatal consumption of the troxerutin improves reflexive motor behaviors in mice pups.

Topics: Animals; Antioxidants; Female; Humans; Hydroxyethylrutoside; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Superoxide Dismutase

Troxerutin, a bioflavonoid with marked immune-modulatory and antioxidant features, has been proven to ameliorate experimental cardiotoxicity, hepatotoxicity, and neurodegeneration. However, its impact on methotrexate (MTX)-induced nephrotoxicity has not been investigated. In the current work, we aimed to investigate the potential of troxerutin to combat MTX-triggered renal injury, exploring immune cell infiltration, inflammation, autophagy, and apoptosis, with emphasis on the HMGB1/RAGE/NF-κB, AMPK/mTOR, and Nrf2/HO-1 pathways.. Troxerutin (150 mg/kg/day) was administered by oral gavage and the renal tissues were examined with the aid of biochemical assays, ELISA, histology, and immunohistochemistry.. Troxerutin mitigated MTX-induced renal dysfunction by significantly lowering creatinine, BUN, and KIM-1 alongside immune-cell infiltration and histopathologic aberrations. These favorable effects were mediated by inhibition of HMGB1/RAGE/NF-κB cascade via downregulating the protein expression of HMGB1, RAGE, and nuclear NF-κBp65 alongside its downstream signals, including COX-2 and TNF-α. Moreover, troxerutin activated the autophagy flux as evidenced by upregulating renal Beclin 1, lowering p62 SQSTM1 accumulation, and activation of AMPK/mTOR pathway, seen by increasing p-AMPK/total AMPK and lowering p-mTOR/total mTOR signals. In tandem, troxerutin combated renal apoptotic changes as proven with lowering caspase-3 activity, Bax expression, and Bax/Bcl-2 ratio and upregulating the proliferation signal PCNA. Additionally, the oxidative insult was attenuated by troxerutin, as evidenced by lowering NOX-1 and lipid peroxides, replenishing GSH, GPx, and SOD antioxidants, and activating Nrf2/HO-1 pathway.. Troxerutin attenuated MTX-triggered renal injury via inhibition of inflammation and apoptosis alongside activation of autophagy. Thus, it may serve as an adjunct modality for the management of MTX-linked nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Apoptosis; Autophagy; Disease Models, Animal; Humans; Hydroxyethylrutoside; Inflammation; Male; Methotrexate; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction; Vasoconstrictor Agents

Background: Renal ischemia-reperfusion injury (RIRI) is the most frequent cause of acute renal failure in clinical conditions such as trauma and shock as well as renal surgeries. Oxerutin is a member of the flavonoid family and possesses antioxidant properties. The aim of this study was to investigate whether oxerutin has protective effects on RIRI.. Twenty-eight male Wistar albino rats were randomly divided into three groups: sham control group (n=8), RIRI group (n=10), and RIRI + oxerutin group (n=10). RIRI was achieved by clamping the left renal artery for 30 min, followed 1-h reperfusion period. Thereafter, blood samples and left kidney tissue samples were taken for histopathological and biochemical examination. Blood urea nitrogen (BUN), urea, creatinine, and cystatin C levels, which are indicators of kidney function, as well as tumor necrosis factor-alpha, which is an indicator of inflammation were analyzed in blood samples. Total antioxidant status and total oxidant status (TOS), which are indicators of oxidative stress were analyzed on renal tissues. The apoptotic index, an indicator of kidney damage, as well as histopathological changes were evaluated on renal tissues.. The apoptotic index, TOS, tumor necrosis factor-alpha, BUN, and urea levels were lower in the RIRI + oxerutin group than in the RIRI group (p<0.05). The results demonstrated that the histopathological and biochemical properties of oxerutin protected rats from RIRI.. The findings obtained in this study show that prophylactic administration of oxerutin has protective effects on apoptosis and renal failure caused by RIRI. Therefore, oxerutin can be used as an effective prophylactic agent in the treatment of RIRI.

Topics: Animals; Antioxidants; Apoptosis; Hydroxyethylrutoside; Kidney; Male; Rats; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha; Urea

Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. The VPA was administered to pregnant rats on

Topics: Animals; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Female; Humans; Hydroxyethylrutoside; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Social Behavior; Valproic Acid

Clinical application of doxorubicin (DOX) is restricted due to its cardiotoxicity, reinforcing the significance of exploring new strategies to counteract DOX-induced cardiotoxicity. The present work aimed to investigate the ameliorative impact of combination therapy with nicotinamide mononucleotide (NMN) and troxerutin (TXR) on DOX-induced cardiotoxicity, with mitochondrial function/biogenesis and inflammatory response approach.. Male Wistar rats (n = 30, 250-300 g) were divided into groups with/without DOX and/or NMN and TXR, alone or in combination. Rats underwent 6 consecutive intraperitoneal injections of DOX (cumulative dose: 12 mg/kg). NMN (100 mg/kg/day; intraperitoneally) and/or TXR (150 mg/kg/day; orally) were administered for 28 days before DOX challenge. Seven days following the last injection of DOX, evaluation of cardiac histopathological changes, BNP and LDH levels, mitochondrial function (membrane potential, ROS generation, and ATP levels), expression of proteins involved in mitochondrial biogenesis (PGC-1α, NRF1, and TFAM), and inflammatory cytokines (TNF-α, IL-1β, and IL-6) was performed.. Combination of NMN and TXR significantly decreased the severity of histopathological damages, and BNP and LDH levels (P < 0.01 to P < 0.001). It also restored mitochondrial functional endpoints, and expression of proteins involved in mitochondrial biogenesis (P < 0.05 to P < 0.001), and decreased inflammatory cytokines (P < 0.01 to P < 0.001). The positive impacts of this combination therapy were more potent as compared to monotherapies.. These findings shed new light on the understanding of additive properties of NMN/TXR combination therapy in protecting against DOX-induced cardiotoxicity. The cardioprotective effect of this combination therapy may be mediated in part through the restoration of mitochondrial function/biogenesis associated with the PGC-1α/NRF1/TFAM pathway, and suppression of inflammatory response.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiotoxicity; Cytokines; Doxorubicin; Hydroxyethylrutoside; Male; Nicotinamide Mononucleotide; Organelle Biogenesis; Oxidative Stress; Rats; Rats, Wistar

This study is intended to explore the anticancer, antiproliferative, and chemopreventive action of troxerutin (TX) in human non-small-cell lung cancer cell (A549) using BALB/c nude mice. 2 × 106 A549 cells were subcutaneously injected into mice, along with 10 μM and 20 μM/kg body weight of TX orally for 19 days. On the last day, tumor weight and volume were assessed. Stress marker enzymes such as Aryl hydrocarbon hydroxylase (AHH), lactate dehydrogenase (LDH), 5'Nucleotidase (5'ND), and γ-glutamyltranspeptidase (γ-GT) were estimated in the lung tissues. Cytotoxicity of TX was assessed using MTT assay. Expression of carcinoembryonic antigen (CEA) and inflammatory cytokines were also analyzed. Histopathological examination of tissue sections and immunohistochemical examination of proliferating cell nuclear antigen (PCNA) were also performed. mRNA expression of p53, p21, cyclin D1, P13k, Akt, and mTOR were analyzed using RT-PCR. TX administered orally in a dose-dependent manner markedly reverted the level of stress marker enzymes to a significant extent. TX also exhibited significant protection against lung cancer cells, as evidenced by cytotoxicity assay and histopathological studies. It was also found to reduce the expression of PCNA, cyclin D1, P13k, Akt, and mTOR, but increase the expression of p53 and p21. TX has also been shown to reduce cancer cell inflammation, as was evidenced by reduced expression of inflammatory cytokines. Thus TX could be used as an effective chemopreventive and anticancer agent in treating cancer.

Topics: A549 Cells; Animals; Antineoplastic Agents; Biomarkers; Carcinoma, Non-Small-Cell Lung; Cell Survival; Enzymes; Gene Expression Regulation, Neoplastic; Humans; Hydroxyethylrutoside; Lung Neoplasms; Male; Mice, Inbred BALB C; Xenograft Model Antitumor Assays

Inflammatory, oxidative stress, and endothelial dysfunction play a key role in the pathogenesis of long-term cardiovascular complications in patients with diabetes. The present observational prospective study is aimed at evaluating the effects of micronutrients and phytochemicals contained in the dietary supplement Flebotrofine® (AMNOL Chimica Biologica) on biochemical markers of inflammation, endothelial dysfunction, and glycemic control in patients with diabetes.. 105 type 1 or type 2 diabetes patients regularly took a daily dose of the dietary supplement Flebotrofine® for three consecutive months, and haematological and biochemical parameters were checked at baseline, after three months of treatment, and one month after its suspension. Statistical comparison of the laboratory parameters was performed using the two-tailed ANOVA test for repeated samples with a statistical significance level set at. The daily use of Flebotrofine® might be a valid supplement of arginine, the precursor of NO, and essential in the prevention of endothelial dysfunction. The regular intake of arginine and phytochemicals also improved the antioxidant and antithrombotic profile of enrolled patients. Therefore, Flebotrofine® could be a useful dietary supplement to prevent long-term complications in patients with diabetes.

Topics: Antioxidants; Apolipoprotein A-I; Apolipoprotein B-100; Arginine; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Supplements; Diosmin; Endothelium, Vascular; Female; Hesperidin; Humans; Hydroxyethylrutoside; Male; Middle Aged; Oxidative Stress; Pilot Projects; Prospective Studies

Cerebral ischemic reperfusion (I/R) infarction is mostly associated with serious brain injury, cognitive damage, and neurological deficits. The oxidative stress mechanisms in the neurological region lead to higher reactive oxygen species production followed by oxidative stress, inflammation of neurons, and death of brain cells. The current work aims to evaluate the effect of troxerutin (TXN) on cerebral injury stimulated by I/R-induced ischemic stroke and examines the mechanistic effect of TXN on neuroinflammation in the Sprague Dawley model. The experimental rats were randomized in to four groups: (i) sham control, (ii) I/R + vehicle, (iii) I/R + 10 mg/kg bw TXN, and (iv) I/R + 20 mg/kg bw TXN. In the TXN administration and control, groups were injected intraperitoneally 15 min before reperfusion and every day for 7 days, except the sham group. Orally administered TXN (10 and 20 mg/kg/bw) modulated the water content, lowered the infarct volume, and abrogated score defects of neuron and changes in the brain tissue sample. In our study, the TXN-stimulated cerebral injury exhibited leakage of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) of the neuronal sample of tissues and showed higher antioxidant enzymes superoxide dismutase, catalase, the oxidized form of glutathione peroxidase, and the reduced form of glutathione levels. This biochemical result was additionally proved by histopathological assessment. Changes were made in antioxidant and inflammatory markers expressions interleukin-6 (IL-6), IL-4, IL-10, vascular endothelial growth factor, and cerebral induced rats. The overall findings showed that TXN protected the brain tissues from neuroinflammatory oxidative stress by reducing cerebral injury in Sprague Dawley rats. Further, the messenger RNA expression of cerebral I/R-induced animal tissues down-regulated NLRP3, caspase-1, tumor necrosis factor-α, ASC, IL-1β, and Toll-like receptor 3 (TLR3). Therefore, the TXN action on TLR3 induced brain stroke is an excellent therapeutic approach for brain damage.

Topics: Animals; Anticoagulants; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hydroxyethylrutoside; Ischemia; Neuroinflammatory Diseases; Neurons; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Topics: Animals; Anticoagulants; Disease Models, Animal; Hydroxyethylrutoside; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Neurovascular Coupling; Rats; Rats, Sprague-Dawley

Troxerutin is a natural flavonoid present abundantly in tea, coffee, olives, wheat, and a variety of fruits and vegetables. Due to its diverse pharmacological properties, this flavonoid has aroused interest for treatment of various diseases, and consequently prompted investigation into its toxicological characteristics. The aim of this study was to evaluate the genotoxic and mutagenic effects and chemoprotective activity attributed to troxerutin using human peripheral blood leukocytes (PBLs) through several well-established experimental protocols based upon different parameters. Data demonstrated that troxerutin (100 to 1000 µM) induced no marked cytotoxic effect on PBLs after 24 hr, and did not produce strand breaks and mutagenicity. Regarding chemoprevention, this flavonoid attenuated cytotoxicity, genotoxicity, and mutagenicity initiated by hydrogen peroxide (H

Topics: Anticoagulants; Glutathione; Humans; Hydrogen Peroxide; Hydroxyethylrutoside; Leukocytes; Oxidants; Oxidative Stress; Protective Agents

Gestational hypertension is a high-risk disease for women, and the current treatments have limited efficacies. Here, we aimed to evaluate troxerutin, which is a natural monomer of flavone, in the treatment of gestational hypertension. Pregnant mice with or without pregnancy-induced hypertension (PIH) were treated with troxerutin (20 and 40 mg/kg) or vehicle. Blood pressure and proteinuria were monitored during treatment. The expression of vasodilation converting enzyme (VCE), angiotensin, TNFα, IL-6, IL-1β and IL-10 was measured by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by measuring the reactive oxygen species (ROS) levels and antioxidant enzyme concentrations. Western blot analysis was used to assess the expression of p-STAT3, STAT3, SHP-1, and RNF6. Troxerutin reduced blood pressure and the expression of VCE, angiotensin, urinary protein and pro-inflammatory cytokines in a dose-dependent manner while increasing the expression of anti-inflammatory cytokines. The levels of ROS were decreased, and the levels of antioxidant enzymes were increased. Troxerutin treatment significantly suppressed STAT3/RNF6 signaling. Overexpression of RNF6 attenuated the effects of troxerutin in ameliorating inflammation and oxidative stress. Our data support the use of troxerutin for reducing gestational hypertension due to the role of troxerutin in reducing inflammation and oxidative stress.

Topics: Animals; Female; Flavonoids; Hydroxyethylrutoside; Hypertension, Pregnancy-Induced; Mice; Pregnancy; Signal Transduction; STAT3 Transcription Factor

Troxerutin (Tx), known as vitamin P

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Catalase; Cytokines; Hydroxyethylrutoside; Inflammation Mediators; Lipopolysaccharides; Liver; Male; Malondialdehyde; Mice; Peroxidase; Sepsis; Superoxide Dismutase

Screening potential compounds for improving ulcerative colitis (UC) from clinical medication is an effective strategy for drug repurposing. We applied bioinformatics and network pharmacology to the drug screening process in this study, which helped us to screen out troxerutin that could improve UC. Troxerutin belongs to flavonoids and is used clinically as an anticoagulant and thrombolytic agent. This study found a new pharmacological activity of troxerutin, that is, it had a significant improvement effect on UC in mice. Experimental results of

Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Hydroxyethylrutoside; Inflammation; Mice

Topics: AMP-Activated Protein Kinases; Animals; Anticoagulants; Cardiomegaly; Hydroxyethylrutoside; Isoproterenol; Rats; TOR Serine-Threonine Kinases

Topics: Anticoagulants; Enzyme Stability; Humans; Hydroxyethylrutoside; Protein Aggregates; Protein Aggregation, Pathological; Protein Multimerization; Rutin; Superoxide Dismutase-1

Unilateral ureteral obstruction (UUO) induces renal injury and troxerutin attenuates the inflammatory parameters and decreases oxidative stress. Accordingly, this study explored the renoprotective effect of troxerutin in UUO-induced renal oxidative stress, inflammation, and apoptosis in male Wistar rats. Animals were randomly separated into five groups (n = 8): control, UUO, and three UUO groups treated with troxerutin (1, 10, and 100 mg/kg). UUO-induced and vehicle/troxerutin administration was continued for 3 days. Then serum creatinine, mean arterial pressure (MAP), renal perfusion pressure (RPP), renal vascular resistance (RVR), and renal blood flow (RBF) were measured. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels as some oxidative stress parameters were measured in the left kidney. The immunoblotting method was applied to evaluate the cleaved caspase-3 Bax, Bcl-2, and TNF-α proteins level. The hematoxylin and eosin method was used to assess the kidney tissue damage score (KTDS). In 3 days, UUO significantly increased serum creatinine level, KTDS, RVR, MDA, Bax, cleaved caspase-3, and TNF-α protein levels (p < 0.05); and decreased RBF, TAC, SOD, catalase, GPx activity levels and Bcl-2 protein expression level in the left kidney (p < 0.05). Troxerutin (100 mg/kg) significantly attenuates the indicators alteration induced by UUO. Our findings represented that the renoprotective effect of troxerutin may be related to its anti-oxidative stress, anti-inflammation, anti-apoptosis, and RBF improver properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Disease Models, Animal; Hemodynamics; Hydroxyethylrutoside; Inflammation Mediators; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Rats, Wistar; Renal Circulation; Signal Transduction; Tumor Necrosis Factor-alpha; Ureteral Obstruction

Because of limitation of doxorubicin (DOX) clinical application in chemotherapy due to its cardiotoxicity, finding new strategies to reduce DOX challenge and improve patients' outcomes is crucial. Due to positive cardiovascular impacts of troxerutin (TXR), here we have investigated the effect of TXR on DOX-induced cardiotoxicity by evaluating the myocardial oxidative stress and expression of genes regulating mitochondrial biogenesis. Male Wistar rats (250-300 g) were randomly allocated into four groups: control, TXR, DOX, and TXR + DOX. Troxerutin (150 mg/kg) was orally administrated once a day through a gavage tube for 4 weeks before DOX challenge. The TXR-treated and time-matched control rats received intraperitoneal injection of DOX (20 mg/kg). Three days after DOX challenge, the left ventricular samples were obtained to determine the expression of genes regulating mitochondrial biogenesis via real-time PCR. Myocardial creatine kinase (CK-mB), oxidative stress markers, and mitochondrial function (generation of reactive oxygen species or ROS and ATP levels) were also evaluated using commercial kits and spectrophotometric and fluorometric methods. DOX administration significantly increased the levels of CK-mB, malondialdehyde (MDA), and mitochondrial ROS levels, while reduced the cellular ATP production and expression levels of SIRT-1, PGC-1α, and NRF-2 as well as superoxide dismutase, glutathione peroxidase, and catalase activity in comparison to control group (P < 0.05 to P < 0.01). Pretreatment of DOX-received rats with TXR significantly upregulated the expression of all biogenesis genes and antioxidant enzymes with non-significant effect on catalase activity, and significantly reduced CK-mB and MDA levels toward control values (P < 0.05 to P < 0.01). Mitochondrial ROS and ATP levels were also restored significantly by pretreatment with TXR (P < 0.05). The data suggested that preconditioning of rats with TXR had protective effect on DOX-induced cardiotoxicity through inducing antioxidative properties and restoring the mitochondrial function and the expression profiles of myocardial SIRT-1/PGC-1α/NRF-2 network.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Cardiotonic Agents; Cardiotoxicity; Doxorubicin; Gene Expression Regulation; Hydroxyethylrutoside; Male; Mitochondria; Organelle Biogenesis; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species

Troxerutin, a natural flavonoid guards against oxidative stress and apoptosis with a high capability of passing through the blood-brain barrier. Our aim was to investigate the role of troxerutin in experimentally induced retinal neurodegeneration by modulating the interferon-gamma (IFNγ)-extracellular signal-regulated kinases 1/2 (ERK1/2)-CCAAT enhancer-binding protein β (C/EBP-β) signaling pathway. Three groups of rats (10 each group) were included. Group I (control group), group II (rotenone treated group): the rats were injected subcutaneously with a single rotenone dosage of 3 mg/kg repeated every 48 hours for 60 days to trigger retinal neurodegeneration. Group III (troxerutin-treated group): rats received troxerutin (150 mg/kg/day) by oral gavage 1 hour before rotenone administration. A real-time polymerase chain reaction technique was applied to measure messenger RNA (mRNA) levels of retinal C/EBP-β. Enzyme-linked immunosorbent assay technique was utilized to assay tumor necrosis factor-α (TNF-α), IFNγ, and ERK1/2 levels. Finally, reactive oxygen species (ROS), as well as carbonylated protein (CP) levels, were assessed spectrophotometrically. Improved retinal neurodegeneration by downregulation of C/EBP-β mRNA gene expression, also caused a significant reduction of TNF-α, IFNγ, ERK1/2 as well as ROS and CP levels compared with the diseased group. These findings could hold promise for the usage of troxerutin as a protective agent against rotenone-induced retinal neurodegeneration.

Topics: Animals; CCAAT-Enhancer-Binding Protein-beta; Disease Models, Animal; Down-Regulation; Gene Expression; Hydroxyethylrutoside; Interferon-gamma; Male; MAP Kinase Signaling System; Neurodegenerative Diseases; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Retinal Diseases; RNA, Messenger; Rotenone; Tumor Necrosis Factor-alpha

Diabetes‑associated cognitive decline is a recently identified a potential complication of diabetes. The present study was designed to examine the effects of troxerutin, a potent antioxidant, on cognitive function in rats with streptozotocin‑induced diabetes and to further explore the potential underlying mechanisms. Cognitive functions were investigated by the Morris water maze test. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in the hippocampus were assessed as the parameters of oxidative stress. Subunits of the NADPH oxidase (NOX) expression and nuclear factor erythroid 2‑related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathway were detected to explore the potential underlying mechanisms. The water maze test revealed that troxerutin significantly improved cognitive impairment in diabetic rats. Troxerutin treatment attenuated oxidative stress in the hippocampus of diabetic rats, as evidenced by the decreased MDA level and the increased SOD activity. Moreover, troxerutin activated the Nrf2/ARE signaling pathway via Nrf2 nuclear translocation in the cells in the hippocampus of diabetic rats. Troxerutin elevated the expression levels of the antioxidant enzymes, heme oxygenase‑1 (HO‑1) and NAD(P)H:quinone oxidoreductase (NQO1), and decreased the expression levels of the NOX subunits, gp91phox, p47phox and p22phox. On the whole, these findings demonstrate that troxerutin exerts neuroprotective effects against diabetes‑associated cognitive decline by suppressing oxidative stress in the hippocampus of rats with streptozotocin‑induced diabetes. Troxerutin may thus prove to be a potential therapeutic medicine for the treatment of diabetes‑associated cognitive decline.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Hippocampus; Hydroxyethylrutoside; Male; Malondialdehyde; Maze Learning; NADPH Oxidases; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction

The vast majority of type 1 diabetes leads to a higher prevalence of reproductive system's impairments. Troxerutin has attracted much attention owing to its favorable properties, including antihyperglycemic, anti-inflammatory, and antiapoptotic effects. This investigation was proposed to evaluate whether pretreatment with troxerutin could prevent apoptosis-induced testicular disorders in prepubertal diabetic rats.. Fifty prepubertal male Wistar rats were randomly allocated into five groups: control (C), troxerutin (TX), diabetic (D), diabetic+troxerutin (DTX), and diabetic+insulin (DI). Diabetes was induced by 55 mg/kg of streptozotocin applied intraperitoneally. In TX and DTX groups, 150 mg/kg troxerutin was administered by oral gavage. Diabetic rats in DI group received 2-4 U NPH insulin subcutaneously. Troxerutin and insulin treatments were begun immediately on the day of diabetes confirmation. After 30 days, the testicular lipid peroxidation and antioxidant activity, apoptosis process, and stereology as well as serum glucose and insulin levels were assessed.. The results showed that diabetes caused a significant increase in the blood glucose, the number of TUNEL positive cells and tubules, and the malondialdehyde level as well as a significant decrease in serum insulin level compared to controls. The stereological analysis also revealed various alterations in diabetic rats compared to controls. Troxerutin treatment improved these alterations compared to the diabetic group.. Troxerutin-pretreatment may play an essential role in the management of the type-1 diabetes-induced testicular disorders by decreasing blood glucose and modulating apoptosis.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Hydroxyethylrutoside; Hypoglycemic Agents; Insulin; Male; Oxidative Stress; Rats; Rats, Wistar; Sexual Maturation; Testicular Diseases

Myocardial ischemia‑reperfusion (MI/R) injury is a complex pathological process that occurs when tissues are reperfused following a prolonged period of ischemia. Troxerutin has been reported to have cardioprotective functions. However, the underlying mechanism by which troxerutin protects against MI/R injury has not been fully elucidated. The aim of the present study was to explore whether troxerutin‑mediated protection against oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced H9C2 cell injury was associated with the inhibition of oxidative stress and the inflammatory response by regulating the PI3K/AKT/hypoxia‑inducible factor‑1α (HIF‑1α) signaling pathway. The results of the present study suggested that troxerutin pretreatment prevented the OGD/R‑induced reduction in cell viability, and the increase in lactate dehydrogenase activity and apoptosis. Troxerutin reversed OGD/R‑induced the inhibition of the PI3K/AKT/HIF‑1α signaling pathway as demonstrated by the increased expression of PI3K and HIF‑1α, and the increased ratio of phosphorylated AKT/AKT. LY294002, a selective PI3K inhibitor, inhibited the PI3K/AKT/HIF‑1α signaling pathway and further attenuated the protective effect of troxerutin against OGD/R‑induced H9C2 cell damage. Furthermore, small interfering (si)RNA‑mediated knockdown of HIF‑1α reduced troxerutin‑induced protection against OGD/R injury. Troxerutin pretreatment alleviated OGD/R‑induced oxidative stress, as demonstrated by the reduced generation of reactive oxygen species and malonaldehyde content, and the increased activities of superoxide dismutase and glutathione peroxidase, which were reduced by HIF‑1α‑siRNA. Troxerutin‑induced decreases in the levels of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α in OGD/R conditions were also reduced by HIF‑1α‑siRNA. The results from the present study indicated that troxerutin aggravated OGD/R‑induced H9C2 cell injury by inhibiting oxidative stress and the inflammatory response. The primary underlying protective mechanism of troxerutin was mediated by the activation of the PI3K/AKT/HIF‑1α signaling pathway.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Line; Cell Survival; Hydroxyethylrutoside; Hypoxia-Inducible Factor 1, alpha Subunit; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction

Obesity is a chronic low-grade inflammatory state associated with immune cell infiltration into the adipose tissue (AT). We hypothesize that the anti-obesity and anti-inflammatory effects of troxerutin (TX) are mediated through inhibition of elastase.. To determine the inhibitory effect of TX on elastase. Differentiated 3T3-L1 adipocytes were pretreated with TX, elastatinal (ELAS) or sodium salicylate (SAL) before exposure to TNFα. Lipid accumulation, reactive oxygen species (ROS) generation and oxidant-antioxidant balance were examined. The mRNA and protein expression of TNFα, interleukin-6, monocyte chemoattractant protein-1, adiponectin, leptin, resistin, chemerin, and elastase were analyzed. Elastase inhibition by TX and ELAS in a cell free system and docking studies for HNE with TX and ELAS were performed.. TX, ELAS or SAL pretreatment had lowered lipid droplets formation and TG content. TX suppressed ROS generation, oxidative stress and improved antioxidant status. The expression of inflammatory cytokines and elastase was downregulated while that of adiponectin was upregulated by TX. The concentration required to produce 50% inhibition. TNFα induces inflammation of 3T3-L1 cells through elastase activation. TX inhibits elastase activity, downregulates expression and binds with elastase.. The antioxidant and anti-inflammatory activities of TX in AT could be of relevance in the management of obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Cytokines; Hydroxyethylrutoside; Inflammation; Leukocyte Elastase; Lipid Metabolism; Mice; Obesity; Oxidative Stress; Reactive Oxygen Species; Serine Proteinase Inhibitors

Troxerutin (TRX) is a water-soluble flavonoid which occurs commonly in the edible plants. Recent studies state that TRX improves the functionality of the nervous system and neutralizes Amyloid-ß induced neuronal toxicity. In this study, an in vitro assay based upon Neural stem cell (NSCs) isolated from the subventricular zone of the postnatal balb/c mice was established to explore the impact of TRX on individual neurogenesis processes in general and neuroprotective effect against ß-amyloid 1-42 (Aß42) induced inhibition in differentiation in particular. NSCs were identified exploiting immunostaining of the NSCs markers. Neurosphere clonogenic assay and BrdU/Ki67 immunostaining were employed to unravel the impact of TRX on proliferation. Differentiation experiments were carried out for a time span lasting from 48 h to 7 days utilizing ß-tubulin III and GFAP as neuronal and astrocyte marker respectively. Protective effects of TRX on Aß42 induced depression of NSCs differentiation were determined after 48 h of application. A neurosphere migration assay was carried out for 24 h in the presence and absence of TRX. Interestingly, TRX enhanced neuronal differentiation of NSCs in a dose-dependent manner after 48 h and 7 days of incubation and significantly enhanced neurite growth. A higher concentration of TRX also neutralized the inhibitory effects of Aß42 on neurite outgrowth and length after 48 h of incubation. TRX significantly stimulated cell migration. Overall, TRX not only promoted NSCs differentiation and migration but also neutralized the inhibitory effects of Aß42 on NSCs. TRX, therefore, offers an interesting lead structure from the perspective of drug design especially to promote neurogenesis in neurological disorders i.e. Alzheimer's disease.

Topics: Amyloid beta-Protein Precursor; Animals; Astrocytes; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Flavonoids; Hydroxyethylrutoside; Lateral Ventricles; Male; Mice; Mice, Inbred BALB C; Neural Stem Cells; Neurites; Neurogenesis; Neuronal Outgrowth; Neurons; Neuroprotection; Neuroprotective Agents

The exact pathogenesis of polycystic ovary syndrome (PCOS), the most common neuroendocrine disorder in women of reproductive age, has not been fully elucidated. Recent studies suggested that chronic inflammation and neurotransmitter disorder involved in the progress of PCOS. Troxerutin, a natural flavonoid, was reported to possess neuroprotective effect in several disease models by inhibiting inflammation or enhancing neurotrophic factor. In this study, we investigated the possible protective effect and mechanism of troxerutin in a dihydrotestosterone (DHT)-induced rat model of PCOS. The PCOS rat models were treated with troxerutin at a dose of 150 mg/kg or 300 mg/kg for up to 4 weeks. Results showed that 300 mg/kg troxerutin significantly decreased the body weight gain and improved the pathological changes of ovary induced by DHT. Meanwhile, the elevated gonadotrophin-releasing hormone (GnRH), gonadotrophin and testosterone in the serum of PCOS rats were reduced with the treatment of troxerutin. The expression of kisspeptin and NKB in arcuate nucleus and their receptors kiss1r and NK3r in GnRH positive neurons of median eminence were markedly decreased in troxerutin-treated rats. Of note, the GnRH inhibitory regulator GABA and stimulatory regulator glutamate were also restored to the normal level by troxerutin. The present study indicated that troxerutin may exhibit a protective effect in PCOS rat model via regulating neurotransmitter release.

Topics: Animals; Body Weight; Dihydrotestosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gene Expression Regulation; Gene Regulatory Networks; Gonadotropin-Releasing Hormone; Gonadotropins; Hydroxyethylrutoside; Polycystic Ovary Syndrome; Rats; Testosterone

Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome-the Hereditary Hypertriglyceridaemic rats (HHTg).. Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks).. Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01).. Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.

Topics: Animals; Disease Models, Animal; Glucose; Glycogen; Hydroxyethylrutoside; Hypolipidemic Agents; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Muscle, Skeletal; Oxidative Stress; Rats; Rats, Inbred Strains; Real-Time Polymerase Chain Reaction; Transcriptome

This study aimed at investigating the metabolic and behavioural effects of troxerutin treatment in the offspring of high fat diet (HFD) fed dams. Female Wistar rats (n = 40) received normal diet (ND) or HFD for 8 weeks prior to breeding. After mating, pregnant animals were assigned to four subgroups: ND, ND + Tro (troxerutin 150 mg/kg/day), HFD, and HFD + Tro. On the 21st day, male offspring were weaned and fed ND until 12 weeks old. Behavioural tests were performed on postnatal day (PND) 80 and 90. Compared to the controls, the HFD offspring showed more anxiety- and depressive-like behaviours, higher blood glucose, cholesterol, and cortisol levels. On the other hand, chronic troxerutin administration during gestation restored metabolic and behavioural changes to normal. In summary, troxerutin improved anxiety- and depressive-like behaviours, as well as metabolic status in the offspring of the HFD fed dams. More studies are needed to determine the underlying mechanisms.

Topics: Animals; Anxiety; Behavior, Animal; Blood Glucose; Cholesterol; Depression; Diet, High-Fat; Female; Hydroxyethylrutoside; Lactation; Male; Phenotype; Pregnancy; Rats; Rats, Wistar

Cisplatin (CP) is a synthetic and anticancer drug, and one of the major side effects of CP is nephrotoxicity. This study was done to evaluate the renoprotective effects of troxerutin (Tro) in nephrotoxicity induced by CP in male mice.. In this experimental study, 28 male mice were divided randomly into four groups. Mice were treated with CP (20 mg/kg, i.p.) then Tro (75 and 150 mg/kg/day, po) was administered for three consecutive days. Blood samples were collected to determine serum creatinine (Cr) and blood urea nitrogen (BUN) levels. The kidney tissues were used for histological examination and biochemical assays. Malondialdehyde (MDA) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were assessed in renal tissue.. Results showed a significant increase in the Cr, BUN and MDA levels and a significant decrease in the renal SOD and GPx activity by CP administration. Treatment with Tro for three consecutive days attenuated these changes. Also, the renoprotective effect of the Tro was confirmed by the histological examination of the kidneys.. Our results demonstrated that Tro has protective effects against CP-induced nephrotoxicity through improving the biochemical indices and the oxidative stress parameters.

Topics: Acute Kidney Injury; Animals; Anticoagulants; Antineoplastic Agents; Biomarkers; Cisplatin; Disease Models, Animal; Hydroxyethylrutoside; Male; Mice; Oxidative Stress

Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in-depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA-induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up-regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin-induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin-induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA-induced nephrosis and associated systemic energy metabolism disorders.-Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.

Topics: Adipose Tissue, Brown; Animals; CLC-2 Chloride Channels; Energy Metabolism; Hydroxyethylrutoside; Inflammation; Kidney; Lipid Metabolism; Male; Mice; Mice, Inbred ICR; Ochratoxins; Respiration

Troxerutin (TX), a bioflavonoid widely present in various fruits and vegetables, has shown to exhibit numerous pharmacological properties including anti-neoplastic and anti-cancer activities. Nrf2 and NF-κB are the key transcription factors that regulate oxidative stress and inflammation, therefore we assessed whether TX modulate these pathways and its downstream proteins in HuH-7 hepatocarcinoma cells. TX induced apoptotic cellular and nuclear changes were examined by fluorescence staining techniques, agarose gel electrophoresis and flow cytometry. Oxidative stress was determined through biochemical analysis of antioxidant enzymes and lipid peroxidation profile. The protein expressions of NF-κB and Nrf2 pathway regulators, cell proliferation markers and apoptotic pathway mediators were evaluated by performing immunoblotting, immunocytochemistry and molecular docking. Our results revealed that TX inhibits the growth of HuH-7 cells in a concentration and time-dependent manner. TX treated HuH-7 cells exhibited increased heme oxygenase (HO)-1 protein expression, augmented nuclear translocation of Nrf2, and reduced oxidative stress. Furthermore, TX suppressed the expression of IKKβ which subsequently inhibited the nuclear translocation of NF-κB (p65 subunit), and thus downregulated NF-κB mediated inflammatory responses, proliferation and cell survival. Collectively, our results indicate that TX exerts anti-cancer effect in HuH-7 hepatocarcinoma cells possibly through simultaneous regulation of the molecular signalling pathways, Nrf2 and NF-κB.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Hydroxyethylrutoside; Liver Neoplasms; NF-E2-Related Factor 2; NF-kappa B; Signal Transduction

The aim of the current study was to investigate the effects and the underlying mechanisms of troxerutin on myocardial cell apoptosis during ischemia-reperfusion (I/R) injury. Hypoxia/reoxygenation (H/R) model in neonatal rat cardiomyocytes, and I/R model in rats, were established following troxerutin preconditioning. The quantitative real-time polymerase chain reaction analysis was performed to examine the messenger RNA miR-146a-5p expression in cardiomyocytes and myocardial tissues. Hemodynamic parameters and serum creatine kinase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-10 were evaluated. Infarct size was examined by 2,3,5-triphenyltetrazolium chloride staining. Besides, myocardial apoptosis was detected by terminal deoxynucleotidyl transferase (dUTP) nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the protein levels of caspase-3, Bax, and Bcl-2. The results showed that, troxerutin decreased rat cardiomyocyte apoptosis during H/R injury. Furthermore, the antiapoptotic effect of troxerutin against I/R injury was mediated by miR-146a-5p downregulation. In vivo experiments suggested that troxerutin alleviated myocardial I/R injury in rats via inhibition of miR-146a-5p. In conclusion, troxerutin exerted cardioprotective effects during I/R injury by downregulating miR-146a-5p.

Topics: Animals; Animals, Newborn; Apoptosis; Down-Regulation; Gene Expression Regulation; Hemodynamics; Hydroxyethylrutoside; Male; MicroRNAs; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar

Topics: Animals; Antioxidants; Blood Pressure; Hydroxyethylrutoside; Lipid Metabolism; Lipid Peroxidation; Male; Oxidative Stress; Rats, Wistar

It's difficult to diagnose and treat synovitis-acne-pustulosis-hyperostosis-osteomyelitis (SAPHO) syndrome due to its rare and unknown pathogenesis. There is no effective treatment for SAPHO syndrome and the consequences of empirical treatment are unpredictable. This study reports a case of a young female diagnosed as SAPHO syndrome with pathological fractures of vertebral bodies.. A 29-year-old female complained of the right sternoclavicular joint and back pain accompanied limited activities and cutaneous lesions. Laboratory assays revealed abnormal inflammatory factors. Multiple imaging studies illustrated bone lesions and pathological fractures of vertebral bodies. A diagnosis of SAPHO syndrome was made. The patient was treated with Compound Troxerutin and Poreine Cerebroside Injection, non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, corticosteroids and the thoracolumbar brace. The patient was followed up for 6 months and showed improved results.. The case supports that multiple image inspections and laboratory tests contribute to diagnose SAPHO syndrome, and combination therapies of Compound Troxerutin and Poreine Cerebroside Injection, NSAIDs, bisphosphonates, corticosteroids and the thoracolumbar brace in the treatment of SAPHO syndrome with pathological fractures of vertebral bodies are crucial to regain health.

Topics: Acquired Hyperostosis Syndrome; Adult; Anti-Inflammatory Agents, Non-Steroidal; Braces; Female; Fractures, Spontaneous; Humans; Hydroxyethylrutoside; Spinal Fractures; Spine

The mycotoxin citrinin is often produced during fermentation of Monascus products. We studied the effects of flavonoids on citrinin production by Monascus aurantiacus Li AS3.4384 (MALA) by adding rutin, α-glucosylrutin, or troxerutin to the fermentation medium, in a first-of-its-kind study. Appropriate amounts of rutin, α-glucosylrutin, or troxerutin did not affect normal mycelial growth. Addition of 5.0 g/l of rutin only weakly reduced (29.2%) citrinin production, relative to inhibition by 5 g/l α-glucosylrutin or troxerutin (by 54.7% and 40.6%, respectively). In starch inorganic liquid culture media, addition of 20.0 g/l of troxerutin, followed by fermentation for 12 days, reduced citrinin yield by 75.26%. Addition of 15.0 g/l of troxerutin to low-starch peptone liquid fermentation media reduced citrinin yield by 87.9% after 14 days of fermentation, and addition of 30.0 g/l troxerutin to yeast extract sucrose liquid media for 12 days reduced citrinin yield by 53.7%.

Topics: Citrinin; Culture Media; Fermentation; Hydroxyethylrutoside; Monascus; Rutin; Trisaccharides

Brain ischemia, including cerebral ischemia and cerebrovascular ischemia, leads to poor oxygen supply or cerebral hypoxia, and causes brain tissue death or cerebral infarction/ischemic stroke. The troxerutin and cerebroprotein hydrolysate injection (TCHI), is widely applied in China to improve blood supply in ischemic brain tissues and to enhance neuroprotective effects in clinical practice. However, the benefits and detailed underlying mechanism elaborating the effectiveness of TCHI in cerebrovascular diseases require further investigation. Therefore, in the present study, experimental in vivo and in vitro models were employed to investigate the potential mechanisms of TCHI on cerebral ischemic injury. The results demonstrated that TCHI increased the lactate dehydrogenase levels in the brain homogenate and conversely decreased lactic acid levels. TCHI was further observed to significantly increase superoxide dismutase activity and decrease malondialdehyde levels in ischemic brain tissues. In addition, TCHI significantly induced vascular maturation processes, including proliferation, adhesion, migration and tube formation in cultured human umbilical vein endothelial cells. Additionally, TCHI significantly stimulated microvessel formation in the rat aortic ring and chick chorioallantoic membrane assays. Taken together, these results provided strong evidence that TCHI stimulated angiogenesis at multiple steps, and indicated that TCHI attenuated cerebral ischemic damage through the amelioration of oxidative stress and promotion of angiogenesis.

Topics: Animals; Anticoagulants; Biomarkers; Brain Ischemia; Cell Adhesion; Cell Movement; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Hydroxyethylrutoside; Male; Neovascularization, Pathologic; Neuroprotective Agents; Oxidative Stress; Rats; Reactive Oxygen Species

Troxerutin (TRX), a naturally occurring flavonoid in various fruits, has been reported to exhibit numerous pharmacological and biological activities in vitro and in vivo. However, the molecular mechanisms underlying TRX as a treatment for disease are poorly understood.. Using pharmacophore mapping and inverse docking, a set of potential TRX target proteins that have been associated with multiple forms of diseases was obtained. Bioinformatic analyses were performed using the Enrichr and STRING servers to analyse the related biological processes and protein-protein networks. Furthermore, we investigated the potential protective effect of TRX against lipopolysaccharide-induced acute lung injury (ALI) using a mouse model. Morphological changes in the lungs were assessed using haematoxylin and eosin staining. Inflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-10 were investigated using ELISA. Activation of MAPK and NF-κB was detected using western blotting.. Our network pharmacology analysis revealed the existence of multiple TRX-related chemical-target interactions and the related biological processes. We found that pretreatment with TRX protected against histological changes and obviously regulated the inflammatory cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid. Based on bioinformatic and western blot analyses, TRX may exert a protective effect against ALI by inhibiting MAPK and NF-κB signalling.. TRX can ameliorate pulmonary injury by inhibiting the MAPK and NF-κB signalling pathways and has a potential protective effect against ALI. This study may be helpful for understanding the mechanisms underlying TRX action and for discovering new drugs from plants for the treatment of ALI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Computer Simulation; Cytokines; Drug Evaluation, Preclinical; Gene Ontology; Hydroxyethylrutoside; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice, Inbred BALB C; Molecular Targeted Therapy; NF-kappa B; Phytotherapy; Plant Extracts; Pulmonary Edema

This study was conducted to clarify the potential mechanisms of Troxerutin neuroprotection against Lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting the SIRT1/SIRT3 signaling pathway. To establish a model, a single dose of LPS (500μg/kg body weight) was injected to male Wistar rats intraperitoneally. Troxerutin (100 mg/kg body weight) was injected intraperitoneally for 5 days after induction of the model. Cognitive and behavioral evaluations were performed using Y-maze, single-trial passive avoidance, and novel object recognition tests. The expression of inflammatory mediators, SIRT1/SIRT3, and P53 was measured using the ELISA assay. Likewise, the expression levels of SIRT1/SIRT3 and NF-κB were determined using Western blot assay. Brain acetyl-cholinesterase activity was determined by utilizing the method of Ellman. Reactive oxygen species (ROS) was detected using Fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA). Furthermore, malondialdehyde (MDA) levels were determined. A single intraperitoneal injection of LPS was led to ROS production, acute neuroinflammation, apoptotic cell death, and inactivation of the SIRT1/SIRT3 signaling pathway. Likewise, ELISA assay demonstrated that post-treatment with Troxerutin considerably suppressed LPS-induced acute neuroinflammation, oxidative stress, apoptosis and subsequently memory impairments by targeting SIRT1/SIRT3 signaling pathway. Western blot assay confirmed ELISA results about SIRT1/SIRT3 and NF-κB proteins. These results suggest that Troxerutin can be a suitable candidate to treat neuroinflammation caused by neurodegenerative disorders.

Topics: Animals; Avoidance Learning; Behavior, Animal; Hippocampus; Hydroxyethylrutoside; Inflammation; Lipopolysaccharides; Male; Malondialdehyde; Maze Learning; Neuroprotective Agents; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Sirtuin 1; Sirtuin 3

As a chronic degenerative joint disease, osteoarthritis (OA) is clinically characterized by a high incidence, long-term pain, and limited joint activity but without effective preventative therapy. Troxerutin (Tx) is a natural flavonoid, also called vitamin P4, which is widely present in plants consumed as part of our daily diet, such as cereals, various fruits and vegetables, tea, and coffee, and possesses various biological activities, especially an anti-inflammatory effect. Here, we aimed to investigate the potential chondroprotection of Tx in experimental OA development. In in vitro studies, human chondrocytes were isolated and exposed in advanced glycation end-products (AGEs) to simulate OA development. It was found that Tx pretreatment inhibited the AGE-induced production of pro-inflammatory factors in chondrocytes, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Meanwhile, AGE-medicated extracellular matrix (ECM) degradation was decreased in Tx-pretreated chondrocytes. Furthermore, we found that Tx pretreatment suppressed the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in AGE-exposed chondrocytes. In vivo, Tx treatment prevented the narrowing of the joint space, the calcification of cartilage, and the loss of proteoglycans in the mouse OA model. In brief, Tx is considered as a potential therapeutic agent for OA.

Topics: Animals; Anti-Inflammatory Agents; Chondrocytes; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Glycation End Products, Advanced; Humans; Hydroxyethylrutoside; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis; Tumor Necrosis Factor-alpha

Troxerutin (TXER) a rutin derivative is known for its anticancer effect against hepatocellular carcinoma (HCC). As part of large study, recently we have shown TXER interact with genetic material and its anti-mutagenic property. In the present study we have explored its possible mode of action in HCC. Since TXER alone did not show significant anticancer effect on Huh-7 cells, in vitro biochemical assays were performed for determining anticancer efficacy of TXER + metal complex using transition metals such as Cu, Zn, and Fe. The anticancer efficacy of TXER + Cu on Huh-7 cells were evaluated using MTT assay, DCFDA, JC-1 staining, comet assay, cell cycle analysis, immunocytochemistry, and Western blotting. Non-toxic nature of TXER was analyzed on primary rat hepatocytes. The in vivo efficacy of TXER was tested in N-nitrosodiethylamine initiated and γ-benzene hexachloride and partial hepatectomy promoted rat liver cancer. Liver markers, transition metal levels, histopathological examination, and expression levels of GST-P, 8-OHdG and Ki-67 were studied to assess the in vivo anticancer effect of TXER. We observed that TXER + Cu induced extensive cellular death on Huh-7 cells through generating free radicals and did not possess any toxic effect on normal hepatocytes. The in vivo studies revealed that TXER possess significant anti-cancer effect as assessed through improved liver markers and suppressed GST-P, 8-OHdG, and Ki-67 expression. TXER treatment reduced the hepatic Cu level in cancer bearing animals. Current study brings the putative mechanism involved in anti-cancer effect of TXER, further it will help to formulate phytoconstituents coupled anti-cancer drug for effective treatment of HCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Catalase; Cell Line, Tumor; Coordination Complexes; Copper; Deoxyguanosine; DNA Damage; Glutathione S-Transferase pi; Humans; Hydroxyethylrutoside; Ki-67 Antigen; Liver; Liver Neoplasms; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides

Troxerutin (TRX) is a mixture of semisynthetic hydroxyethylrutosides (Hers) arising from hydroxyethylation of rutin, a natural occurring flavonoid. TRX is commonly used for its anti-oxidant and anti-inflammatory properties in chronic venous insufficiency and other vascular disorders. In recent studies, the protective effects of TRX in Alzheimer's disease, colon carcinogenesis and hepatocellular carcinoma are emerged. However, the chemical stability of TRX has never been studied. Hence, the aims of the work were to study the TRX chemical stability through a forced degradation study and to develop and validate a new stability indicating LC-UV method for determination of TRX. In order to perform the study, TRX stability was tested in various stress conditions analysing the degradation samples by LC-MS. Three degradation products (DPs; D1, D2 and D3, 3',4',7-Tri-O-(β-hydroxyethyl)quercetin, 3',4',5,7-Tetra-O-(β-hydroxyethyl)quercetin and 3',4'-Di-O-(β-hydroxyethyl)quercetin respectively) arising from degradation in acidic conditions were identified and synthesized: among them, D1 resulted the stability indicator for hydrolytic degradation. Furthermore, a stability-indicating LC-UV method for simultaneous determination of triHer (3',4',7-Tri-O-(β-hydroxyethyl)rutin, the principal component of the mixture) and D1 was developed and validated. The LC-UV method consisted in a gradient elution on a Phenomenex Kinetex EVO C18 (150 × 3 mm, 5 μm) with acetonitrile and ammonium bicarbonate buffer (10 mM, pH 9.2). The method was linear for triHer (20-60 μg mL

Topics: Calibration; Chromatography, High Pressure Liquid; Drug Contamination; Drug Stability; Hydroxyethylrutoside; Limit of Detection; Linear Models; Molecular Structure; Reference Standards; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Technology, Pharmaceutical

Medicinal plants are increasingly used in the treatment of cardiovascular diseases due to their multifaceted properties. This study was designed to investigate anti-arrhythmic and anti-inflammatory potentials of the natural bioflavonoid, troxerutin (TXR) in myocardial ischemia/reperfusion (I/R) injury in diabetic rats.. Male Wistar rats were randomly divided into 4 groups (control, control + TXR [150 mg/kg, daily], diabetic, and diabetic + TXR). Type-1 diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg) and lasted for 10 weeks. After mounting on the Langendorff apparatus, isolated hearts in all groups received a normal Krebs-Henseleit solution for 20 min of stabilization period, followed by 30 min of regional ischemia through ligation of the left anterior descending coronary artery, and 60 min of full reperfusion. During the experiment, the electrocardiograms were recorded and the arrhythmias [number, duration and incidence of premature ventricular complexes (PVC), ventricular tachycardia (VT), ventricular fibrillation (VF), and arrhythmia score] during I/R phases were assessed based on the Lambeth Convention. Ischemic left ventricular samples were used to determine the activities of lactate dehydrogenase (LDH), interleukin-1beta (IL-1β), and tumor necrosis factor (TNF-α).. The arrhythmias induced by I/R were not significantly changed in diabetic group as compared to the control group. However, pretreatment with TXR significantly reduced the number of PVC and duration and incidence of VF in ischemic phase in comparison to the untreated animals (P < 0.05). In addition, the duration, and incidence of most arrhythmias during reperfusion phase were significantly declined by TXR administration in both control and diabetic groups (P < 0.05). Pretreatment of rats with TXR significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels after I/R insult in diabetic as well as control hearts (P < 0.05).. Preconditioning with TXR could provide cardioprotection by anti-arrhythmic and anti-inflammatory effects against I/R injury in rat hearts. This effect of TXR can introduce this material as a protective agent in cardiovascular diseases.

Topics: Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Cytokines; Diabetes Mellitus, Experimental; Electrocardiography; Hydroxyethylrutoside; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion Injury; Myocardium; Rats, Wistar

Nickel (Ni) is an important environmental toxicant that can cause cancer and cardiovascular disease. The aim of this study was to examine the protective effects of troxerutin (Txn) Ni-induced renal dysfunction in rats using biochemical and histopathological approaches. Nickel (20 mg/kg body weight [b.w.]/day) was administered intraperitoneally (i.p.) for 20 days. Renal damage from Ni toxicity was evident from the changed levels of serum and urinary markers in Ni-treated rats. The levels of lipid peroxidation markers also significantly increased, while the levels of nonenzymatic and enzymatic antioxidants significantly decreased in the kidney of Ni-intoxicated rats. Troxerutin was administered orally (100 mg/kg b.w.) for 20 days along with Ni, resulting in a reversal of Ni-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. Histopathological studies in the kidneys of rats also showed that troxerutin (100 mg/ kg b.w.) markedly reduced the toxicity of Ni and preserved the normal histological architecture of the renal tissue. The present study results suggest the nephroprotective potential of Txn in Ni toxicity, which might be due to its antioxidant and metal-chelating properties.

Topics: Animals; Environmental Pollutants; Hydroxyethylrutoside; Kidney; Male; Nickel; Protective Agents; Rats; Rats, Wistar

With the change in lifestyle and the aging population, the incidence of cognitive dysfunction in diabetes mellitus is rising sharply. Oxidative stress is an important mechanism in the development of diabetic cognitive dysfunction. Nuclear factor E2-related factor 2 (Nrf2) is the core transcription factor of antioxidative stress. Early prevention and treatment of diabetic cognitive dysfunction can reduce the incidence of dementia and improve the quality of life of diabetic patients.. This study was aimed at determining effect of troxerutin on the development of cognitive dysfunction and the expression level of Nrf2 in the hippocampus of streptozotocin (STZ) diabetic rats, when used in the early preventive stage.. Learning and memory levels were significantly improved in the DT group compared with the DC group. Moreover, in the DT group, the expression level of Nrf2 in the hippocampus was increased, activity of SOD was elevated, and MDA content was decreased.. Prophylactic use of troxerutin delays the development of diabetic cognitive dysfunction and increases the expression level of Nrf2 in the hippocampus of STZ diabetic rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Behavior, Animal; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Hippocampus; Hydroxyethylrutoside; Male; Maze Learning; NF-E2-Related Factor 2; Rats, Sprague-Dawley

Topics: Albumins; Animals; Carrier Proteins; Chemokine CXCL12; Creatinine; Cyclooxygenase 2; Halogenated Diphenyl Ethers; Hydroxyethylrutoside; Kidney; Male; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Protective Agents; Reactive Oxygen Species; Receptors, CXCR4; RNA Interference; RNA, Small Interfering; Signal Transduction; Thioredoxins

Neurovascular dysfunction caused by traumatic brain injury (TBI) is characterized by cerebralvascular damage, blood-brain barrier (BBB) breakdown, brain edema, etc. This study was designed to assess the protective role of 5 days troxerutin cerebroprotein hydrolysate (TCH) injection treatment against TBI, as well as the potential mechanism.. The weight-drop model of TBI in male Sprague-Dawley rats was chosen to induce TBI model, rats either with TCH or a vehicle via intraperitoneal injection were examined 3 days after TBI.. TCH resulted in alleviation of neurological deficits, reduction of infarct volume, improvement of regional cerebral blood flow (rCBF), amelioration of neuronal death, astrocyte proliferation, endothelial cell loss, and BBB dysintegrity. These effects of TCH treatment against TBI were through endothelial nitric oxide synthase (eNOS) coupling/decoupling status adjustment, which not only increased nitric oxide (NO) level, but also decreased peroxynitrate level expression.. All the results indicated that TCH injection has multifaceted protective effects of neurovascular unit (NVU) against TBI via eNOS pathway regulation.

Topics: Animals; Astrocytes; Blood-Brain Barrier; Brain; Brain Injuries, Traumatic; Hydroxyethylrutoside; Male; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type III; Rats, Sprague-Dawley; Signal Transduction; Tight Junction Proteins

Postmenopausal osteoporosis is a bone metabolism disease that is caused by an imbalance between bone-resorbing osteoclast and bone-forming osteoblast actions. Herein, we describe the role of troxerutin (TRX), a trihydroxyethylated derivative of rutin, in ovariectomy (OVX)-induced osteoporosis and its effects on the regulation of osteoclasts and osteoblasts.. In vivo, OVX female mice were intraperitoneally injected with either saline, 50 mg/kg TRX, or 150 mg/kg TRX for 6 weeks and then sacrificed for micro-computed tomography analyses, histological analyses, and biomechanical testing. In vitro, RAW264.7 cell-derived osteoclasts and MC3T3-E1 cell-derived osteoblasts were treated with different concentrations of TRX to examine the effect of TRX on osteoclastogenesis and bone resorption, as well as on osteogenesis and mineralization.. In this study, we demonstrated that TRX prevented cortical and trabecular bone loss in ovariectomized mice by reducing osteoclastogenesis and promoting osteogenesis in vivo. In vitro, TRX inhibited the formation and activity of RAW264.7-derived osteoclasts and the expression of nuclear factor of activated T-cells 1 and cathepsin K. Meanwhile, TRX improved the osteogenesis and mineralization of MC3T3-E1 by enhancing the expression of Runt-related transcription factor 2, Osterix, and collagen type 1 alpha 1.. Our data demonstrated that TRX could prevent OVX-induced osteoporosis and be used in a novel treatment for postmenopausal osteoporosis.

Topics: Animals; Anticoagulants; Bone Resorption; Cell Differentiation; Female; Humans; Hydroxyethylrutoside; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis, Postmenopausal; Ovariectomy; Protective Agents; RAW 264.7 Cells

Flavonoid glycosides have many beneficial effects on health, but these bioactivities tend to decrease after oral administration owing to their poor lipophilicity. In this study, a facile whole-cell-based method was developed for selective preparation of monoester or diester of troxerutin, a flavonoid derivative. In addition, the bioavailabilities and antioxidant properties of troxerutin and its acylated derivatives were also investigated in cells.. A facile and efficient whole-cell biocatalysis method was developed to synthesize troxerutin-acylated derivatives, markedly enhancing the bioavailability and antioxidant activities of troxerutin in cells. Additionally, the mechanism underlying the observed difference in the antioxidant activities of troxerutin and its esters was ascribed to both their free radical scavenging abilities and distribution on the cell membrane surface.

Topics: Anticoagulants; Antioxidants; Biological Availability; Humans; Hydroxyethylrutoside

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide that lacks proper medical prognosis and treatment. In the present study, the anti-tumoral potential of troxerutin (TX), an ethnomedicine, was examined in relation to its effects on the promoter 2-acetylaminofluorene (2-AAF) in N-nitrosodiethylamine (NDEA) initiated HCC, as compared to its effects on HCC induced by NDEA alone. Liver samples from each experimental group were collected and evaluated for histological, biochemical and cellular characterization. The protein expressions of apoptotic and cell proliferation markers were determined via immunohistochemistry and western blotting. Molecular docking was also performed to delineate the inhibitory mechanism of TX on HCC. The results show that only higher doses of TX showed a significant reduction in the incidence of hepatic nodule formation, and they also counteracted NDEA plus 2-AAF induced alterations in the enzymic status. The frequencies of glutathione-S-transferase and proliferating cell nuclear antigen, markers of S phase progression, were markedly reduced during TX treatment. TX also modulated the imbalance in the MDM2-p53 interaction. The molecular docking results confirmed the interaction of TX with the upstream kinases that regulate apoptosis. This study provides evidence that a copious dose of TX is required to counteract the differential mitoinhibitory effect of 2-AAF in NDEA initiated hepatomas, and TX exhibits an anti-tumoral effect via suppressing oxidative stress, regulating liver function enzymes, inhibiting inflammatory responses and modulating MDM2-p53 interactions, thus inducing apoptosis, and thereby suggesting that TX may provide promising therapeutic effects for the chemoprevention of HCC.

Topics: 2-Acetylaminofluorene; Animals; Antineoplastic Agents; Apoptosis; Carcinogenesis; Disease Progression; Glutathione Transferase; Humans; Hydroxyethylrutoside; Liver Neoplasms; Male; Molecular Docking Simulation; Proliferating Cell Nuclear Antigen; Protein Binding; Proto-Oncogene Proteins c-mdm2; Rats; Rats, Wistar; Tumor Suppressor Protein p53

Gentamycin is an aminoglycoside antibiotic that is widely employed for controlling Gram negative bacterial infections including that caused by the antibiotic-resistant Pseudomonas species. The clinical use of gentamycin is substantially limited by its side effects particularly acute kidney injury (AKI). The aim of the current study was to investigate the protective effect of the plant flavonoid troxerutin (150 mg kg-1 day-1 for 15 days) against gentamycin-induced AKI using Wistar rats as an experimental mammalian model. The results of the present work revealed that troxerutin significantly improved renal function as demonstrated by the increase in the glomerular filtration rate and the decrease in the levels of urinary albumin, urinary albumin to creatinine ratio, serum creatinine, and blood urea nitrogen (p < 0.001). In addition, troxerutin significantly attenuated gentamycin-induced renal tissue injury as indicated by the decreased protein expression of the renal tubular injury marker KIM-1, the attenuation of the renal histopathological changes, and the modulation of the oxidative stress markers as reflected by the decrease in the levels of lipid and protein oxidative modifications and the increase in the levels of reduced glutathione and total antioxidant capacity (p < 0.001). Furthermore, troxerutin down-regulated the levels of inflammatory cytokines (IL-10, TNF-α, and IL-6), attenuated apoptotic cell death, and enhanced the renal tissue regenerative capacity as demonstrated by the increase in the protein expression of the proliferating cell nuclear antigen, PCNA (p < 0.001). Collectively, the results of the current study highlight, for the first time, the ameliorating effects of troxerutin against gentamycin-induced AKI in rats that is potentially mediated via the modulation of p38 MAPK signaling as well as via antioxidant, anti-inflammatory and anti-apoptotic activities.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cell Adhesion Molecules; Gentamicins; Humans; Hydroxyethylrutoside; Kidney; Male; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Regeneration; Signal Transduction

Troxerutin is a bioflavonoid, which can be used to treat venous disorders, thrombosis and cerebrovascular diseases. Recent studies have demonstrated that it may also be used to prevent edemas. However, it is not known whether troxerutin protects against the cardiomyopathic complications of diabetes. In the present study, a rat model of type 2 diabetes was used to investigate the potential for troxerutin to protect against diabetic cardiomyopathy, through changes to nuclear factor‑κB (NF‑κB) expression. Troxerutin administration significantly reduced heart rate, blood pressure, blood glucose and plasma triglyceride levels across all measured time points. Furthermore, troxerutin significantly reduced reactive oxygen species levels, NF‑κB protein expression, and suppressed the phosphorylated forms of AKT, insulin receptor substrate 1 (IRS1) and c‑Jun N‑terminal kinase (JNK). These results suggested that troxerutin protects against cardiomyopathy via alterations in NF‑κB, AKT and IRS1 signaling, in a rat model of type 2 diabetes.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Hydroxyethylrutoside; Insulin Receptor Substrate Proteins; JNK Mitogen-Activated Protein Kinases; Male; NF-kappa B; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction

Gastric cancer still presents a significant problem for public health worldwide. Troxerutin (TXN), a flavonoid present in tea, coffee, cereal grains, and a variety of fruits and vegetables, exhibits various pharmacological and biological activities in vitro and in vivo. We investigated the ability of TXN to reverse the in vitro and in vivo drug resistance of human gastric cancer cells, which were resistant to treatment of 5-Fluorouracil (5-FU). 5-Fu is a pyrimidine analog, which is widely used in the treatment of cancers. Here, we found the growth inhibitory effects of TXN on human gastric cancer cell, resistant to 5-FU. TXN and 5-FU co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of phosphorylated signal transducers and activation of transcription 3 (STAT3) was included in suppression of p65 by TXN with 5-FU in combination. Additionally, the presence of TXN sensitized gastric cancer cells resistant to 5-FU to 5-FU-induced apoptosis by suppressing Bcl-2. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspase cleavage, leading to apoptosis. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the TXN or 5-FU treatment alone. Our data indicated a novel therapeutic strategy to potentiate 5-FU-induced anti-tumor effect in gastric cancer cells with resistance to 5-FU by TXN through suppression of p-STAT3/NF-κB (p65 and p50) and Bcl-2.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Drug Synergism; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Hydroxyethylrutoside; Male; Mice, Nude; Neoplasm Proteins; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Random Allocation; RNA Interference; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Mitochondrial oxidative stress plays a major role in the pathogenesis of myocardial apoptosis in metabolic syndrome (MS) patients. In this study, we investigated the effect of troxerutin (TX), an antioxidant on mitochondrial oxidative stress and apoptotic markers in heart of mice fed fat and fructose-rich diet. Adult male Mus musculus mice were fed either control diet or high fat, high fructose diet (HFFD) for 60 days to induce MS. Mice from each dietary group were divided into two on the 16th day and were either treated or untreated with TX (150 mg/kg bw, p.o) for the next 45 days. At the end of the study, mitochondrial reactive oxygen species (ROS) generation, oxidative stress markers, levels of intracellular calcium, cardiolipin content, cytochrome c release and apoptotic markers were examined in the myocardium. HFFD-feeding resulted in diminution of antioxidants and increased ROS production, lipid peroxidation and oxidatively modified adducts of 8-OHG, 4-HNE and 3-NT. Further increase in Ca

Topics: Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Calcium; Cardiolipins; Caspase 3; Caspase 9; Cytochromes c; Diet, High-Fat; DNA Adducts; Fructose; Heart; Hydroxyethylrutoside; Mice; Mitochondria; Myocardium; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

2,2,4,4-Tetrabromodiphenyl ether (BDE-47), one of the persistent organic pollutants, seriously influences the quality of life; however, its pathological mechanism remains unclear. Troxerutin is a flavonoid with pharmacological activity of antioxidation and anti-inflammation. In the present study, we investigated troxerutin against BDE-47-induced kidney cell apoptosis and explored the underlying mechanism. The results show that troxerutin reduced renal cell apoptosis and urinary protein secretion in BDE-47-treated mice. Western blot analysis shows that troxerutin supplement enhanced the ratio of Bcl-2/Bax; inhibited the release of cytochrome c from mitochondria, the activation of procaspase-9 and procaspase-3, and the cleavage of PARP; and reduced FAS, FASL, and caspase-8 levels induced by BDE-47. In addition, troxerutin decreased the production of reactive oxygen species (ROS) and increased the activities of antioxidative enzymes. Furthermore, troxerutin blunted Nrf2 ubiquitylation, enhanced the activity of Nrf2, decreased the activity of NOX2, and ameliorated kidney oxidant status of BDE-47-treated mice. Together, these results confirm that troxerutin could alleviate the cytotoxicity of BDE-47 through antioxidation and antiapoptosis, which suggests that its protective mechanism is involved in the inhibition of apoptosis via suppressing NOX2 activity and increasing Nrf2 signaling pathway.

Topics: Animals; Anticoagulants; Apoptosis; Halogenated Diphenyl Ethers; Hydroxyethylrutoside; Kidney; Kidney Diseases; Male; Mice; NF-E2-Related Factor 2

Troxerutin, a semi-synthetic derivative of the natural bioflavanoid rutin, has been reported to possess many beneficial effects in human bodies, such as vasoprotection, immune support, anti-inflammation and anti-aging. However, the effects of troxerutin on genome-wide transcription in blood cells are still unknown. In order to find out effects of troxerutin on gene transcription, a high-throughput RNA sequencing was employed to analysis differential gene expression in blood cells consisting of leucocytes, erythrocytes and platelets isolated from the mice received subcutaneous injection of troxerutin. Transcriptome analysis demonstrated that the expression of only fifteen genes was significantly changed by the treatment with troxerutin, among which 5 genes were up-regulated and 10 genes were down-regulated. Bioinformatic analysis of the fifteen differentially expressed genes was made by utilizing the Gene Ontology (GO), and the differential expression induced by troxerutin was further evaluated by real-time quantitative PCR (Q-PCR).

Topics: Animals; Gene Expression; Hydroxyethylrutoside; Male; Mice; Real-Time Polymerase Chain Reaction; Transcriptome

Troxerutin, also known as vitamin P4, has been commonly used in the treatment of chronic venous insufficiency (CVI) disease. However, its effect on in vivo myocardial ischemia/reperfusion (I/R) injury, a model that closely mimics acute myocardial infarction in humans, is still unknown.. The myocardial I/R injury rat model was created with troxerutin preconditioning. Myocardial infarct size was evaluated by the Evans blue-TTC method. Hemodynamic parameters, including the heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximal rate of rise in blood pressure in the ventricular chamber (+dp/dt max), and maximal rate of decline in blood pressure in the ventricular chamber (-dp/dt max) were monitored. Serum TNF-α and IL-10 were determined by ELISA kit. Cell apoptosis was detected by MTT method.. Troxerutin preconditioning significantly reduced myocardial infarct size, improved cardiac function, and decreased the levels of creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the I/R injury rat model. The serum and mRNA levels of TNF-α and IL-10 as well as some apoptosis markers (Bax, Caspase 3) also decreased. Moreover, troxerutin pretreatment markedly increased the phosphorylation of Akt, and blocking PI3K activity by LY294002 abolished the protective effect of troxerutin on I/R injury.. Troxerutin preconditioning protected against myocardial I/R injury via the PI3K/Akt pathway.

Topics: Animals; Apoptosis; Aspartate Aminotransferases; Blood Pressure; Chromones; Creatine Kinase; Heart Rate; Heart Ventricles; Hydroxyethylrutoside; Interleukin-10; Ischemic Preconditioning, Myocardial; Male; Morpholines; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Tumor Necrosis Factor-alpha

Troxerutin (TXER), a trihydroxyethylated derivative of the natural bioflavonoid rutin, abundantly found in tea, various fruits and vegetables, is known to exhibit ample pharmacological properties. In the present investigation, we examined the antineoplastic, therapeutic efficacy and furthermore the possible mechanisms of action of TXER against NAFLD/NASH progression to hepatocarcinogenesis.. The effect of TXER (12.5, 25 or 50 mg/kg b.w/day) was evaluated on the nitrosodiethylamine (NDEA) model of hepatocarcinogenesis in rats, after 16 weeks of oral treatment, with special focus on liver specific enzymes, xenobiotic metabolizing enzymes, antioxidant status, lipid peroxidation profile, DNA damage, fibrosis, cell proliferation and inflammatory status.. Administration of TXER to hepatocellular carcinoma-bearing rats restored the enzyme activities and the hepatic architecture. Furthermore, TXER significantly curtailed NDEA-induced DNA damage, cell proliferation, inflammation, fibrosis and hepatic hyperplasia.. This study provides the evidence that troxerutin exerts a significant therapeutic effect against liver cancer by modulating liver function enzymes, xenobiotic enzymes, oxidative damage, inhibiting cell proliferation, suppressing inflammatory response and induction of apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Diethylnitrosamine; Disease Models, Animal; DNA Damage; Hydroxyethylrutoside; Lipid Peroxidation; Liver; Liver Neoplasms; Male; Oxidative Stress; Rats; Rats, Wistar

Topics: Albumins; Glycation End Products, Advanced; Glycosylation; Humans; Hydroxyethylrutoside; Maillard Reaction; Protein Aggregation, Pathological

Mitochondrial abnormality is thought to play a key role in cardiac disease originating from the metabolic syndrome (MS). We evaluated the effect of troxerutin (TX), a semi-synthetic derivative of the natural bioflavanoid rutin, on the respiratory chain complex activity, oxidative stress, mitochondrial biogenesis and dynamics in heart of high fat, high fructose diet (HFFD) -induced mouse model of MS. Adult male Mus musculus mice of body weight 25-30 g were fed either control diet or HFFD for 60 days. Mice from each dietary regimen were divided into two groups on the 16th day and were treated or untreated with TX (150 mg/kg body weight [bw], per oral) for the next 45 days. At the end of experimental period, respiratory chain complex activity, uncoupling proteins (UCP)-2 and -3, mtDNA content, mitochondrial biogenesis and dynamics, oxidative stress markers and reactive oxygen species (ROS) generation were analyzed. Reduced mtDNA abundance with alterations in the expression of genes related to mitochondrial biogenesis and fission and fusion processes were observed in HFFD-fed mice. Disorganized and smaller mitochondria, reduction in complexes I, III and IV activities (by about 55%) and protein levels of UCP-2 (52%) and UCP-3 (46%) were noted in these mice. TX administration suppressed oxidative stress, improved the oxidative capacity and biogenesis and restored fission/fusion imbalance in the cardiac mitochondria of HFFD-fed mice. TX protects the myocardium by modulating the putative molecules of mitochondrial biogenesis and dynamics and by its anti-oxidant function in a mouse model of MS.

Topics: Animals; Diet, High-Fat; Dietary Sucrose; Electron Transport; Fructose; Hydroxyethylrutoside; Male; Metabolic Syndrome; Mice; Mitochondria, Heart; Organelle Biogenesis; Oxidative Stress; Reactive Oxygen Species; RNA, Messenger

Protective effects of ischemic postconditioning in myocardial ischemia/reperfusion (I/R) injury have been ever demonstrated, but the exact mechanisms remain unclear. Because of their multiplex activities, using natural pharmaceuticals seems to be clinically interesting. The aim of present study was to investigate the effects of troxerutin preconditioning and ischemic postconditioning on inflammatory responses after myocardial I/R injury in a rat model. Twenty-four Wistar rats were divided into four groups as the control, troxerutin receiving (TXR), postconditioning receiving (PostC), and combined therapy (TXR + PostC). Rats' isolated hearts underwent 30-min LAD regional ischemia followed by 45-min reperfusion. Troxerutin was orally administered for a month before I/R. Ischemic PostC was applied by alternative three cycles of 30-s R/I at the onset of reperfusion. The coronary effluent and ischemic left ventricular samples were used to determine the activities of creatine kinase (CK), intercellular adhesion molecule-1 (ICAM-1), interlukin-1beta (IL-1β), tumor-necrosis factor (TNF-α), and also histopathological studies. Pretreatment of rats with troxerutin significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels and ICAM-1 activity after I/R insult compared to those of control I/R hearts (P < 0.05). Application of PostC showed similar impacts on those parameters. In fact, anti-inflammatory mechanisms of both treatments were associated with their protective effects against myocardial damages causing from I/R injury. Pretreatment with troxerutin as well as postconditioning can induce cardioprotection through prevention of the cell-cell interaction and release of inflammatory mediators, minimizing I/R pathological changes in myocardial cells. These two treatments may share same mechanisms in their actions since they showed no significant additive effects.

Topics: Animals; Heart Ventricles; Hydroxyethylrutoside; Inflammation; Inflammation Mediators; Ischemic Postconditioning; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Premedication; Rats; Rats, Wistar; Transplantation Conditioning

Radiotherapy is one of the most effective non-surgical treatments for many tumors. However, radiation damage remains a major negative consequence of radiotherapy. At present, radio-protective effect of troxerutin has been confirmed, but the mechanism of this radioprotection has not been elucidated. Here, this study showed that troxerutin protected thymus tissue of irradiated mice, and its radio-protective effect on thymocytes was significant in the range of 0.625-10μg/ml. Troxerutin significantly inhibited apoptosis of irradiated thymocytes at the concentration of 10μg/ml. Computer-aided drug design was used to investigate potential candidate targets for troxerutin, and an excellent correlation was identified between troxerutin and AKT (Pharm mapper and KEGG signal pathway). Troxerutin inhibited the activation of PTEN to stimulate AKT, which in turn prevented the activation of JNK to protect cells. Our results showed that troxerutin enhanced radioprotection at least partially by activating AKT to inhibit the activation of JNK.

Topics: Animals; Apoptosis; Cell Survival; Enzyme Activation; Hydroxyethylrutoside; JNK Mitogen-Activated Protein Kinases; Male; Mice; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Radiation-Protective Agents; Thymus Gland

Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression.

Topics: Animals; Cognition Disorders; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Glutamate-Cysteine Ligase; Hippocampus; Hydroxyethylrutoside; Hypoglycemic Agents; Male; Maze Learning; Nootropic Agents; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; Thioctic Acid

One of the pivotal mechanisms projected for bioflavonoids in cancer chemoprevention is through their intervention against mutagen-DNA interaction. Recent literatures emphasize the role of troxerutin (TXER) as an emerging anticancer agent. However, there are no reports on its intervention in any carcinogen-DNA interaction. The present study investigates the possibility of TXER, in prevention of 2-aminoanthracene (2-AA) contact with DNA. Steady state and time resolved fluorescence spectroscopy results, highlight the direct contact of 2-AA with DNA, while presence of TXER prevented this interaction. Gel-electrophoresis study clearly revealed that, TXER inhibits 2-AA+UVA radiation induced DNA damage. Fluorescence microscopic studies elucidated that, TXER treatment obstructs the 2-AA interaction with cellular DNA, while molecular docking showed the energetically favourable structure of TXER/2-AA/TXER complex. Further anti-mutagenicity experiment revealed that, TXER prevents the mutation induced colony formation in mutant strain of S. typhymurium. Our in vitro and ex vivo experimental findings provide imperative evidence about the protective role of TXER against environmental carcinogens through the inhibition of carcinogen-DNA interaction, implicating its potential for therapeutic applications in cancer.

Topics: 3T3 Cells; Animals; Anthracenes; Antimutagenic Agents; DNA; DNA Damage; Genotype; Hydroxyethylrutoside; Mice; Models, Molecular; Molecular Docking Simulation; Mutagens; Salmonella typhimurium; Sophora; Ultraviolet Rays

In the current study, the effects of troxerutin (TRX) on muscle fatigue and gene expression of Bcl-2 and Bax in the hepatic tissue of rats was investigated. Forty male Wistar rats were randomly divided into 4 groups and designated as control and TRX treatment at 75 (TRX75), 150 (TRX150), and 300 mg/kg per day (TRX300). The treated groups and control group received TRX and water orally for 7 days. After an exhaustive swimming test on the 7th day, all animals were euthanized immediately and several biochemical parameters related to fatigue and gene expression of Bcl-2 and Bax in the hepatic tissue were measured. Our results showed that the exhaustion swimming time in the TRX300 groups significantly increased 1.2-fold compared with the control group (P < 0.001). TRX300 significantly reduced ALT (P < 0.05) activity and increased liver SOD activity compared with the control group (P < 0.01). Additionally, TRX significantly reduced the liver mRNA expressions of Bax (P < 0.001) and increased the Bcl-2/Bax ratio (P < 0.001) compared with the control group. Based on our data, TRX possesses anti-apoptotic and hepatoprotective action following exhaustive swimming exercise.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Dose-Response Relationship, Drug; Gene Expression Regulation; Glutathione Peroxidase; Hydroxyethylrutoside; Liver; Male; Muscle Fatigue; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Superoxide Dismutase; Swimming

The aim of this study was to investigate effects of troxerutin (TRX) on endurance capacity, oxidative stress and matrix metalloproteinase-9 (MMP-9) levels in trained male rats. Forty male Wistar rats were divided into five groups. The control (Vehicle) and exercise training (5 days/week) with vehicle treatment (Exercise), exercise training with TRX treatment at 75 (Ex-TRX75), 150 (Ex-TRX150), and 300 mg/kg (Ex-TRX300). The treated groups received TRX by gavage every day while the other groups received water for 30 days. On the 30th day, rats were sacrificed immediately after exhaustive swimming test, and some biochemical parameters were measured. Exhaustion swimming time in the Ex-TRX75, Ex-TRX150 and Ex-TRX300 groups significantly increased 1.2-, 1.93- and 2.1-fold compared to the vehicle group, respectively. TRX significantly increased glucose level (P < 0.05) and reduced creatine kinase activity (P < 0.001) compared to the vehicle and exercise groups. TRX300 significantly reduced alkaline phosphatase and lactate dehydrogenase activities (P < 0.05) and blood urea nitrogen (P < 0.05) and MMP-9 levels (P < 0.05) compared to the vehicle and exercise groups. Additionally, TRX300 and TRX150 significantly increased superoxide dismutase activity compared to the vehicle group (P < 0.05). Our results provide experimental evidence in supporting clinical use of TRX as an effective agent against fatigue.

Topics: Animals; Anticoagulants; Dose-Response Relationship, Drug; Hydroxyethylrutoside; Male; Matrix Metalloproteinase 9; Muscle Fatigue; Oxidative Stress; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Wistar; Swimming

Parkinson's disease (PD) is a neurodegenerative disease with progressive loss of mesencephalic dopaminergic neurons of the substantia nigra and with multiple incapacitating motor and non-motor symptoms. Troxerutin is a natural bioflavonoid with nephro- and hepato-protective, antioxidant, and anti-inflammatory properties. In this study, we evaluated its possible neuroprotective effect in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with troxerutin at a dose of 150mg/kg/day for 1 week. Results showed that troxerutin mitigates apomorphine-induced motor asymmetry and lowered the latency to initiate and the total time in the narrow beam task and this beneficial effect was lost following central application of estrogen receptor β (ERβ) antagonist or phosphatidylinositol 3-kinase (PI3K) inhibitor. In addition, troxerutin reduced striatal malondialdehyde (MDA) as an index of lipid peroxidation, reactive oxygen species, glial fibrillary acid protein (GFAP) as a marker of astrogliosis, and DNA fragmentation as an apoptotic marker with no significant alteration of catalase activity and nitrite level. Meanwhile, troxerutin was capable to prevent loss of nigral tyrosine hydroxylase (TH)-positive neurons. These findings indicate neuroprotective potential of troxerutin in 6-OHDA rat model of PD through mitigation of apoptosis, astrogliosis, and oxidative stress and part of its effect is dependent on PI3K/ERβ signaling.

Topics: Animals; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogen Receptor beta; Hydroxyethylrutoside; Male; Neurons; Neuroprotective Agents; Oxidative Stress; Oxidopamine; Parkinson Disease; Phosphatidylinositol 3-Kinases; Rats; Signal Transduction

The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability.. The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7 mg/kg) in male Wistar rats.. The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20 nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution.. These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.

Topics: Administration, Oral; Animals; Anticoagulants; Biological Availability; Cell Membrane Permeability; Chemistry, Pharmaceutical; Dogs; Drug Compounding; Drug Delivery Systems; Drug Stability; Emulsions; Hydroxyethylrutoside; Intestinal Absorption; Madin Darby Canine Kidney Cells; Male; Particle Size; Permeability; Rats; Rats, Wistar; Water

Troxerutin (TRX) is a flavonoid present in tea, coffee, cereal grains, various fruits and vegetables have been reported to exhibit radioprotective, antithrombotic, nephro and hepato-protective effects. A systematic study was undertaken to evaluate its free radical scavenging ability and anti-apoptotic activity in cell-free and cellular systems. TRX scavenged superoxide, nitric oxide and also other model stable radicals like 1,1-diphenyl-2-picryl-hydazyl, and 2,2'-azinobis3-ethylbenzothiazoline-6-sulfonic acid. It reacted with hydroxyl radicals, carbonate and thiocyanate anions, as evaluated by pulse radiolysis and stopped flow techniques. TRX protected different cell types (epithelial cells, fibroblasts and lymphocytes) against peroxyl radical-induced apoptosis, necrosis and mitotic death. It scavenged intracellular basal and inducible ROS levels and also restored depletion of intracellular GSH levels, suggesting that free radical scavenging ability may be responsible for the observed cytoprotection of different cell types. TRX may find application as an adjuvant in treating various diseases attributed to oxidative stress.

Topics: Antioxidants; Cell Death; Flavonoids; Free Radicals; Hydroxyethylrutoside; Oxidative Stress; Plant Extracts; Reactive Oxygen Species

Troxerutin, a flavonoid best known for its radioprotective and antioxidant properties is of considerable interest of study due to its broad pharmacological activities. The present study on troxerutin highlights its abilities to bind DNA and enhance cancer cell killing in response to radiation. Troxerutin showed strong binding with calf thymus DNA in vitro. Troxerutin-DNA interaction was confirmed by CD spectropolarimetry. The mode of binding of troxerutin to DNA was assessed by competing troxerutin with EtBr or DAPI, known DNA intercalator and a minor groove binder, respectively. DAPI fluorescence was drastically reduced with linear increase in troxerutin concentration suggesting possible binding of troxerutin to DNA minor groove. Further, computational studies of docking of troxerutin molecule on mammalian DNA also indicated possible troxerutin-DNA interaction at minor groove of DNA. Troxerutin was found to mainly localize in the nucleus of prostate cancer cells. It induced cytotoxicity in radioresistant (DU145) and sensitive (PC3) prostate cancer cells. When troxerutin pre-treated DU145 and PC3 cells were exposed to γ-radiation, cytotoxicity as estimated by MTT assay, was found to be further enhanced. In addition, the % subG1 population detected by propidium iodide staining also showed similar response when combined with radiation. A similar trend was observed in terms of ROS generation and DNA damage in DU145 cells when troxerutin and radiation were combined. DNA binding at minor groove by troxerutin may have contributed to strand breaks leading to increased radiation induced cell death.

Topics: Antineoplastic Agents; DNA; DNA Damage; Flavonoids; Humans; Hydroxyethylrutoside; Male; Models, Molecular; Molecular Docking Simulation; Neoplasms; Prostatic Neoplasms; Reactive Oxygen Species

Nickel (Ni)-induced oxidative damage is a serious problem that leads to reproductive system failure through testicular damage. The present investigation was carried out to determine the effect of troxerutin (Txn) on testicular toxicity induced by Ni in experimental rat testes. The oral administration of Txn (100 mg/kg body weight [bw]) showed a significant (p < 0.01) increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), reduced glutathione, ascorbate, total sulphydryl groups, and testis-organ weight. Subsequently, the administration of Txn also significantly reduced the accumulation of Ni, lipid peroxidation products, and protein carbonyl levels in Txn-treated animals. Testicular protection in the experimental animals by Txn is further substantiated by a remarkable reduction of Ni, which was revealed through testicular tissue histopathology. These studies suggest that Txn could prevent oxidative damage and testicular toxicity induced by Ni in experimental animals.

Topics: Animals; Antioxidants; Cell Membrane; Chemical and Drug Induced Liver Injury; Hydroxyethylrutoside; Male; Nickel; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Testis

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.

Topics: Animals; Anti-Inflammatory Agents; Diet, High-Fat; Endoplasmic Reticulum Stress; Gluconeogenesis; Hydroxyethylrutoside; Hyperglycemia; Liver; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nod Signaling Adaptor Proteins; Oxidative Stress; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases

This study aimed to investigate the influence of the flavonoid oxerutin (Venoruton®, Novartis, Basel, Switzerland) on endothelial cell apoptosis and transendothelial migration of peripheral blood mononuclear cells and to elucidate the potential mechanisms affecting these processes.. Human endothelial cells were treated with Venoruton to assess the potential effect on apoptosis and on the transendothelial migration process. Endothelial nitric oxide synthase and inducible nitric oxide synthase expression in endothelial cell after Venoruton treatment as well as reactive oxygen species levels were analyzed.. Low-dose Venoruton shows a protective effect on endothelial cells and inhibits transendothelial migration of peripheral blood mononuclear cells through an endothelial monolayer, but high-dose Venoruton inversely elevated transendothelial migration of peripheral blood mononuclear cells. Meanwhile, a dose-dependent action of Venoruton on endothelial cell apoptosis could be observed. Endothelial nitric oxide synthase and inducible nitric oxide synthase expression were gradually increased in endothelial cells with increasing Venoruton dosage. In addition, reactive oxygen species were significantly reduced by 0.1 mM and 0.5 mM Venoruton and elevated after high dose treatment.. These data suggest that the increased transendothelial migration of peripheral blood mononuclear cells is related to the excessive activation of the nitric oxide-axis and subsequent relaxation of the endothelial cells.

Topics: Apoptosis; Cell Line; Endothelial Cells; Female; Flavonoids; Humans; Hydroxyethylrutoside; Leukocytes, Mononuclear; Male; Nitric Oxide Synthase Type III; Transendothelial and Transepithelial Migration

Emerging evidence indicates that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD(+)-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD(+)-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity.

Topics: Animals; Antioxidants; Halogenated Diphenyl Ethers; Hazardous Substances; Hydroxyethylrutoside; Liver; Mice; NF-kappa B; Oxidative Stress

Four simple, accurate, sensitive and precise spectrophotometric methods were developed and validated for simultaneous determination of Troxerutin (TXN) and Carbazochrome (CZM) in their bulk powders, laboratory prepared mixtures and pharmaceutical dosage forms. Method A is first derivative spectrophotometry (D(1)) where TXN and CZM were determined at 294 and 483.5 nm, respectively. Method B is first derivative of ratio spectra (DD(1)) where the peak amplitude at 248 for TXN and 439 nm for CZM were used for their determination. Method C is ratio subtraction (RS); in which TXN was determined at its λmax (352 nm) in the presence of CZM which was determined by D(1) at 483.5 nm. While, method D is mean centering of the ratio spectra (MCR) in which the mean centered values at 300 nm and 340.0 nm were used for the two drugs in a respective order. The two compounds were simultaneously determined in the concentration ranges of 5.00-50.00 μg mL(-1) and 0.5-10.0 μg mL(-1) for TXN and CZM, respectively. The methods were validated according to the ICH guidelines and the results were statistically compared to the manufacturer's method.

Topics: Adrenochrome; Dosage Forms; Hydroxyethylrutoside; Regression Analysis; Reproducibility of Results; Spectrophotometry

Proteasome dysfunction has been associated with the pathogeneses of a variety of diseases and with the neurotoxicities of environmental chemicals; however, whether proteasome dysfunction plays a role in the cellular toxicity of polybrominated diphenyl ethers (PBDEs) has not been investigated to date. Emerging evidence suggests that antioxidants exhibit evident beneficial effects on the cellular toxicity associated with PBDEs. In the present study, we investigated whether troxerutin attenuates BDE-47-induced hepatocyte apoptosis by restoring proteasome function and explored the mechanisms underlying this effect. Our results revealed that proteasome dysfunction was involved in the BDE-47-induced hepatocyte apoptosis in the mouse liver. Furthermore, our results revealed that troxerutin effectively inhibited hepatocyte apoptosis by restoring oxidative stress-mediated proteasome dysfunction in BDE-47-treated mice. Consequently, troxerutin markedly suppressed endoplasmic reticulum (ER) stress in the livers of the BDE-47-treated mice. The inhibitory effects of troxerutin on ER stress and apoptotic pathways were markedly blunted by treatment with epoxomicin (a selective inhibitor of proteasome). Ultimately, troxerutin dramatically blocked TRAF2-ASK1-JNK signaling and CHOP-mediated apoptosis signaling in the BDE-47-treated mouse livers. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be a candidate for the prevention of and therapy for BDE-47-induced hepatotoxicity.

Topics: Animals; Apoptosis; Endoplasmic Reticulum Stress; Halogenated Diphenyl Ethers; Hepatocytes; Hydroxyethylrutoside; Male; Mice; Mice, Inbred ICR; Oligopeptides; Oxidative Stress; Proteasome Endopeptidase Complex

Troxerutin (TXER) is a derivative of naturally occurring bioflavonoid rutin. It possesses different biological activities in rising clinical world. The biological activity possessed by most of the drugs mainly targets on macromolecules. Hence, in the current study we have examined the interaction mechanism of TXER with calf thymus DNA (CT-DNA) by using various spectroscopic methods, isothermal titration calorimetry (ITC) and molecular docking studies. Further, DNA cleavage study was carried out to find the DNA protection activity of TXER. UV-absorption and emission spectroscopy showed low binding constant values via groove binding. Circular dichroism study indicates that TXER does not modify native B-form of DNA, and it retains the native B-conformation. Furthermore, no effective positive potential peak shift was observed in TXER-DNA complex during electrochemical analysis by which it represents an interaction of TXER with DNA through groove binding. Molecular docking study showed thymine guanine based interaction with docking score -7.09 kcal/mol. This result was compared to experimental ITC value. The DNA cleavage study illustrates that TXER does not cause any DNA damage as well as TXER showed DNA protection against hydroxyl radical induced DNA damage. From this study, we conclude that TXER interacts with DNA by fashion of groove binding.

Topics: Animals; Cattle; DNA; Hydroxyethylrutoside; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Spectrum Analysis

Dermal papilla (DP) cells function as important regulators of the hair growth cycle. The loss of these cells is a primary cause of diseases characterized by hair loss, including alopecia, and evidence has revealed significantly increased levels of reactive oxygen species (ROS) in hair tissue and DP cells in the balding population. In the present study, troxerutin, a flavonoid derivative of rutin, was demonstrated to have a protective effect against H2O2-mediated cellular damage in human DP (HDP) cells. Biochemical assays revealed that pretreatment with troxerutin exerted a protective effect against H2O2-induced loss of cell viability and H2O2-induced cell death. Further experiments confirmed that troxerutin inhibited the H2O2-induced production of ROS and upregulation of senescence-associated β-galactosidase activity. Using microRNA (miRNA) microarrays, the present study identified 24 miRNAs, which were differentially expressed in the troxerutin-pretreated, H2O2-treated HDP cells. Subsequent prediction using bioinformatics analysis revealed that the altered miRNAs were functionally involved in several cell signaling pathways, including the mitogen-activated protein kinase and WNT pathways. Overall, these results indicated that ROS-mediated cellular damage was inhibited by troxerutin and suggested that the use of troxerutin may be an effective approach in the treatment of alopecia.

Topics: Antioxidants; Cell Line; Cell Survival; Dermis; Hair Follicle; Humans; Hydrogen Peroxide; Hydroxyethylrutoside; MicroRNAs; Reactive Oxygen Species; Transcriptome

A previous study from our laboratory showed that troxerutin (TX) provides cardioprotection by mitigating lipid abnormalities in a high-fat high-fructose diet (HFFD)-fed mice model of metabolic syndrome (MS). The present study aims to investigate the reversal effect of TX on the fibrogenic changes in the myocardium of HFFD-fed mice. Adult male Mus musculus mice were grouped into four and fed either control diet or HFFD for 60 days. Each group was divided into two, and the mice were either treated or untreated with TX (150 mg/kg bw, p.o) from the 16th day. HFFD-fed mice showed marked changes in the electrocardiographic data. Increased levels of myocardial superoxide, p22phox subunit of NADPH oxidase, transforming growth factor (TGF), smooth muscle actin (α-SMA), and matrix metalloproteinases (MMPs)-9 and -2, and decreased levels of tissue inhibitors of MMPs-1 and -2 were observed. Furthermore, degradation products of troponin I and myosin light chain-1 were observed in the myocardium by immunoblotting. Rise in collagen was observed by hydroxyproline assay, while fibrotic changes were noticed by histology and Western blotting. Hypertrophy of cardiomyocytes and myocardial calcium accumulation were also observed in HFFD-fed mice. TX treatment exerted cardioprotective and anti-fibrotic effects in HFFD-fed mice by improving cardiac contractile function, reducing superoxide production and by favorably modifying the fibrosis markers. These findings suggest that TX could be cardioprotective through its antioxidant and antifibrogenic actions. This new finding could pave way for translation studies to human MS.

Topics: Animals; Calcium; Diet, High-Fat; Disease Models, Animal; Fibrosis; Fructose; Gene Expression Regulation; Hydroxyethylrutoside; Insulin Resistance; Male; Metabolic Syndrome; Mice; Myocytes, Cardiac

Diabetes has various interactions with ischemic heart diseases. Troxerutin, a flavonoid, owns outstanding pharmacological potentials in cardiovascular medicine. The purpose of this study was to investigate the effects of troxerutin on phosphorylation of GSK-3β protein and apoptosis induced by myocardial ischemia-reperfusion injury in healthy and diabetic hearts. Male Wistar rats (n=36, 250-300 g) were randomly divided into four groups: healthy, diabetic, healthy-troxerutin and diabetic-troxerutin. Diabetes was induced by a single injection of streptozotocin (50 mg/kg; ip) and the diabetic period was lasted for ten weeks. Six weeks after induction of diabetes, troxerutin-treated groups received 150 mg/kg/day troxerutin by oral gavage for 4 weeks. The rats' hearts were transferred to the Langendorff apparatus and then subjected to 30 min regional ischemia followed by 45 min reperfusion. Supernatants of the left ventricle were used to measure the levels of cardiac troponin-I (cTnI) by ELISA, total and phosphorylated form of GSK-3β by western blotting and tissue apoptosis by TUNEL assay. Troxerutin administration significantly decreased the cTnI levels in healthy and diabetic groups, as compared to the corresponding controls (P<0.05). In addition, troxerutin significantly increased the level of phosphorylated form and the ratio of phosphorylated to total form of GSK-3β in diabetic and control groups (P<0.05). Tissue apoptosis level and apoptotic index also showed a significant decrease after administration of troxerutin in control and diabetic groups (P<0.05). The findings indicated that the attenuation of GSK-3β activity and subsequent reduction of apoptosis by troxerutin play significant roles in its cardioprotection on reperfusion injuries.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cytokines; Diabetes Mellitus, Experimental; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hydroxyethylrutoside; In Situ Nick-End Labeling; Male; Myocardial Reperfusion Injury; Perfusion; Phosphorylation; Rats, Wistar

The studies on the interaction between tRNA (transfer RNA) and small molecules are an area of remarkable recent attention. For this notion a fundamental knowledge of the molecular features involving the interaction of small molecules with tRNA is crucial. Hence, in the present study we have investigated the interaction of TXER (troxerutin), natural bioflavonoid rutin derivative with yeast tRNA by using various spectroscopic techniques and molecular docking studies. The UV absorption and fluorescence emission studies demonstrated external binding of TXER on tRNA with low binding constant values as compared to strong binders. Circular dichroism (CD) spectroscopy study revealed that TXER did not show any significant modification on native conformation of tRNA. Furthermore in electrochemical study, the complex of TXER-tRNA did not expose any noticeable positive potential peak shift which indicated an interaction of TXER with tRNA by electrostatic or external binding mode. The docking study showed that the hydrogen and hydrophobic interactions were involved in binding of TXER-tRNA with docking score -7.0 kcal/mol. These findings led us to confirm the interaction of TXER on tRNA through external binding with low binding affinity, indicating its potential bioapplication in the future.

Topics: Binding Sites; Circular Dichroism; Electrochemical Techniques; Hydrophobic and Hydrophilic Interactions; Hydroxyethylrutoside; Molecular Docking Simulation; Nucleic Acid Conformation; RNA, Transfer; Spectrometry, Fluorescence; Static Electricity

Neuropathic pain was regarded as a main form of chronic pain condition that remains difficult to treat. Conventional pharmacotherapy for neuropathic pain responsed vary and side effects limited their compliance. These prompted us to find new alternatives. In this study, we investigated the effect of troxerutin on treatment of CCI-induced neuropathic pain. Results showed that troxerutin significantly reversed mechanical allodynia and thermal hyperalgesia. In L4-6 spinal cord, troxerutin reduced the expression of INF-γ, IL-1β, TNF-α, and activation of NF-κB(p65). Immunofluorescence results showed that troxerutin significantly inhibited microglia activation induced by CCI surgery. Further, troxerutin treatment significantly induced AMPK activation and inhibited CCI-induced SIRT1 decrease. However, AMPK inhibitor compound C and SIRT1 inhibitor EX527 inhibited analgesic effect of troxerutin in CCI mice. This demonstrated the involvement of AMPK/SIRT1 pathway in anti-allodynic effect of troxerutin in CCI mice. Troxerutin could be developed as a potential therapeutic agent for neuropathic pain.

Topics: AMP-Activated Protein Kinases; Animals; Constriction; Gene Expression Regulation; Hydroxyethylrutoside; Hyperalgesia; Interferon-gamma; Interleukin-1beta; Male; Mice; Microglia; Neuralgia; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Signal Transduction; Sirtuin 2; Transcription Factor RelA; Tumor Necrosis Factor-alpha

The reversal effect of troxerutin (TX) on obesity, insulin resistance, lipid accumulation, oxidative damage, and hypertension induced in the high-fat-high-fructose diet (HFFD)-fed mice model of metabolic syndrome was investigated. Adult male Mus musculus mice of body weight 25-30 g were fed either control diet or HFFD. Each group was divided into two and treated or untreated with TX (150 mg/kg bw, p.o.) from the 16th day. Assays were done in plasma and heart after 30 and 60 days of the experimental period. Significant increase in the levels of glucose and insulin, blood pressure (BP), and oxidative stress were observed after 30 days of HFFD feeding as compared to control. Animals fed HFFD for 60 days developed more severe changes in the above parameters compared to those fed for 30 days. Hearts of HFFD-fed mice registered downregulation of peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor gamma coactivator-1α, carnitine palmitoyl transferse-1b and AMP-activated protein kinase; and upregulation of cluster of differentiation 36, fatty acid-binding protein-1, and sterol regulatory element-binding protein-1c after 60 days. TX administration restricted obesity (as seen by Lee's index); improved whole body insulin sensitivity; reduced BP, lipid accumulation, and oxidative damage; upregulated fatty acid (FA) oxidation; and downregulated FA transport and lipogenesis. Histology of heart revealed that TX diminishes inflammatory cell infiltration and fatty degeneration in HFFD-fed mice. The antioxidant property of TX and its ability to influence lipid regulatory genes could be the underlying mechanisms for its beneficial effects.

Topics: Animals; Antioxidants; Diet, High-Fat; Drug Evaluation, Preclinical; Fatty Acid Transport Proteins; Fructose; Gene Expression; Hydroxyethylrutoside; Lipid Metabolism; Male; Metabolic Syndrome; Mice; Myocardium; Oxidative Stress; PPAR alpha; Sterol Regulatory Element Binding Protein 1

The present study was aimed to investigate the chemopreventive potential of troxerutin on 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the antioxidant and lipid peroxidation (LPO) status. Rats were randomly divided into six groups. Group I rats served as control. Group II rats received troxerutin (50 mg/kgb.w., p.o.) for 16 weeks. Groups III-VI rats received subcutaneous injections of DMH (20 mg/kgb.w., s.c.) once a week, for the first 4 weeks. In addition to DMH, groups IV-VI rats received troxerutin at the doses of 12.5, 25 and 50 mg/kgb.w., respectively. In DMH treated rats, our results showed decreased activities of antioxidants and increased levels of LPO in the liver. Moreover, LPO and antioxidants in the colon were found to be significantly diminished in DMH the treated rats. Furthermore, enhanced activity of colonic vitamin C and vitamin E levels were observed in DMH alone treated rats (group III), which was significantly reversed on troxerutin supplementation. Troxerutin at the dose of 25 mg/kgb.w. had shown profound beneficial effects by exhibiting near normal biochemical profile and well-preserved colon histology as compared to the other two tested doses (12.5 and 50 mg/kgb.w.). These findings suggest that troxerutin could serve as a novel agent for colon cancer chemoprevention.

Topics: 1,2-Dimethylhydrazine; Administration, Oral; Animals; Antineoplastic Agents; Ascorbic Acid; Carcinogens; Catalase; Colon; Colonic Neoplasms; Glutathione; Hydroxyethylrutoside; Lipid Peroxidation; Liver; Male; Rats; Rats, Wistar; Superoxide Dismutase; Vitamin E

Ultraviolet light B (UVB), contained in sunlight, induces damaging effects on skin by impairing cells in the epidermis and dermis. In particular, keratinocytes in the epidermis are those cells which are mainly affected by UVB light. UVB radiation induces cell death, growth arrest, DNA damage and restricts cell migration. Various phytochemicals have been shown to alleviate UVB-induced cellular damage. Troxerutin is a natural flavonoid rutin mainly found in extracts of Sophora japonica, and is a well-known antioxidant and anti-inflammatory compound used in experimental mouse models. In this study, we examined the effects of troxerutin on UVB-induced damage in HaCaT cells. HaCaT cells were pre-treated with troxerutin (0-10 µM) and then exposed to UVB radiation (50 mJ/cm2). Cell viability, cell cycle and migration assays were performed to determine the protective effects of troxerutin on the cells. DNA repair activity was also measured. Troxerutin protected the cells against UVB-induced damage, such as cell death, growth arrest, restriction of cell migration and decreased DNA repair activity in HaCaT cells. Analyses of microRNA (miRNA) expression demonstrated that the protective effects of troxerutin correlated with alterations in miRNA expression, as indicated by Gene Ontology analyses of putative target genes. Overall, our data demonstrate that troxerutin exerts protective effects against UVB-induced damage by regulating miRNA expression.

Topics: Animals; Cell Cycle; Cell Line; Cell Movement; Cell Survival; Computational Biology; Cytoprotection; DNA Repair; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Humans; Hydroxyethylrutoside; Keratinocytes; Mice; MicroRNAs; Protective Agents; Ultraviolet Rays; Up-Regulation

The aim of this study was to investigate the mechanisms by which troxerutin protects cells against ultraviolet B (UVB) radiation. First, we demonstrate that pre-treatment with troxerutin protects normal human dermal fibroblasts (nHDFs) against UVB-induced cytotoxicity. As shown by migration assay and DNA repair analysis, troxerutin increased cell migration and DNA repair activity in the nHDFs. Subsequently, we analyzed microRNA (miRNA) expression profiles in the nHDFs. miRNAs are 19- to 24-nucleotide (nt) non-coding RNA molecules that regulate the translation of target genes through RNA interference. In UVB-exposed cells, miRNAs act on crucial functions, such as apoptosis and cellular senescence. miRNA expression is significantly altered during the protective process induced by phytochemicals. Therefore, understanding changes that occur in miRNA expression profiles may help to elucidate the protective mechanisms of troxerutin. We identified 11 miRNAs that were significantly (>2-fold) upregulated and 12 that were significantly downregulated (>2-fold) following treatment of the nHDFs with troxerutin. In addition, we investigated the biological functions of these miRNAs through the prediction of miRNA targets and Gene Ontology analysis of the putative targets. Overall, our findings indicate that pre-treatment with troxerutin increases the viability of UVB-exposed nHDFs through the alteration of the miRNA expression profiles.

Topics: Cell Death; Cell Movement; Cytoprotection; Dermis; DNA Repair; Down-Regulation; Fibroblasts; Gene Expression Profiling; Gene Ontology; Humans; Hydroxyethylrutoside; MicroRNAs; Protective Agents; Ultraviolet Rays; Up-Regulation

Colon cancer is the third most global oncologic problem faced by medical fraternity. Troxerutin, a flavonoid present in tea, coffee, cereal grains, and a variety of fruits and vegetables, exhibits various pharmacological and biological activities. This study was carried out to investigate the effect of troxerutin on xenobiotic metabolizing enzymes, colonic bacterial enzymes and the development of aberrant crypt foci (ACF) during 1,2-dimethylhydrazine (DMH) induced experimental rat colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control. Group 2 received troxerutin (50 mg/kg b.w., p.o. every day) for 16 weeks. Groups 3-6 received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups 4-6 received different doses of troxerutin (12.5, 25, 50 mg/kg b.w., p.o. every day respectively) along with DMH injections. Our results reveal that DMH treated rats exhibited elevated activities of phase I enzymes such as cytochrome P450, cytochrome b5, cytochrome P4502E1, NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase and reduced activities of phase II enzymes such as glutathione-S-transferase (GST), DT-diaphorase (DTD) and uridine diphospho glucuronyl transferase (UDPGT) in the liver and colonic mucosa of control and experimental rats. Furthermore, the activities of fecal and colonic mucosal bacterial enzymes, such as β-glucronidase, β-glucosidase, β-galactosidase and mucinase were found to be significantly higher in DMH alone treated rats than those of the control rats. On supplementation with troxerutin to DMH treated rats, the alterations in the activities of the biotransforming enzymes, bacterial enzymes and the pathological changes were significantly reversed, the effect being more pronounced when troxerutin was supplemented at the dose of 25 mg/kg b.w. Thus troxerutin could be considered as a good chemopreventive agent against the formation of preneoplastic lesions in a rat model of colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Anticoagulants; Biotransformation; Carcinogens; Cell Transformation, Neoplastic; Colonic Neoplasms; Cytochrome P-450 Enzyme System; Glucuronosyltransferase; Glutathione Transferase; Hydroxyethylrutoside; Male; Oxidoreductases; Rats; Rats, Wistar

Alzheimer׳s disease (AD) is a neurodegenerative disorder with a progressive cognitive decline and memory loss. Multiple pathogenetic factors including aggregated β-amyloid (Aβ), neurofibrillary tangles (NFTs), cholinergic dysfunction and oxidative stress are involved in AD. Aβ, a major constituent of the senile plaques, is a potent neurotoxic peptide and has a pivotal role in cognitive deficit and reduced synaptic plasticity in AD. In the present study we examined the protective effect of troxerutin, as a multipotent bioflavonoid, on Aβ (1-42)-induced impairment of evoked field potential in hippocampal DG neurons. Male Wistar rats were divided into four groups including Aβ (42-1), Aβ (1-42), Aβ (1-42) plus troxerutin and Aβ (42-1) plus troxerutin groups. Aβ was injected intracerebroventricularly (i.c.v.) into right lateral ventricle and after two weeks the evoked field potential recorded from perforant path-DG synapses to assess paired pulse paradigm and long term potentiation (LTP). Administration of Aβ (1-42) drastically attenuated the LTP of DG neurons, while there was no significant difference in evoked field potentials between Aβ (1-42) plus troxerutin group with respect to Aβ (42-1) group. This study revealed that troxerutin improves the synaptic failure induced by Aβ peptide and can be introduced as a promising multi-potent pharmacological agent in prevention or treatment of AD in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dentate Gyrus; Electrophysiological Phenomena; Hydroxyethylrutoside; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Rats; Rats, Wistar; Synapses

Troxerutin is a trihydroxyethylated derivative of the flavonoid, rutin. It has been reported to possess the hepatoprotective, nephroprotective, antioxidant, anti-inflammatory, and antihyperlipidemic activities. Troxerutin treatment reduced the blood glucose and glycosylated hemoglobin levels in high-cholesterol-induced insulin-resistant mice and in type-2 diabetic patients. However, the mechanism by which it exhibits antidiabetic property was unknown. Therefore, the present study was designed to evaluate the effect of troxerutin on insulin signaling molecules in gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic rats. Wistar male albino rats were selected and divided into five groups. Group I: Control. Group II: High fat and sucrose-induced type-2 diabetic rats. Group III: Type-2 diabetic rats treated with troxerutin (150 mg/kg body weight/day orally). Group IV: Type-2 diabetic rats treated with metformin (50 mg/kg body weight/day orally). Group V: Normal rats treated with troxerutin (150 mg/kg body weight/day orally). After 30 days of treatment, fasting blood glucose, oral glucose tolerance, serum lipid profile, and the levels of insulin signaling molecules, glycogen, glucose uptake, and oxidation in gastrocnemius muscle were assessed. Diabetic rats showed impairment in insulin signaling molecules (IR, p-IRS-1(Tyr632), p-Akt(Ser473), β-arrestin-2, c-Src, p-AS160(Thr642), and GLUT4 proteins), glycogen concentration, glucose uptake, and oxidation. Oral administration of troxerutin showed near normal levels of blood glucose, serum insulin, lipid profile, and insulin signaling molecules as well as GLUT4 proteins in type-2 diabetic rats. It is concluded from the present study that troxerutin may play a significant role in the management of type-2 diabetes mellitus, by improving the insulin signaling molecules and glucose utilization in the skeletal muscle.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucose Transporter Type 4; Hydroxyethylrutoside; Hypoglycemic Agents; Insulin; Male; Muscle, Skeletal; Rats; Rats, Wistar; Signal Transduction

Recent evidences suggest that NAD(+) depletion leads to abnormal hepatic lipid metabolism in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD); however, the contributing mechanism is not well understood. Our previous study showed that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, effectively inhibited obesity, and normalized hyperglycemia and hyperlipidemia in high-cholesterol diet-induced diabetic mice. Here we investigated whether troxerutin improved hepatic lipid metabolism via preventing NAD(+) depletion in HFD-induced NAFLD mouse model and the mechanisms underlying these effects. Our results showed that troxerutin markedly prevented obesity, liver steatosis and injury in HFD-fed mice. Troxerutin largely suppressed oxidative stress-mediated NAD(+)-depletion by increasing nicotinamide phosphoribosyltransferase (NAMPT) protein expression and decreasing poly (ADP-ribose) polymerase-1 (PARP1) protein expression and activity in HFD-treated mouse livers. Consequently, troxerutin remarkably restored Silent mating type information regulation 2 homolog1 (SirT1) protein expression and activity in HFD-treated mouse livers. Therefore, troxerutin promoted SirT1-mediated AMP-activated protein kinase (AMPK) activation to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling, which enhanced nuclear lipin 1 localization, lowered cytoplasmic lipin 1 localization and the ratio of hepatic Lpin 1β/α. Ultimately, troxerutin improved lipid homeostasis by enhancing fatty acid oxidation and triglyceride secretion, and suppressing lipogenesis in HFD-fed mouse livers. In conclusion, troxerutin displayed beneficial effects on hepatic lipid homeostasis in HFD-induced NAFLD by blocking oxidative stress to restore NAD(+)-depletion-mediated dysfunction of lipin 1 signaling. This study provides novel mechanistic insights into NAFLD pathogenesis and indicates that troxerutin is a candidate for pharmacological intervention of NAFLD via restoring NAD(+) levels.

Topics: Animals; Diet, High-Fat; Fatty Liver; Hydroxyethylrutoside; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred ICR; NAD; Nuclear Proteins; Obesity; Oxidative Stress; Phosphatidate Phosphatase; Signal Transduction; Sirtuin 1

The C/EBP β is a basic leucine zipper transcription factor that regulates a variety of biological processes, including metabolism, cell proliferation and differentiation, and immune response. Recent findings show that C/EBP β-induced inflammatory responses mediate kainic acid-triggered excitotoxic brain injury. In this article, we show that protein kinase C ζ enhances K-ras expression and subsequently activates the Raf/MEK/ERK1/2 pathway in the hippocampus of domoic acid (DA)-treated mice, which promotes C/EBP β expression and induces inflammatory responses. Elevated production of TNF-α impairs mitochondrial function and increases the levels of reactive oxygen species by IκB kinase β/NF-κB signaling. The aforementioned inflammation and oxidative stress lead to memory deficits in DA-treated mice. However, troxerutin inhibits cyclin-dependent kinase 1 expression, enhances type 1 protein phosphatase α dephosphorylation, and abolishes MEK/ERK1/2/C/EBP β activation, which subsequently reverses the memory impairment observed in the DA-treated mice. Thus, troxerutin is recommended as a potential candidate for the prevention and therapeutic treatment of cognitive deficits resulting from excitotoxic brain damage and other brain disorders.

Topics: Animals; Butadienes; CCAAT-Enhancer-Binding Protein-beta; CDC2 Protein Kinase; Gene Knockdown Techniques; Genes, ras; Hippocampus; Hydroxyethylrutoside; Inflammation; Inflammation Mediators; Kainic Acid; Male; Memory Disorders; Mice; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidases; Nitriles; Oxidative Stress; Phosphoprotein Phosphatases; Phosphorylation; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

This study investigates the effects of troxerutin on nickel (Ni)-induced oxidative stress in rats.. Nickel as nickel sulfate (20 mg/kg body weight (b.w.)) was administered intraperitoneally for 20 days to induce toxicity in the subject rats. The levels of stress markers AST, ALT, ALP, LDH, and GGT in the hepatic tissue were significantly increased while a decrease in the levels of enzymic and non-enzymic antioxidants was observed in Ni intoxicated rats.. Oral administration of troxerutin along with Ni for 20 days in a dose-dependent manner significantly reverted the stress markers in the liver tissue to near normal level. Troxerutin exhibited significant protection at 100 mg/kg b.w. Histopathological studies also supported the above findings.. Thus, we conclude that troxerutin preserved the histo-architecture and ameliorated stress markers in the liver tissue of Ni-intoxicated rats.

Topics: Alanine Transaminase; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Hydroxyethylrutoside; Lipid Peroxides; Liver; Male; Nickel; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

The purpose of this study was to conduct research in mice to determine the radioprotective effects of troxerutin. Thirty-day survival, oxidative status and histological changes in the liver were all evaluated.. Troxerutin was administered orally to mice for six days before irradiation with different doses (6, 7, 8 and 10 Gy) of γ-rays and the mice were observed for 30 days after radiation to calculate 30-day survival and median lethal dose of 30 days (LD50/30). Its radioprotective efficacy was compared with the positive drug amifostine which is currently the most effective radioprotector. The animals pretreated with troxerutin for 6 days were sacrificed on day 11 after radiation (6 Gy) in order to make 10% homogenate and histological sections of liver. Antioxidant enzymes were detected in strict accordance with kit requirements. Histological liver sections were examined by hematoxylin-eosin (HE) staining.. Pretreatment with troxerutin resulted in a significantly higher 30-day survival rate for 70% of mice compared with 30% of irradiation group after exposure to a potentially lethal dose of 8 Gy; LD50/30 of drug treatment group was 9 Gy compared with 7.7 Gy for irradiation group. The results indicated that troxerutin increased the activity of various antioxidant enzymes, such as superoxide dismutase (SOD) in mice liver, which was reduced by radiation treatment. Maleic dialdehyde (MDA) levels were significantly reduced by troxerutin, which was increased after 6 Gy radiation. These results were further confirmed by histopathological examinations which indicated that pre-administration with the effective dose of troxerutin reduced the hepatic damage induced by radiation.. Administration of troxerutin before irradiation, provided higher survival of experimental mice, improvement of biochemical parameters, and preserved major histological parameters of the liver. These results collectively indicate that troxerutin is an effective radioprotective agent.

Topics: Animals; Antioxidants; Gamma Rays; Hydroxyethylrutoside; Lethal Dose 50; Liver; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Radiation-Protective Agents; Survival Analysis

Comparative studies of enzymatic acylation of troxerutin by the alkaline protease from Bacillus subtilis under ultrasound and shaking were carried out in nonaqueous media. Using divinyl dicarboxylates (CH(2)CH-OOC-(CH(2))(n)-COO-CHCH(2), n=2, 3, 4, 7, 8, 11) featuring different chain length as acyl donors, troxerutin was regioselectively acylated at B ethoxyl group, whether under ultrasound or shaking. Ultrasonic treatment increased the reaction rate and led to high conversion. Several factors, such as pre-irradiation on the enzyme, the power and frequency of the ultrasound, operation manner, as well as the length of the acyl donors were investigated. Using enzyme pre-irradiated for 8 h, the conversion of troxerutin was increased to 87.3% compared with 56.3% obtained from the untreated enzyme. Experimental results also showed that continual ultrasound caused greater rate acceleration than interval ultrasound. Powers of 100, 150 and 200 W, frequencies of 40, 80 and 100 kHz all showed significant improvement on the transesterification, with the greatest effect observed at 150 W, 80 kHz. The acceleration effect increased as the chain length of the acyl donors decreased from C(13) to C(4).

Topics: Bacillus subtilis; Bacterial Proteins; Endopeptidases; Esters; Hydroxyethylrutoside; Solvents; Ultrasonics

Recent findings suggest that neurotoxicity is the mechanism underlying the induction of neuronal insulin resistance by a high cholesterol diet. Troxerutin, a naturally occurring flavonoid, has been reported to possess biological activity beneficial to human health. Our recent studies have demonstrated that troxerutin attenuates cognitive impairment and oxidative stress induced by D-galactose in mouse brain through decreasing advanced glycation end products, reactive oxygen species and protein carbonyl levels and enhancing phosphoinositide 3-kinase/Akt activation. In this study, we evaluated the effect of troxerutin on cognitive impairment induced by brain insulin resistance in mice fed a high-cholesterol diet, and explored its potential mechanism. Our results showed that oral administration of troxerutin to these mice significantly improved behavioural performance in a step-through passive avoidance task and a Morris water maze task, at least in part, by decreasing the levels of reactive oxygen species, protein carbonyl and advanced glycation end products and blocking endoplasmic reticulum stress via reduced phosphorylation of the pancreatic endoplasmic reticulum-resident kinase and eukaryotic translation initiation factor 2α. Furthermore, troxerutin significantly inhibited the activation of c-jun N-terminal kinase 1 and IκB kinase β/nuclear factor-κB induced by endoplasmic reticulum stress and enhanced insulin signalling pathway, which prevented obesity, restored normal levels of blood glucose, fatty acids and cholesterol and increased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and the expression levels of c-fos in the hippocampus. Moreover, troxerutin significantly inhibited endoplasmic reticulum stress-induced apoptosis and decreased the activation of caspase-12 and caspase-3, and reduced the mean optical density of the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end label-positive cells in the hippocampus. However, intra-cerebroventricular infusion of PI-103, a specific phosphoinositide 3-kinase 110α inhibitor, significantly inhibited the expression levels of phosphoinositide 3-kinase 110α and phosphoinositide 3-kinase downstream signalling in the hippocampus of mice co-treated with high cholesterol and troxerutin and vehicle control mice. These results suggest that troxerutin could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in typ

Topics: Animals; Avoidance Learning; Blood Glucose; Body Weight; Brain; Cholesterol; Cognition Disorders; CREB-Binding Protein; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Gene Expression Regulation; Glycation End Products, Advanced; Hydroxyethylrutoside; Immunoprecipitation; In Situ Nick-End Labeling; Infusions, Intraventricular; Insulin Resistance; Male; Maze Learning; Mice; Mice, Inbred C57BL; Neuroprostanes; Phosphorylation; Protein Carbonylation; Reactive Oxygen Species; Signal Transduction; Triglycerides

This study was purposed to explore the effect of troxerotin and cerebroproptein hydrolysate injection (TCHI) on platelet aggregation in vitro and thrombosis in vivo. The inhibitory rate of TCHI at different concentrations on platelet aggregation was determined by platelet aggregometer. The relationship between dose and effect was established. The effect of troxerutin and cerebroproptein hydrolysate injection on thrombosis was determined by the carotid thrombosis model of rats. The results showed that the TCHI could inhibit thrombosis and platelet aggregation in a concentration-dependent way. When the concentration of TCHI total nitrogen was 5 µg/ml, the inhibition rate of platelet aggregation reached to the highest value of 28.61 ± 22.07%, which is 2.5 times as much as that with 100 µg/ml aspirin. It is concluded that the TCHI has antiaggregative and antithrombotic activity effects against platelet aggregation and thrombosis.

Topics: Animals; Hydroxyethylrutoside; Platelet Aggregation; Protein Hydrolysates; Rabbits; Rats; Rats, Wistar; Thrombosis

This registry evaluation was conducted in post-thrombotic syndrome (PTS) patients (with a minimum five-year follow up). The study evaluated: 1) variations in peripheral edema with an analogue scoring system; 2) ankle circumference at the PTS limb in comparison with the normal contralateral limb.. The difference was expressed in percent increase in circumference measured at the PTS limb; 3) other end-points were observed in a five-year follow-up that created a specific PTS registry. Subjects could follow a management system including: 1) compression; 2) compression and Venoruton® (1 g/day); 3) compression and Venoruton® (2 g/day).. The groups of patients with chronic venous insufficiency (CVI) resulted comparable. The occurrence of a new deep venous thrombosis (DVT) episode was considered a drop out. At five years there were four new DVTs (in 90 patients) in the compression group. There was one case (90 patients included) in the compression and HR (1 g) group and no DVT in group 3. The outcome in groups 2 and 3 was significantly better (0.05) than in group 1. The need for surgery or sclerotherapy (for larger varicose veins), the occurrence of lipodermatosclerosis and ulcerations were significantly lower in the HR groups with a better outcome in the higher dose group (P<0.05). The number of ulcerations were also significantly reduced in the HR groups. The difference in ulcerations was significantly better in the higher dose group in comparison with the other groups (P<0.05). The edema score was significantly reduced at five years in the HR groups (P<0.05) in comparison with the compression group. The higher dose resulted more effective in controlling edema. Both edema score and ankle circumference at five years were significantly lower (P<0.05) in the HR-treated groups with a significant decrease in edema score and ankle circumference in the higher dosage group.. The study confirms the long-term efficacy of HR in PTS, CVI patients. Controlling signs/symptoms and edema in CVI with HR prevents the most severe complications of CVI including lipodermatosclerosis and venous ulcerations. An early therapeutic program including exercise, risk factor controls, compression an edema-controlling treatment with HR is effective in decreasing the classic complications of PTS syndrome. The important restrictions and difficulties to the use of elastic stockings (in regions with warmer climates) are not applicable to HR that is well tolerated and can be used all the time alone or in association with compression.

Topics: Adult; Ankle; Combined Modality Therapy; Edema; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Postthrombotic Syndrome; Registries; Secondary Prevention; Stockings, Compression; Treatment Outcome; Venous Insufficiency

The purpose of this study was to determine radioprotective effects of troxerutin. Cell experiments were carried out to test the cytotoxicity of troxerutin on V79 cells and to observe effects on apoptosis caused by 60CO γ rays. A model of 8 Gy ray-caused damage of mice was established to observe the effect that troxerutin has on the physical symptom of irradiated mice and to calculate the 30-day survival rate. It showed that troxerutin had no obvious cytotoxicity at the level of less than 20 μg/ml; but had a redioprotective effect in dose-dependence on viability of V79 cells at the range of 0.2-5 μg/mL irradiated by 5 Gy ray of 60CO γ ray. After the 8 Gy irradiation, the mice lost some weight, were dried up in fur and feather, low spirit, awkward in movement, shrinking in body and handicapped in sight, while mice with troxerutin were much better. So it was clear that troxerutin could increase the 30-day survival rates of irradiated mice dramatically. These results collectively indicate that troxerutin is an effective radioprotective agent.

Topics: Animals; Apoptosis; Cell Line; Cricetinae; Dose-Response Relationship, Radiation; Gamma Rays; Hydroxyethylrutoside; Male; Mice; Mice, Inbred BALB C; Radiation-Protective Agents; Survival Rate; Whole-Body Irradiation

We aimed to assess the effects of local troxerutin and heparinoid (HEP) treatments in a model of flap necrosis. Three groups of Wistar albino rats, each comprising 10 animals were used. A cranially based 6x3-cm full-thickness random-pattern skin flap was raised and sutured to the same area in each model. The control group was treated daily with normal saline, the second with topical HEP and the third with topical troxerutin. The amount of flap necrosis was measured in all groups by the end of the seventh day. Flap tissues were excised for histological analysis and evaluation of the expression of vascular endothelial growth factor (VEGF) levels. Assessment of the blood levels of nitric oxide was also performed in each animal by cardiac puncture. The mean area of flap necrosis was 110.6mm(2) in the control, 39.44 mm(2) in the troxerutin and 47.11 mm(2) in the heparinoid-treated rats. The treatment arms exhibited significant reduction in areas of flap necrosis, compared with the control group (p<0.001), but it was similar among treatment groups (p=0.60). The rates of fibroblast proliferation were decreased in control group as compared to HEP and troxerutin arms (p<0.001). The mean level of collagen density, collagen organisation, granulation tissue and demarcation were similar in all rats. Measurement of VEGF expression did not show any significant difference between the groups (p=0.30). Nitric oxide levels were significantly higher in control rats, as compared to treatment groups (p<0.0001), but were similar in treatment arms (p=0.45). Our results suggest that troxerutin and HEP effectively reduce the flap necrosis and improve flap survival. The observed effects might be due to their anti-oedematogenic, radical-scavenging, antioxidant effects and supportive activities on capillary permeability and transudation.

Topics: Administration, Topical; Animals; Anticoagulants; Disease Models, Animal; Female; Follow-Up Studies; Heparinoids; Hydroxyethylrutoside; Immunohistochemistry; Male; Necrosis; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Skin; Skin Transplantation; Spectrophotometry; Surgical Flaps; Treatment Outcome; Vascular Endothelial Growth Factor A; Vasoconstrictor Agents; Wound Healing

Previous evidence showed that administration of d-galactose (d-gal) increased ROS production and resulted in impairment of cholinergic system. Troxerutin, a natural bioflavonoid, has been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of troxerutin against d-gal-induced impairment of cholinergic system, and explored the potential mechanism of its action. Our results displayed that troxerutin administration significantly improved behavioral performance of d-gal-treated mice in step-through test and morris water maze task. One of the potential mechanisms of this action was decreased AGEs, ROS and protein carbonyl levels in the basal forebrain, hippocampus and front cortex of d-gal-treated mice. Furthermore, our results also showed that troxerutin significantly inhibited cholinesterase (AchE) activity, increased the expression of nicotinic acetylcholine receptor alpha 7 (nAchRalpha7) and enhanced interactions between nAchRalpha7 and either postsynaptic density protein 95 (PSD95) or N-methyl-d-aspartate receptors subunit 1 (NMDAR1) in the basal forebrain, hippocampus and front cortex of d-gal-treated mice, which could help restore impairment of brain function.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Animals; Avoidance Learning; Brain; Disks Large Homolog 4 Protein; Frontal Lobe; Galactose; Glycation End Products, Advanced; Guanylate Kinases; Hippocampus; Hydroxyethylrutoside; Intracellular Signaling Peptides and Proteins; Male; Maze Learning; Membrane Proteins; Mice; Neuroprotective Agents; Neuropsychological Tests; Prosencephalon; Protein Carbonylation; Random Allocation; Reactive Oxygen Species; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

Topics: Adult; Aged; Female; Humans; Hydroxyethylrutoside; Urinary Incontinence; Vasoconstrictor Agents

D-galactose-(D-gal)-treated mouse, with cognitive impairment, has been used for neurotoxicity investigation and anti-neurotoxicity pharmacology research. In this study, we investigated the mechanism underlying the neuroprotective effect of troxerutin. The results showed that troxerutin improved behavioral performance in D-gal-treated mice by elevating Cu, Zn-superoxide dismutases (Cu, Zn-SOD) activity and decreasing reactive oxygen species levels. Furthermore, our results showed that troxerutin significantly promoted nerve growth factor (NGF) mRNA expression which resulted in TrkA activation. On one hand, NGF/TrkA induced activation of Akt and ERK1/2, which led to neuronal survival; on the other hand, NGF/TrkA mediated CaMKII and CREB phosphorylation and increased PSD95 expression, which improved cognitive performance. However, the neuroprotective effect of troxerutin was blocked by treatment with K252a, an antagonist for TrkA. No neurotoxicity was observed in mice treated with K252a or troxerutin alone. In conclusion, administration of troxerutin to D-gal-injected mice attenuated cognitive impairment and brain oxidative stress through the activation of NGF/TrkA signaling pathway.

Topics: Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carbazoles; Cognition Disorders; CREB-Binding Protein; Disease Models, Animal; Disks Large Homolog 4 Protein; Enzyme Inhibitors; Galactose; Gene Expression Regulation; Guanylate Kinases; Hydroxyethylrutoside; Indole Alkaloids; Intracellular Signaling Peptides and Proteins; Male; Maze Learning; Membrane Proteins; Mice; Nerve Growth Factor; Neuroprotective Agents; Reactive Oxygen Species; Receptor, trkA; Signal Transduction; Superoxide Dismutase

Troxerutin, a natural bioflavonoid, has been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of troxerutin against D-gal-induced oxidative DNA damage in mouse kidney, and explored the potential mechanism of its action. Our data showed that troxerutin significantly decreased levels of urea, uric acid and creatinine in serum and the renal histological injury in D-gal-treated mice. Troxerutin markedly restored Cu/Zn-SOD, CAT and GPx activities in the kidney of D-gal-treated mouse. Furthermore, the increase of 8-hydroxydeoxyguanosine (a marker of oxidative DNA damage) induced by d-gal was effectively suppressed by troxerutin. Internucleosomal DNA ladder fragmentation and the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated mice were inhibited by troxerutin, which might be attributed to its antioxidant property by decreasing activities of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and levels of reactive oxygen species (ROS). In conclusion, these results suggested that troxerutin could protect the mouse kidney against D-gal-induced injury by improving renal function, attenuating histopathologic changes, reducing ROS production, renewing the activities of antioxidant enzymes and decreasing DNA oxidative damage. This study provided novel insights into the protective mechanisms of troxerutin in D-gal-induced kidney injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Catalase; Creatinine; Deoxyguanosine; DNA Damage; DNA Fragmentation; Galactose; Glutathione Peroxidase; Hydroxyethylrutoside; In Situ Nick-End Labeling; Kidney; Male; Mice; NADPH Oxidases; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Urea; Uric Acid

The objective of the study was to estimate the association of pregnant women with varicose veins of lower extremities (VVLE) and the possible risk for adverse birth outcomes and among them different congenital abnormalities (CAs) in their children. Prospectively and medically recorded VVLE were evaluated in 332 pregnant women who delivered infants with CA (case group) and 566 pregnant women with VVLE who delivered infants without CA (control group) and matched to cases were compared in the population-based data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980-1996. About one-quarter of pregnant women had chronic VVLE while new onset VVLE occurred in the rest of pregnant women. There was no higher risk for adverse birth outcomes of pregnant women with VVLE, in fact the rate of preterm birth and low birth weight was somewhat lower than in the newborns of pregnant women without VVLE. The comparison of VVLE occurrence in pregnant women who had offspring with 21 different CA groups and in pregnant women who later delivered babies without CA showed a higher risk only for pectus excavatum, a mild CA. In conclusion, VVLE in pregnant women does not associate with obvious hazard for their fetuses.

Topics: Adult; Anticoagulants; Case-Control Studies; Congenital Abnormalities; Female; Funnel Chest; Humans; Hungary; Hydroxyethylrutoside; Infant, Newborn; Logistic Models; Male; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Retrospective Studies; Risk Factors; Varicose Veins

This study was carried out to investigate the protective effect of troxerutin against D-galactose (D-gal)-induced renal injury in mice. Hematoxylin and eosin (H&E) stained sections of kidneys revealed D-gal could cause renal injury and troxerutin could significantly attenuate the injury. We further investigated the mechanisms involved in the protective effects of troxerutin on mouse kidney. The following antioxidant defense enzymes were measured: cytosolic Cu/Zn superoxide dismutase (SOD-1), catalase (CAT) and glutathione peroxidase (GPx). The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. In D-gal-treated mice, antioxidant enzymes activities were significantly decreased and the level of MDA was significantly higher than those in the vehicle controls. Our results indicated that the protective effect of troxerutin against D-gal induced renal injury might be caused, at least in part, by increasing the activity of antioxidant enzymes with a reduction in lipid peroxidation product. Furthermore, we also examined the inflammatory signal mediators of nuclear factor-kappaB (NF-kappaB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanoid receptor subtype EP2 by Western blot. After treatment with D-gal, the NF-kappaB p65, iNOS, COX-2 and EP2 were markedly upregulated. Upon co-treatment with the troxerutin, however, the expressions of the NF-kappaB p65, iNOS, COX-2 and EP2 markedly reduced, compared to D-gal treatment alone. These results indicated that troxerutin has significantly inhibitory effects on the NF-kappaB-mediated inflammatory response. These findings suggest troxerutin could attenuate renal injury induced by D-gal probably through its antioxidant and anti-inflammation properties.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blotting, Western; Catalase; Galactose; Glutathione Peroxidase; Hydroxyethylrutoside; Immunohistochemistry; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Malondialdehyde; Mice; Oxidative Stress; Superoxide Dismutase

Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Body Weight; Chemical and Drug Induced Liver Injury; Galactose; Hydroxyethylrutoside; Lipid Peroxidation; Liver; Male; Mice; Oxidative Stress; Transcription Factor RelA

Examination of 118 patients with chronic generalized parodontitis of medium and heavy severity was performed and treatment was elaborated with the use of laser therapy and angioprotectants' photophoresis and mesophotophoresis. Use of the mentioned physical and physical-pharmacological methods in comprehensive cure let to shorten the course of treatment and increase remission duration.

Topics: Adult; Chronic Disease; Combined Modality Therapy; Female; Gels; Humans; Hydroxyethylrutoside; Laser Therapy; Male; Middle Aged; Periodontal Diseases; Photopheresis; Vasoconstrictor Agents; Young Adult

The method of high-performance liquid chromatography (HPLC) with UV-vis detection was used and validated for the simultaneous determination of six flavonoids (puerarin, rutin, morin, luteolin, quercetin, kaempferol) and troxerutin in rat urine and chicken plasma. Chromatographic separation was performed using a VP-ODS column (150 mm x 4.6 mm, 5.0 microm) maintained at 35.0 degrees C. The mobile phase was a mixture of water, methanol and acetic acid (57:43:1, v/v/v, pH 3.0) at the flow rate of 0.8 mL/min. Six flavonoids and troxerutin were analyzed simultaneously with good separation. On optimum conditions, calibration curves were found to be linear with the ranges of 0.10-70.00 microg/mL (puerarin, rutin, morin, luteolin, quercetin, kaempferol) and 0.50-350.00 microg/mL (troxerutin). The detection limits were 0.010-0.050 microg/mL. The method was validated for accuracy and precision, and it was successfully applied to determine drug concentrations in rat urine and chicken plasma samples from rat and chicken that had been orally administered with six flavonoids and troxerutin.

Topics: Animals; Chickens; Chromatography, High Pressure Liquid; Flavonoids; Hydroxyethylrutoside; Rats; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The methanol soluble fraction of the leaves of Buddleia scordioides after column chromatography resulted in the isolation of two known iridoid glucosides, catalpol and methylcatalpol. The structures were elucidated by extensive 1D-2D-NMR spectroscopy. The structure of methylcatalpol was confirmed by single-crystal x-ray diffraction. These compounds showed protective activity against increased (both chloroform and histamine) skin vascular permeability in rabbits. The protective effect was measured as the reduction in leakage of Evans blue. The results showed that the iridoids produced a significant inhibition of microvascular permeability. A comparison was made between the action of the iridoids and a known inhibitor of vascular permeability, troxerutin (50 mg/kg). Methylcatalpol and catalpol were found to be less effective than troxerutin.

Topics: Animals; Buddleja; Capillaries; Glucosides; Hydroxyethylrutoside; Iridoid Glucosides; Iridoids; Male; Permeability; Rabbits; Skin; Vasoconstrictor Agents

The voltammetric responses of troxerutin were investigated at polyvinylpyrrolidone (cross-linked) (PVP) modified carbon paste electrode (CPE) in 0.1 mol/L KCl by several electrochemical techniques. A well-defined oxidation peak was observed at about 0.97 V. Compared with poor responses of troxerutin at bare electrode that at this modified electrode has been greatly improved. It is PVP that enhances the adsorption of troxerutin to electrode surface based on their hydrophobic property. Under some optimized experimental conditions, a simple and sensitive electroanalytical method was developed for the quantitative analysis of troxerutin. A very low detection limit of 5.0 x 10(-9)mol/L was obtained for 5 min accumulation at open circuit (S/N=3). This proposed method was successfully applied to the detection of troxerutin in pharmaceutical dosage forms and satisfying results had been obtained.

Topics: Adsorption; Calibration; Carbon; Dosage Forms; Electrochemistry; Electrodes; Electrolytes; Hydroxyethylrutoside; Molecular Structure; Oxidation-Reduction; Potassium Chloride; Povidone; Sensitivity and Specificity

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

The vascular changes associated with early diabetic retinopathy, which include the formation of microaneurysms and acellular capillaries, vessel dilation, vascular endothelial growth factor expression, were investigated experimentally in streptozotocin-induced diabetic rats treated with antioxidants: troxerutin (trihydroxy-ethylrutoside, CAS 7085-55-4), Vaccinium myrtillus, and calcium dobesilate (hydroquinone calcium sulfonate, CAS 20123-80-2). The development and progression of retinopathy was followed using fundus photography. After 3 months, the rats were sacrificed and half of the eyes were prepared for neovascularization analysis, and the other half were used for VEGF (vascular endothelial growth factor) analysis. The results from fundus photography and ADPase (adenosine diphosphatase) staining were quantified by the percentage area of the retinal vasculature using a commercial image analyzer. The VEGF protein in the retinal homogenates was assessed using an ELISA (enzyme linked immunosorbent assay) kit and VEGF-mRNA by RT-PCR (reverse transcription polymerase chain reaction). In the ADPase stain, the retinal vascular percent area increased significantly in the diabetic control. Neovascularization and aneurysms were observed in the diabetic control and were attenuated by 50 mg/kg troxerutin, but the retinal vascular percentage area was not significantly different from the diabetic control. The VEGF protein concentration was higher in diabetic rats than in the nondiabetic rats (21.5 +/- 2.1 vs 27.7 +/- 5.8 pg/mg, p < 0.05), and this increase was attenuated by 10 mg/kg troxerutin (24.5 +/- 3.8 pg/mg, p < 0.05) and prevented by 50 mg/kg troxerutin (19.5 +/- 2.2 pg/mg, p < 0.05). However, there were no significant differences between the groups. The VEGF-mRNA density showed a increasing tendency by 20% in the diabetic rats compared with the non-diabetic rats (1.0 +/- 0.1 vs 1.2 +/- 0.1 VEGF/beta-actin), and this increase was corrected by 10 mg/kg troxerutin (1.0 +/- 0.1 VEGF/beta-actin), 50 mg/kg troxerutin (0.9 +/- 0.1 VEGF/beta-actin) and Vaccinium myrtillus (1.1 +/- 0.1 VEGF/beta-actin). Oxidative stress might be involved in the upregulation of retinal VEGF during early diabetes, and it is likely that troxerutin has comparatively effective antioxidant properties. Therefore, troxerutin might be a useful treatment for attenuating diabetic retinopathy.

Topics: Animals; Apyrase; Blood Glucose; Body Weight; Calcium Dobesilate; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Fundus Oculi; Hemostatics; Hydroxyethylrutoside; Phytotherapy; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA; Vaccinium myrtillus; Vascular Endothelial Growth Factor A; Vasoconstrictor Agents

The effect of troxerutin on gamma-radiation-induced DNA strand breaks in different tissues of mice in vivo and formations of the micronuclei were studied in human peripheral blood lymphocytes ex vivo and mice blood reticulocytes in vivo. Treatments with 1 mM troxerutin significantly inhibited the micronuclei induction in the human lymphocytes. Troxerutin protected the human peripheral blood leucocytes from radiation-induced DNA strand breaks in a concentration dependent manner under ex vivo condition of irradiation (2 Gy). Intraperitoneal administration of troxerutin (175 mg/kg body weight) to mice before and after whole body radiation exposure inhibited micronuclei formation in blood reticulocytes significantly. The administration of different doses (75, 125 and 175 mg/kg body weight) of troxerutin 1 h prior to 4 Gy gamma-radiation exposure showed dose-dependent decrease in the yield of DNA strand breaks in murine blood leucocytes and bone marrow cells. The dose-dependent protection was more pronounced in bone marrow cells than in blood leucocytes. Administration of 175 mg/kg body weight of the drug (i.p.) 1 h prior or immediately after whole body irradiation of mice showed that the decrease in strand breaks depended on the post-irradiation interval at which the analysis was done. The observed time-dependent decrease in the DNA strand breaks could be attributed to enhanced DNA repair in troxerutin administered animals. Thus in addition to anti-erythrocytic, anti-thrombic, fibrinolytic and oedema-protective rheological activity, troxerutin offers protection against gamma-radiation-induced micronuclei formation and DNA strand breaks and enhances repair of radiation-induced DNA strand breaks.

Topics: Adult; Animals; Bone Marrow Cells; Comet Assay; DNA; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Gamma Rays; Humans; Hydroxyethylrutoside; Leukocytes; Lymphocytes; Mice; Micronuclei, Chromosome-Defective; Middle Aged; Whole-Body Irradiation

Accumulation of Advanced Lipoxidation End-products (ALE), such as MDA- and HNE-protein adducts, and Advanced Glycation End-products, such as carboxymethyl-lysine (CML), are probably involved in the development of diabetic nephropathy. In this study the effect of some antioxidant treatments (oxerutin, N-acetylcysteine, taurine and N-acetylcysteine+taurine) on kidney lipoxidative damage has been evaluated by immunohistochemistry in streptozotocined rats. Diabetic rats showed marked glomerular positivity for ALE, while the samples from Control rats were negative. All treatments except taurine were able to protect the glomeruli from ALE accumulation; the failure of taurine may be due to residual oxidative properties of its derivatives. These data are consistent with those of our previous study, which showed that all the antioxidants used except taurine protected the glomeruli from diabetes-induced enlargement, increased apoptotic rate, decreased cell density and CML accumulation. These data attest to a role of glycoxidative and lipoxidative damage in diabetes-dependent damage of the kidney, and indicate that specific antioxidants can prevent or attenuate diabetic nephropathy.

Topics: Acetylcysteine; Aldehydes; Animals; Apoptosis; Cell Division; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glycation End Products, Advanced; Hydroxyethylrutoside; Immunohistochemistry; Kidney Glomerulus; Lipid Peroxidation; Lysine; Male; Rats; Rats, Wistar; Taurine

The purpose of our study was to assess the different effectiveness of Troxerutin in association with Pycnogenol compared to the effects obtainable with the same pharmacological principle in monotherapy in patients suffering from venous insufficiency.. Seventy patients with venous insufficiency of the lower extremities at the first stages of the CEAP classification (Cs1,3; Es; As 1; invalidity score 2, clinical score 1-2) were selected and subdivided into 2 groups: one of 50 and one of 20. All patients reported the following symptoms either associated or in isolation: heaviness, cramps, pruritus and pain at palpation. Evaluation of the degree of venous insufficiency was carried out by means of echo-Doppler at recruitment. The 1st group received Troxerutin (470 mg) associated with Pycnogenol (20 mg) in a dose of 1 g/day per os for 60 days; the 2nd group Troxerutin alone (300 mg) in a dose of 2 tablets twice a day per os for 60 days. Controls were set up at 30 and 60 days from the start of treatment and after a period of 3 months from the end of treatment to assess the effects on the symptomatology over time. The effectiveness of the drugs on symptomatology reported by both groups was assessed by means of an analysis of the qualitative variation of the symptoms using the score-scales method: 3=severe; 2=moderate; 1=slight; 0=absent and this variation was expressed as a percentage decrease and analysed using Student's test.. The results of our study after 30 days of treatment highlighted a clinical improvement in all patients with the disappearance of symptoms (score from 3 to 1) in 50% of patients in the 1st group and in 35% in the 2nd with a peak of 96% in patients of the 1st group and 80% in the 2nd at the end of treatment (60 days). This result held stable in the course of follow-up for 96% of patients in the 1st group (p<0.001) and for 50% of those in the 2nd group (p<0.005).. Comparison between the 2 groups showed that the group which received Troxerutin associated with Pycnogenol reported greater therapeutic effectiveness than the control group as regards both the rapidity of disappearance of the symptoms and as regards maintenance of the cure obtained.

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Analysis of Variance; Data Interpretation, Statistical; Drug Therapy, Combination; Female; Flavonoids; Follow-Up Studies; Humans; Hydroxyethylrutoside; Male; Middle Aged; Plant Extracts; Platelet Aggregation Inhibitors; Time Factors; Treatment Outcome; Vasoconstrictor Agents; Venous Insufficiency

The influence of three important cytokines (IL-8, TNF-alpha, and HuIFN-alpha) on ongoing rhinovirus infections has been examined in vitro, individually or as combinations. TNF-alpha was able to transform traces of HRV infections into full-blown infections. Furthermore, TNF-alpha was able to down-regulate the antiviral action of HuIFN-alpha completely, even at levels of just a few pg/ml. This suggests that the induction of TNF-alpha by HRV may be part of the virus's strategy to minimize the interferon response which is part of the host's immune defence system. However, troxerutin (a flavonoid) was able to neutralize the downregulatory action of TNF-alpha on the HuIFN-alpha system at low levels and re-establish the antiviral activity ascribed to IFN-alpha. IL-8 exerted a minor influence on the interferon system, and had no influence on rhinovirus infections. The in vitro findings are supported, in part, by recent in vivo findings in a common cold pilot study.

Topics: Cell Line; Common Cold; Humans; Hydroxyethylrutoside; Interferon-alpha; Interleukin-8; Rhinovirus; Tumor Necrosis Factor-alpha; Virus Replication

The ulcers, located below the knees and remaining for 6 weeks and more, are called trophic leg ulcers. The leg ulcers of different etiology disable 0.8-1% of total Earth population. It was found that blood vessel problems in legs account for more than 80% of ulcers; even 65% from these are caused by venous diseases. In Lithuania about 8000 patients suffer from venous trophic ulcers. Regardless of modern methods the treatment of leg ulcers remains an extremely expensive process. The treatment cost of trophic ulcers is the highest of all surgical wounds and also requires a lot of personal investments. In order to assess the efficiency of autodermoplastics in the treatment of large venous ulcers in legs a prospective study was carried out of 111 patients who were treated in the Department of Plastic Surgery and Burns of Kaunas University of Medicine Hospital from January 2001 to January 2004. The data was analyzed exceptionally of the operated 54 patients with venous origin ulcers open for more 6 months or exceeding 50 cm2. The above-mentioned patients were prepared for surgery by dressing the wounds with hydrocolloid Granuflex bandages and were operated by transplanting a 0.2-0.3 mm thick skin graft. The results were estimated by the surgeon during the dressings after the operation. The graft was taken in 35 (64.81%) cases; in 19 (35.19%) cases the graft was partially not taken and there were no cases when it was not taken at all. We came to the conclusions that skin graft transplantation is efficient in treatment of trophic venous leg ulcers larger than 50 cm2 and cures the trophic leg ulcers of vein origin completely in 2-3 weeks for 64.81% patients.

Topics: Adult; Aged; Aged, 80 and over; Bandages; Colloids; Female; Follow-Up Studies; Hematologic Agents; Humans; Hydroxyethylrutoside; Length of Stay; Male; Middle Aged; Pentoxifylline; Postoperative Care; Preoperative Care; Prospective Studies; Random Allocation; Sampling Studies; Skin Transplantation; Time Factors; Treatment Outcome; Varicose Ulcer; Vasoconstrictor Agents

The flavanoid derivative troxerutin, used clinically for treating venous disorders, protected biomembranes and cellular DNA against the deleterious effects of gamma-radiation. The peroxidation of lipids (measured as thiobarbituric acid-reacting substances, or TBARS) in rat liver microsomal and mitochondrial membranes resulting from gamma-irradiation up to doses of 500 Gy in vitro was prevented by 0.2 mM troxerutin. The administration of troxerutin (175 mg/kg body weight) to tumor-bearing mice by ip one hour prior to 4 Gy whole-body gamma-irradiation significantly decreased the radiation-induced peroxidation of lipids in tissues such as liver and spleen, but there was no reduction of lipid peroxidation in tumor. The effect of troxerutin in gamma-radiation-induced DNA strand breaks in different tissues of tumor-bearing mice was studied by comet assay. The administration of troxerutin to tumor-bearing animals protected cellular DNA against radiation-induced strand breaks. This was evidenced from decreases in comet tail length, tail moment, and percent of DNA in the tails in cells of normal tissues such as blood leukocytes and bone marrow, and these parameters were not altered in cells of fibrosarcoma tumor. The results revealed that troxerutin could preferentially protect normal tissues against radiation-induced damages in tumor-bearing animals.

Topics: Animals; Cell Membrane; DNA; DNA Damage; Dose-Response Relationship, Radiation; Fibrosarcoma; Gamma Rays; Hydroxyethylrutoside; Injections, Intraperitoneal; Liver; Male; Mice; Microsomes, Liver; Mitochondria; Organ Specificity; Radiation Injuries; Radiation Protection; Radiation-Protective Agents; Rats; Spleen

Restless legs syndrome (RLS) is a sensorimotor disorder with a general-population prevalence of 5-10%. Although, data on the prevalence of clinically diagnosed RLS are limited, and there are none regarding incidence, a shortfall compared with general-population values is likely, as not all patients are driven to consult. There may also be poor awareness of the condition among primary care physicians (PCPs).. The General Practice Research Database was used to gather prevalence and incidence data from UK PCPs and to investigate PCP awareness over the period 1994-1998. A total of 1,561,692 persons were covered by the database on January 1, 1999.. A diagnosis of RLS was registered in 3877 patients, giving a prevalence of 0.25%. Incidence values were also low (41.0 per 100,000 person-years), increased with age and were higher in women than in men. Although, at least one RLS diagnosis was made in 94% of medium-to-large practices, sufferers were more likely than age/sex-matched controls to be diagnosed with conditions commonly confused with RLS in 2 years before receiving their RLS diagnosis. Furthermore, at the time of diagnosis, many sufferers were prescribed medications not effective in RLS (principally, oxerutins and quinine).. These data are largely consistent with a lack of awareness of RLS among PCPs in the UK in the period studied.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Cross-Sectional Studies; Diagnosis, Differential; Female; Health Surveys; Humans; Hydroxyethylrutoside; Incidence; Male; Middle Aged; Muscle Relaxants, Central; Primary Health Care; Quinine; Restless Legs Syndrome; Sex Factors; Treatment Failure; United Kingdom; Vasoconstrictor Agents

The interaction of rutin and venoruton (troxerutin), with alpha-, beta- and gamma-cyclodextrin (CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and methyl-beta-cyclodextrin (M-beta-CD) was investigated by reversed-phase thin layer chromatography on polyamide plates. A mobile phase consisted of NH(4)OH; NH(4)Cl buffer solution containing various CD concentrations (pH = 9.7, 20 degrees C) was used as mobile phase. The equilibrium constants (K(f)) and the retention factor (R(f)) were determined and used to study the inclusion process. The in fluence of CDs on the solubility of rutin and venoruton was characterized by R(M) values and the increasing hydrophilicity of drugs. The results show that the inclusion capacity of cyclodextrins follows the order HP-beta-CD > M-beta-CD > beta-CD > gamma-CD, and rutin is more easily included by the studied cyclodextrins than venoruton. In addition, the thermodynamic parameters (Delta H, Delta S) for the formation of complexes were obtained from the van't Hoff equation, displaying the enthalpy-entropy compensation effect.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; beta-Cyclodextrins; Chemical Phenomena; Chemistry, Physical; Chromatography, Thin Layer; Cyclodextrins; gamma-Cyclodextrins; Hydroxyethylrutoside; Rutin; Solubility; Thermodynamics

This study analyzes the effect of chronic treatment with different antioxidants (N-acetyl-cysteine [NAC], taurine, a combination of NAC and taurine, and oxerutin) on long-term experimental diabetes induced by streptozotocin in rats. Glycoxidative damage was evaluated in the skin; glomerular structural changes were studied with morphometry and immunohistochemistry. Oxerutin treatment and the combined NAC plus taurine treatment resulted in reduced accumulation of collagen-linked fluorescence in skin in comparison with untreated diabetic rats. All treatments except taurine reduced glomerular accumulation of N(epsilon)-(carboxymethyl)lysine and protected against the increase in glomerular volume typical of diabetes; furthermore, the apoptosis rate was significantly decreased and the glomerular cell density was better preserved. Glycoxidative markers in the skin turned out to be good indicators of the glomerular condition. The findings that emerged from our study support the hypothesis that glomerular damage in diabetes can be prevented or at least attenuated by supplementation with specific antioxidants. Treatment with oxerutin and combined treatment with NAC plus taurine gave the most encouraging results, whereas the results of taurine-only treatment were either negligible or negative and therefore suggest caution in the use of this molecule in single-drug treatment courses.

Topics: Acetylcysteine; Animals; Anticoagulants; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Hydroxyethylrutoside; Kidney; Male; Rats; Rats, Wistar; Skin; Taurine; Time Factors

Arachidonic acid was investigated for its vascular permeabilizing potential in the rat peritoneal cavity and for its mechanism of action. The antagonistic potential of antioxidants (vitamin E, vitamin C and troxerutin) was also evaluated. Vascular permeability was equated to the rate of extravasation of Evans blue dye from plasma into the peritoneal cavity. Baseline permeability was linear up to 2 h, with a rate constant (k) of 0.0031+/-0.0007 h(-1). Intravenous arachidonate (from 30 microg/kg to 3 mg/kg) induced an immediate, dose-related and significant increase in permeability (ranging from 80% to 150%), which was comparable to the effect induced by similar doses of serotonin. Aspirin (10 mg/kg) reduced the arachidonate-induced permeability by 75%, but interestingly neither the stable thromboxane A(2) receptor agonist U46619 (prostaglandin H(2) endoperoxide epoxymethane) nor prostacyclin was able to increase peritoneal vascular permeability. In contrast, the permeabilizing action of arachidonic acid was very sensitive to antioxidant agents. Thus, vitamin C and the flavonoid compound troxerutin (100 mg/kg) fully abolished arachidonate-induced permeability, whereas vitamin E had only a partial effect (40-100% inhibition). In conclusion, intravenous administration of arachidonic acid strongly enhanced peritoneal vascular permeability in the rat, apparently via free radical generation. This rat peritoneal model can be used to evaluate the in vivo antinflammatory potential of antioxidant drugs.

Topics: Animals; Antioxidants; Arachidonic Acid; Ascorbic Acid; Capillary Permeability; Coloring Agents; Disease Models, Animal; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Hydroxyethylrutoside; Injections, Intravenous; Male; Peritoneal Cavity; Rats; Rats, Wistar; Reactive Oxygen Species; Time Factors; Vitamin E

The hemostatic agent, ethamsylate, inhibits arachidonic acid metabolism by a mechanism independent of cyclooxygenase activity and blocks carrageenan-induced rat paw edema. Here, ethamsylate was investigated for (i) in vivo actions on the free radical-dependent, permeabilizing responses to arachidonic acid and (ii) its antioxidant potential in vitro. Vascular permeability was equated to the extravasation rate of Evans blue from plasma into the rat peritoneal cavity. Antioxidant potential was investigated by classical in vitro tests for superoxide radicals, hydroxyl radicals (OH(.)), and nitric oxide. Intravenous ethamsylate induced a very important and significant reduction of permeability responses to arachidonate, both when given preventively and cumulatively. Thus, (i) ethamsylate significantly reversed arachidonate-induced permeabilization, even at the lowest dose tested (44+/-5% at 10 mg/kg) and (ii) a maximal reversal (about 70%) was reached between 50 and 200 mg/kg ethamsylate. In contrast, ethamsylate (100 mg/kg) was unable to antagonize the vascular permeabilization induced by serotonin (5-HT). In antioxidant assays, ethamsylate showed scavenging properties against hydroxyl radicals generated by the Fenton reaction (H(2)O(2)/Fe(2+)) even at 0.1 microM (-20+/-3%). OH(.) scavenging by ethamsylate reached 42+/-8% at 10 microM and 57+/-7% at 1 mM and was comparable to that of reference compounds (vitamin E, troxerutin, and mannitol). Conversely, ethamsylate was a poor scavenger of superoxide and nitric oxide radicals. In conclusion, intravenous ethamsylate potently antagonized the peritoneal vascular permeabilization induced by arachidonate, an action likely due to its antioxidant properties, particularly against hydroxyl radical. Such a mechanism can explain previous observations that ethamsylate inhibits carrageenan-induced rat paw edema. Whether it also participates in the hemostatic action of ethamsylate deserves further investigation.

Topics: Animals; Antioxidants; Arachidonic Acid; Capillary Permeability; Coloring Agents; Ethamsylate; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Hydroxyethylrutoside; Hydroxyl Radical; Injections, Intravenous; Nitric Oxide; Peritoneal Cavity; Rats; Superoxides; Vitamin E

Topics: Anticoagulants; Antioxidants; Chronic Disease; Endothelium, Vascular; Humans; Hydroxyethylrutoside; Veins; Venous Insufficiency

By its 'protective function', human skin is a potential target for the production of free radicals. The role played by topically applied antioxidants as inhibitors of oxidative stress damage was felt to be worth investigation.. To investigate the free radical scavenging (superoxide, hydroxyl and peroxyl radicals) and skin penetration of troxerutin in association with ascorbyl palmitate and alpha-tocopheryl succinate, esters of two vitamins commonly used in skin care products.. The compounds' scavenging activities, in a concentration-dependent manner, were as follows: hydroxyl radicals in a Fenton-based assay; superoxide radicals in a hypoxanthine/xanthine oxidase system; and lipid peroxidation inhibition of liver microsomes was induced by 2,2'-azobis-(2-amidinopropane) dihydrochloride (ABAP).. A synergic action was observed between alpha-tocopheryl succinate and troxerutin for hydroxyl radical scavenging, between the three compounds for superoxide scavenging and between troxerutin and ascorbyl palmitate in lipid peroxidation inhibition.. Using a stripping method, it was shown that the three substances, incorporated in a pharmaceutical preparation, permeated through human epidermis. Thus, this association can improve skin care products for preventing free radical-mediated damage.

Topics: Adult; Animals; Antioxidants; Ascorbic Acid; Chromatography, High Pressure Liquid; Drug Combinations; Female; Free Radical Scavengers; Free Radicals; Gels; Humans; Hydroxyethylrutoside; Lipid Peroxidation; Male; Microsomes, Liver; Oxidative Stress; Rats; Rats, Wistar; Skin; Skin Absorption; Tocopherols; Vitamin E

Topics: Herbal Medicine; Humans; Hydroxyethylrutoside; Preventive Medicine; Vascular Diseases; Vasoconstrictor Agents

The two-step crystallization of water in multilamellar vesicles (MLVs) of phosphatidylcholines has been investigated. The main crystallization occurs near -15 degrees C and involves bulk water. Contrary to unilamellar vesicles, a sub-zero phase transition is observed for MLVs at -40 degrees C that corresponds to the crystallization of interstitial water, as proved by Fourier transform infrared absorption and differential scanning calorimetry (DSC) experiments. Furthermore, by means of the DSC method and, more specifically, using the enthalpy change values Delta H(sub) at the sub-zero transition, the number of water molecules per 1,2-dipalmitoylphosphatidylcholine (DPPC) molecule giving rise to this transition has been estimated for different H(2)O/DPPC molar ratios. The curve of the molecular fraction of water molecules involved in the sub-zero transition versus the H(2)O/DPPC molar ratio exhibits a maximum for H(2)O/DPPC equal to 27 (40% in mass of water) and tends towards zero for H(2)O/DPPC ratio values approaching that of the swelling limit of the membrane. A smaller enthalpy value of the sub-zero transition is found for 1-oleoyl-2-palmitoyl-3-phosphatidylcholine (OPPC) than for DPPC. This may be explained by the decrease of interstitial water's quantity when the lipid contains an unsaturated chain. When troxerutin, a hydrophilic drug, is added to the DPPC multilayers, the decrease of Delta H(sub) and melting enthalpy of bulk water is attributed to a decrease of the entropy of the liquid phase owing to the network of water molecules surrounding troxerutin molecules. In all cases, the experiments revealed that the sub-zero transition occurs only in the presence of excess water with respect to the swelling limit of membranes. This evidence could be, at least qualitatively, related to an increase of membrane pressure on interstitial water subsequent to bulk water crystallization.

Topics: Anticoagulants; Biophysics; Calorimetry, Differential Scanning; Crystallization; Hot Temperature; Hydroxyethylrutoside; Models, Chemical; Phospholipids; Spectroscopy, Fourier Transform Infrared; Temperature; Thermodynamics; Water

High-altitude retinopathy is a very rare ocular disease in our country, which can occur isolately or as a part of high-altitude illness. This paper presents the case of a patient with high-altitude illness and the diagnosis and treatment problems of this case.

Topics: Adult; Altitude Sickness; Anti-Inflammatory Agents; Diagnosis, Differential; Humans; Hydroxyethylrutoside; Male; Prognosis; Retinal Diseases; Risk Factors; Severity of Illness Index; Treatment Outcome; Vasoconstrictor Agents; Vitamins

To evaluate the efficacy of intraocular infusion of troxerutin in the inhibition of fibrin formation after vitrectomy in a rabbit model.. Lensectomies and vitrectomies were performed in a masked fashion on seven eyes treated with a 10-mM infusion of troxerutin and on seven control eyes that received only a balanced salt solution infusion. Masked grading of intraocular fibrin formation and intravitreal hemorrhage was performed for 1 week.. On postoperative days 1 and 2, the control group exhibited a greater mean fibrin index (MFI) percentage than the troxerutin-treated group (day 1, 27.7% versus 19.5% MFI; day 2, 14.5% versus 6.1% MFI, respectively). On postoperative day 3, both groups showed an MFI of 1.8%. On postoperative days 5 and 7, both groups showed only minimal presence of fibrin. Neither of the two groups had an increased rate of intraocular hemorrhage.. Infusion of 10 mM troxerutin resulted in a relative decrease in the amount of fibrin produced without an increased risk of intraocular hemorrhage in treated eyes compared with controls, but the difference was not statistically significant. Further studies may be warranted to evaluate the optimal dose of troxerutin alone or a possible role for its use in conjunction with other drugs employing a different mechanism of action in the prevention of fibrin formation.

Topics: Animals; Anticoagulants; Fibrin; Fibrinolysis; Follow-Up Studies; Hydroxyethylrutoside; Injections; Postoperative Complications; Rabbits; Treatment Outcome; Vitrectomy

The study aimed at testing the effects of Venoruton on the early postradiation damage in the lungs of rats. The chests of the rats were irradiated with Co-60, fractional dose 250 cGy/DD, total dose 2500 cGy/DD. Venoruton was given intraperitoneally, in quantities of 0.1 ml once daily for 90 days. The experiment have proved that Venoruton lowers the intensity of the early postradiation changes, mainly those which depend on the vascular damage.

Topics: Animals; Culture Techniques; Disease Models, Animal; Hydroxyethylrutoside; Injections, Intraperitoneal; Lung; Radiation Dosage; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats; Rats, Wistar; Reference Values

Atherosclerosis and its clinical manifestations are still one of the most important civilization problems. New questions arise: is it really an inevitable process? Are there any rational methods to prevent the development of atherosclerotic changes or to facilitate its regression? The aim of the work was to evaluate the influence of bioflavonoids extracted from milk thistle (Sylibum marianum L), troxerutin (O-(beta-hydroxy-ethyl)-ruozid and lecithin, administered together and as a single therapy, on the experimental atherosclerosis development in rabbits. Sixty male mixed-breed rabbits were randomly assigned to 6 equal groups: I--control, II--fed on fat-rich diet (FR/DB), III--fed on FR-diet and sylimaryn concentrate (S), IV--animals fed on FR-diet and troxerutin (T), V--rabbits fed on FR-diet and soya bean lecithin (L), VI--animals fed on FR-diet and sylimaryn-phospholipid complex (SF). The whole experiment lasted 12 weeks. Following tests have been performed: electrocardiographic, biochemical, pathomorphological (including macroscopic and microscopic evaluations of aorta). Biochemical analysis included: cholesterol concentration (total, low density lipoprotein fraction cholesterol and high density fraction cholesterol), triglycerides, b-lipoproteins, phospholipids, fibrinogen, trace elements (calcium, magnesium, zinc and copper) and dimalonic aldehyde concentration. Concentrations of ascorbyl free radical, total cholesterol, triglycerides, P-450 cytochrome and phospholipids in liver have been estimated. Evident normalization of lipid metabolism and inhibition of atherosclerotic changes have been observed in the group of animals fed on SF complex. Concentrations of total cholesterol, LDL-cholesterol fraction, phospholipids and triglycerides decreased in serum. Decrease of serum dimalonic aldehyde was followed by increase of ascorbyl free radicals concentration in liver. Significant increase of serum zinc has been also noted, which exceeded values observed in control group. Concentration of P-450 cytochrome increased in liver microsomes. Sylimaryn and lecithin showed less anti-atherosclerotic activity, and troxerutin displayed the least anti-atherosclerotic activity (Tab. 1-2, Fig. 1-2). On the basis of the achieved results the following conclusions were drawn: 1) Sylimaryn and lecithin have anti-atherosclerotic activity in rabbits. 2) Sylimaryn-phospholipid complex shows the strongest anti-atherosclerotic activity. 3) The achieved results allow us to und

Topics: Administration, Oral; Animals; Arteriosclerosis; Cholesterol; Cholesterol, LDL; Cytochrome P-450 Enzyme System; Drug Combinations; Flavonoids; Free Radicals; Hydroxyethylrutoside; Liver; Male; Microsomes; Phosphatidylcholines; Phospholipids; Rabbits; Random Allocation; Silymarin; Triglycerides; Zinc

The effect of a novel flavonoid, venoruton (a mixture of mono-, di-, tri- and tetrahydroxyethylrutosides) has been investigated in healthy rat lenses and compared with diabetic cataract modelled in vitro. One mM venoruton was added to medium simulating healthy and diabetic conditions for the incubated lenses; damage was followed by either stereoscopic photography of the lenses under a Cooperative Cataract Research Group operating microscope or with our recently developed method: the leakage of lactate dehydrogenase (LDH) into the lens culture media. The increased LDH activity in the medium and observable development of the opacity were correlated with cell damage, which has been found to be associated with globular degeneration and cataract formation. The extent of opacification and LDH release is reduced if 1 mM venoruton is included in the medium. The protective effect may be related to antioxidant activity against reactive oxygen species: decreased luminol luminescence was shown after venoruton addition to either superoxide-generating hypoxanthine plus xanthine oxidase, or hydrogen peroxide.

Topics: Animals; Antioxidants; Catalase; Cataract; Culture Media; Diabetes Mellitus, Experimental; Female; Glucose; Hydrogen Peroxide; Hydroxyethylrutoside; L-Lactate Dehydrogenase; Lens Cortex, Crystalline; Organ Culture Techniques; Rats; Rats, Wistar; Superoxides

The uptake and localization of troxerutin, a trihydroxy-ethyl-rutoside, in the venous wall have been studied in patients undergoing long saphenous vein surgery. Troxerutin, an autofluorescent drug, is currently used to relieve oedema and subjective symptoms in patients with chronic venous insufficiency. In order to determine the localization of the troxerutin, a confocal scanning laser microscope has been used to record the fluorescence from vein cross sections. The quantified fluorescence was used as a measure of the local concentration of troxerutin. In order to reduce the effects of local variation, several images have been scanned from each specimen. Then the recorded data have been analysed to see how the fluorescence varies in the radial direction within the venous wall. Results showed that troxerutin was significantly accumulated in both inner and outer parts of the venous wall. Whereas inner wall troxerutin uptake resulted from direct diffusion through the lumen, the outer wall uptake proceeded likely from the vasa vasorum circulation.

Topics: Adult; Aged; Anticoagulants; Data Interpretation, Statistical; Diffusion; Female; Fluorescence; Histological Techniques; Humans; Hydroxyethylrutoside; Lasers; Male; Microscopy, Fluorescence; Microtomy; Middle Aged; Saphenous Vein; Varicose Veins; Vasa Vasorum; Vasoconstrictor Agents; Veins

The aim of this study was to evaluate the pharmacodynamics and pharmacokinetics of a single oral dose of Veliten in 12 patients affected by chronic venous insufficiency. In particular, the pharmacokinetics of two components of Veliten, namely rutine and alpha-tocopherol, were considered, while with respect to pharmacodynamics, studies were made of venous function, haemocoagulative and fibrinolytic balance, and haemorheological parameters. Correlation between such changes and plasma drug levels was also evaluated. We found a significant increase of venous tone, venous capacity and venous distension after drug intake, as well as a significant activation of fibrinolysis (globally evaluated with euglobulin lysis time), related to a slight increase of plasminogen tissue activator. These changes appeared concomitantly with maximal plasma levels of rutine. We did not find any modifications of coagulative and haemorheological parameters.

Topics: Administration, Oral; Adolescent; Adult; Anticoagulants; Blood Coagulation; Female; Fibrinolysis; Humans; Hydroxyethylrutoside; Male; Plasminogen Activators; Time Factors; Venous Insufficiency; Vitamin E

An experimental investigation was made of the influence of 0-(beta-hydroxyethyl)-rutin (HR) on the effect of indomethacin (1, 2 or 4 mg/kg i.p.) in inhibiting rat paw oedema. HR was given once daily during a 6-day pretreatment, with the final dose 90 minutes before the inflammatory reaction was induced. In the group of HR-pretreated rats which also received indomethacin in a dose of 2 or 4 mg/kg, the extent of the carrageenin-oedema was diminished significantly in comparison to that in experimental animals treated merely with indomethacin.

Topics: Animals; Anticoagulants; Carrageenan; Drug Synergism; Edema; Hydroxyethylrutoside; Indomethacin; Inflammation; Male; Rats; Rats, Sprague-Dawley

Diffusion of lipid fractions from blood to fluid in blister induced by cantharidal ointment, applied on the forearm skin, was studied in 54 patients, thereof 18 with normlipidemia, 13 having type II hyperlipidemia, 23 with type IV hyperlipidemia. Concentrations of triglycerides, phospholipids, free fatty acids, total cholesterol, HDL-cholesterol and LDL--cholesterol were studied in blood and fluid before treatment, 10 days after applying clofibrate, 20 days after clofibrate application, and 10 days following the application of rutinosid, i.e. upon completion of therapy. After the treatment it was observed that in all the patients the concentration of lipid fractions in blood was lowered, except for HDL-cholesterol, the level of which was elevated, as was the concentration of all the fractions in the blister fluid. Lipid concentration in serum, with the exception of free fatty acids, was invariably higher than in blister fluid. Free fatty acids, LDL-cholesterol and HDL-cholesterol diffused from blood to fluid in a greater percentage. Lipid fraction concentration in fluid depended mainly on the concentration of HDL-cholesterol and triglycerides in the blood. In normlipidemia, the highest percentage of lipid fractions was diffused to blister fluid; the percentage was lower in type IV hyperlipidemia, the lowest being in type II hyperlipidemia. Clofibrate hypolipemia action correlated best with with HDL-cholesterol and triglyceride activity. After the treatment, the elevated diffusion of all the fractions from blood to blister fluid was, in my opinion, consistent with lipid metabolism, venoruton, as vessel tightening drug, may play a protective role in relation to endothelia in hyperlipidemia.

Topics: Administration, Cutaneous; Adult; Blister; Cantharidin; Diffusion; Drug Interactions; Female; Humans; Hydroxyethylrutoside; Hyperlipidemias; Lipids; Male; Middle Aged; Reference Values

Chronic doxorubicin-induced cardiotoxicity is believed to be caused by the formation of oxygen free radicals. Thus O-(beta-hydroxyethyl)-rutosides, a standardized flavonoid mixture (Venoruton) with iron chelating and radical scavenging activity, might provide protection. Therefore, we investigated the (cardio)protective effect of Venoruton (1.5 g/kg injected i.p. on days 1-5, 8-12, 15-19, and 22-26) in BALB/c mice treated with doxorubicin (4 mg/kg injected i.v. on days 1, 8, 15, and 22) compared with mice treated with doxorubicin alone. Saline-treated animals served as controls. No mortality was encountered in either of the groups; weight gain data suggest little general toxicity of this dose schedule. The basal frequency of the isolated right atria was increased in doxorubicin-pretreated animals as compared to control animals (468 +/- 22 and 366 +/- 20 beats/min, respectively). Venoruton coadministration diminished this increase (373 +/- 17 beats/min). The -log of the concentration giving 50% effect of l-isoprenaline on the right atrium was changed after doxorubicin pretreatment (8.33 +/- 0.04 versus 8.86 +/- 0.06 for control animals). Venoruton coadministration resulted in a smaller shift in the -log of the concentration giving 50% effect (8.51 +/- 0.10) than with doxorubicin alone. The extent of cardiotoxicity found in the functional studies was confirmed by histological scoring of heart ventricle damage. It can be concluded that Venoruton has the potential to protect against doxorubicin-induced cardiotoxicity.

Topics: Animals; Body Weight; Colforsin; Doxorubicin; Drug Administration Schedule; Free Radical Scavengers; Heart; Heart Rate; Hydroxyethylrutoside; Injections, Intraperitoneal; Injections, Intravenous; Isoproterenol; Male; Mice; Mice, Inbred BALB C; Myocardial Contraction; Myocardium; Razoxane; Time Factors

Topics: Chronic Disease; Humans; Hydroxyethylrutoside; Leg; Venous Insufficiency

A new reversible complex between troxerutin and phosphatidylcholine (85-90mg/kg per day), in the form of a liposome-like water microdispersion, was topically applied to the rat thigh in an experimental counterpart of acute lymphedema. After four days there was 75% less hindlimb edema (mean decrease 40% of normal compared to control 10% of normal) in the treated compared with the untreated rats. These findings suggest that this drug preparation may be useful to minimize acute peripheral lymphedema in patients.

Topics: Administration, Topical; Animals; Drug Carriers; Hindlimb; Hydroxyethylrutoside; Liposomes; Lymphedema; Phosphatidylcholines; Rats

Under study was the influence of polyphenolic complexes of great burnet and venoruton upon the thymus, spleen, iliac lymph nodes of the uterus area in experimental phlebo-occlusion syndrome of pregnant rats. The data obtained show the changes of the drainage function of the lymphatic system under the influence of the drugs under study, certain reaction of T- and B- dependent zones of the central (thymus) and peripheral lymphoid organs. The structural-functional shifts had positive effects upon the fetus state. The action of polyphenols of great burnet is more effective as compared with venoruton.

Topics: Animals; Anticoagulants; Drug Evaluation, Preclinical; Female; Flavonoids; Hydroxyethylrutoside; Lymphoid Tissue; Phenols; Plant Extracts; Polymers; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Wistar; Veins; Vena Cava, Inferior

It is now well established that blood behaves like a non Newtonian fluid varying with the shear rate. Blood viscosity pattern relative to various shear rates shows a high viscosity at low shear rate (due to rouleau formation or erythrocyte aggregation) with a decrease at high shear rate. This high blood viscosity will be of a great importance only while pathological blood flowing with low output or stasis. Pathological variations of one factor determining blood viscosity and clinical signs define hyperviscosity syndrome. From an hemodynamical point of view, the appearance of an hyperviscosity syndrome, may, as a result of feedback mechanism, aggravate the disorders leading to a slowing down and even to a stop in local blood flow, subsequently encouraging ischemia. Moreover hyperviscosity also leads to a theoretical lowering capacity of oxygen transport by blood approximatively in proportion with the haematocrit/blood viscosity ratio. With regard to therapeutic aspect, the pharmacology of rheological influence drugs must be displaced into the wider outline proposed by Virchow. So we could distinguish between therapeutic action of drugs upon haematocrit, plasmatic proteins level, red blood cell deformability and erythrocyte aggregation. Among this last category disaggregating effect of rutosides has been first pointed out by Schmid-Schöenbein and Col. Our results of an in vitro study of troxerutine effect with ranging concentrations from 10(-5) to 10(-2) M upon blood viscosity and erythrocyte aggregation are reported.

Topics: Anticoagulants; Blood Flow Velocity; Blood Proteins; Blood Viscosity; Erythrocyte Aggregation; Erythrocyte Deformability; Hematocrit; Hematology; Humans; Hydroxyethylrutoside; Oxygen Consumption; Rheology

Topics: Amino Acids; Anticoagulants; Choline; Coronary Disease; Folic Acid; Homocysteine; Humans; Hydroxyethylrutoside; Pyridoxine; Riboflavin; Vitamin B 12

Efficacy of Venoruton--O-(hydroxyethyl) Rutoside--as a radioprotector has been tested on haematological profile of rats which were subjected to whole body radiation (500 rads). The results show radiation induced lesions in respect of total (TLC) and differential leukocyte counts (DLC)/and haemoglobin are significantly lessened when Venoruton was administered prior to radiation exposure.

Topics: Animals; Hydroxyethylrutoside; Male; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats

Rat tail thrombosis (RTT) induced by i.v. injection of kappa-carrageenin was not inhibited by p.o. or i.p. administration of the aglucon of rutin, quercetin, but it was slightly inhibited by rutoside-containing Venoruton. The RTT was significantly inhibited by didymlaevulinate, Helodym 88, whereas samarium-containing Phlogosol gave inconsistent results because of the solvent propylene glycol. The RTT model is suitable to detect substances of the flavonoid and lanthanide types with weak antithrombotic activity.

Topics: Animals; Carrageenan; Female; Flavonoids; Hydroxyethylrutoside; Metals, Rare Earth; Quercetin; Rats; Tail; Thrombosis; Time Factors

A new system to evaluate capillary permeability, the vacuum suction chamber (VSC) device, was used to assess the effects of Venoruton in patients with venous hypertension. A temporary, superficial skin lesion (wheal) was produced with the VSC device by negative pressure (30 mmHg) applied for 10 minutes on the internal, perimalleolar region. Wheals disappear in less than 60 minutes in normals while in patients with venous hypertension the wheal is more persistent, requiring a significantly longer time to disappear. This new technique was used in association with laser-Doppler flowmetry to evaluate the efficacy of Venoruton (1000 mgs t.i.d.) administered for 2 weeks on venous hypertension. Results indicate a positive effect of Venoruton in reducing the abnormally increased capillary permeability in venous hypertension and are proportional to the changes observed in signs and symptoms after treatment.

Topics: Adult; Capillary Permeability; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Rutin; Skin Tests; Venous Pressure

Elevated plasma homocysteine and lipid levels are risk factors for atherosclerosis. The plasma levels of homocysteine, determined in acid hydrolyzates of plasma, were found to be correlated with total cholesterol (r = 0.47, P less than 0.001), triglycerides (r = 0.40, P less than 0.01), and body mass index (r = 0.42, P less than 0.01) in 52 males, aged 30-60. A group of 12 male survivors of acute myocardial infarction was given pyridoxine, folate, cobalamin, choline, riboflavin, and troxerutin for 21 days. The plasma concentrations of homocysteine and alpha-amino adipic acid declined to 68% (P less than 0.001) and 57% (P less than 0.001) of the pretreatment values, and the cholesterol, triglycerides, and LDL apo B declined to 79% (P less than 0.001), 68% (P less than 0.01), and 63% (P less than 0.001) of the pretreatment values, respectively. The results suggest a new strategy for control of the metabolic abnormalities in atherosclerosis through the use of naturally occurring, non-toxic nutrients which minimize homocysteine accumulation.

Topics: Adult; Anticoagulants; Choline; Coronary Artery Disease; Coronary Disease; Drug Therapy, Combination; Folic Acid; Homocysteine; Humans; Hydroxyethylrutoside; Lipids; Male; Middle Aged; Pyridoxine; Riboflavin; Vitamin B 12

Quercetin is an effective inhibitor of human myeloperoxidase (MPO) activity, both with purified enzyme (IC50 = 3.5 microM) and in a system using stimulated human neutrophils. Quercetin is significantly more potent than three other related compounds (rutin, rutin sulfate and troxerutin) and than methimazole, a previously-known myeloperoxidase inhibitor. The inhibitory activity of quercetin is of the competitive type. Moreover, quercetin is directly able to scavenge hypochlorous acid (HOCl), a chlorinated species generated by the MPO/H2O2/Cl- system.

Topics: Chemical Phenomena; Chemistry; Flavonoids; Humans; Hydroxyethylrutoside; Hypochlorous Acid; Methimazole; Neutrophils; Peroxidase; Quercetin; Rutin; Spectrophotometry

The protective effect of venoruton O-(beta-hydroxy-ethyl) rutoside, HR was investigated against drug induced catatonia in rats. Perphenazine, haloperidol, reserpine and meperidine produced frank catalepsy in rats. The cataleptic effect of these neuroleptics was significantly attenuated when the animals were pretreated with venoruton. The protective effect of venoruton is speculated to be due to its inhibitory action on superoxide formation and free radicals are considered to have a role in the neurotoxicity caused by the above agents.

Topics: Animals; Anticoagulants; Antipsychotic Agents; Catatonia; Female; Haloperidol; Hydroxyethylrutoside; Male; Meperidine; Muscle Rigidity; Perphenazine; Rats; Rats, Inbred Strains; Reserpine; Rutin

The cardioprotective agents troxerutin and methionine are radical scavengers and compete with the DMPO adduct formation of .OH generated by the Fenton reaction. The concentration of trapped .O2- generated by the xanthine oxidase/hypoxanthine reaction is lowered in the presence of troxerutin. The decay of DMPO-OH is decreased by troxerutin compared to the control. In the presence of methionine a carbon-centered radical is produced. The investigations support the opinion that the scavenging of oxygen derived free radicals is of importance for the cardioprotective action of these agents.

Topics: alpha-Linolenic Acid; Anticoagulants; Cyclic N-Oxides; Dithioerythritol; Electron Spin Resonance Spectroscopy; Ethanol; Free Radicals; Hydroxides; Hydroxyethylrutoside; Hydroxyl Radical; Linolenic Acids; Mannitol; Methionine; Rutin; Spin Labels

Topics: Adult; Blood Viscosity; Humans; Hydroxyethylrutoside; Hypertension; Middle Aged; Rutin

A bioflavonoid, o-(beta-hydroxyethyl)-rutoside, has been investigated for its potential to increase the therapeutic index of the combined treatment modalities of whole body hypothermia (WBH) (41.5 degrees C) and chemotherapy (cisplatin) in studies utilizing a transplantable fibrosarcoma solid tumor model in Fischer rats. When whole body WBH was induced 45 min after cisplatin administration, a significantly increased tumor growth delay was noted beyond that achieved by either treatment modality alone. The combination of WBH and cisplatin treatments, however, produced an unacceptable increase in renal injury. o-(beta-Hydroxyethyl)-rutoside administration was found to effectively block the renal injury without interfering with the antitumor efficacy of the combined regimen. Potential explanations for the ability of o-(beta-hydroxyethyl)-rutoside to affect the increase in WBH-cisplatin therapeutic regimen are discussed.

Topics: Animals; Body Weight; Cisplatin; Free Radicals; Glomerular Filtration Rate; Hydroxyethylrutoside; Hyperthermia, Induced; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasms, Experimental; Rutin

During ischemic perfusion and reperfusion of isolated rat hearts, OH and carbon-centered radicals were trapped in the perfusate. Both radicals were found to occur during LPO which was enhanced in the myocardium. The increase of LPO as well as of enzyme leakage were reduced by mannitol and the flavonoid troxerutin showing antioxidative action of greater than 500 and greater than 5 microM, respectively. The assumption is supported that radical-induced LPO is of pathogenetic relevance during myocardial reperfusion injury for which antioxidants could be of therapeutic advantage.

Topics: Animals; Antioxidants; Coronary Disease; Electron Spin Resonance Spectroscopy; Free Radicals; Hydroxyethylrutoside; In Vitro Techniques; L-Lactate Dehydrogenase; Lipid Peroxides; Male; Mannitol; Myocardium; Rats; Rats, Inbred Strains

Topics: Anticoagulants; Hydroxyethylrutoside; Rutin

Cianidanol ((+)-2-(3,4-dihydroxyphenyl)-3, 5, 7-chromantriol) is a flavonoid which has been associated with severe immune haemolysis by as yet unclear mechanisms. We report six patients who developed haemolysis while receiving the drug. The disorder was episodic in all patients and resolved after discontinuing the drug. The causative antibodies could be demonstrated in all six cases, even when the haemolytic episode was more than 1 year prior to this study. One patient had developed drug-independent IgG autoantibodies, another simultaneously developed autoantibodies and drug-dependent antibodies (ddab) of the IgG class, while the remaining four patients had only ddab of the IgM and/or the IgG classes. All ddab were reactive with red blood cells (RBC) in the presence of the drug and/or its metabolites (ex vivo antigens), and, quite unexpectedly, also with RBC coated with the drug (metabolites) in vitro or in vivo. This reactivity did not change either by preincubating the antibodies with the drug or by adding large amounts of the drug to the mixture of drug-coated cells plus antibody. It seems that the stable association of cianidanol with RBC generates antigenic sites against which a heterogeneous immune response is elicited giving rise to long-lasting drug-dependent antibodies as well as autoantibodies.

Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Antibody Formation; Autoantibodies; Catechin; Erythrocytes; Female; Hemagglutination Tests; Humans; Hydroxyethylrutoside; Male; Middle Aged; Rutin; Silymarin

Topics: Adolescent; Adult; Allergens; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Female; Humans; Hydroxyethylrutoside; In Vitro Techniques; Male; Neutrophils; Rutin

Troxerutin, a flavonoid derivative, used in vascular diseases was studied in 4 mutagenicity tests: the Ames test, the point mutation test (V79/HPRT), the in vitro metaphase analysis in human lymphocytes and the micronucleus test in mice. The aglycone trihydroxyethylquercetin (THEQ) and quercetin were studied too. Troxerutin was not mutagenic, whereas quercetin was positive in the Ames test, V79 cells and in vitro metaphase analysis. THEQ was negative in the Ames test. The substitution of quercetin with hydroxyethyl groups in 7,3' and 4' positions abolished mutagenic activity of quercetin.

Topics: Animals; Chemical Phenomena; Chemistry; Chromosome Aberrations; Humans; Hydroxyethylrutoside; Lymphocytes; Metaphase; Mice; Mutagenicity Tests; Mutagens; Quercetin; Rutin

During treatment with flavonoid drugs a number of patients developed adverse reactions such as fever, various skin eruptions and intravascular hemolysis. The appearance of flavonoid-specific IgE and IgG antibodies and its possible relation to the observed side effects was studied on a total of 168 individuals treated with flavonoid drugs: 71 patients received troxerutin (Venoruton) parenterally to improve tolerance of radiation therapy, 12 patients were treated intravenously with silymarin (Legalon) for amanita intoxication and 77 patients received various flavonoid drugs for other indications. Flavonoid treatment often induced specific IgG antibodies and less frequently IgE antibodies. After short treatment IgE antibodies were more frequently detected than after treatment of longer duration which nearly always induced IgG antibodies. Patients with hemolysis had the highest IgG titers. In cases with fever and skin eruptions no correlation with antibody titers became evident. Antibody production in patients undergoing radiation therapy appeared to be lower than in non-irradiated patients. Both the IgE and IgG antibody test show a remarkable cross-reactivity between four different flavonoids. Prospective studies will be necessary to decide whether or not this method for the detection of anti-flavonoid antibodies will be suitable for recognizing increased risk of side reactions upon reexposure to flavonoid drugs.

Topics: Catechin; Cross Reactions; Drug Eruptions; Drug Hypersensitivity; Female; Fever; Flavonoids; Hemolysis; Humans; Hydroxyethylrutoside; Immunoglobulin E; Immunoglobulin G; Male; Radiation-Protective Agents; Radioallergosorbent Test; Silymarin

The endothelo-protective activity of a series of low-molecular oxygen-derived free radical scavengers (OFRS) was tested in rats. A model of endothelaemia provoked by intravenous administration of hydrogen peroxide was used. With each OFRS the activity in the hydrogen peroxide model was compared with that in the less specific model using the provocation by citrate as a calcium chelating agent. Relatively unspecific but biologically important OFRS, ascorbic acid, tocopherol, troxerutin and glutathione were tested in the first phase of the study. A marked optimum of endothelo-protective activity was shown with all agents, the optimum against hydrogen peroxide having been observed at doses from 3 to 50 times lower than against citrate. Ascorbic acid, troxerutin and the combination of both were also tested in another model based on leg ischaemia produced by ligature of the common femoral artery. Without OFRS, a marked increase of endothelaemia was observed after 30-60 min ischaemia showing a second peak after the release of the ligature. This second peak was completely abolished by the preventive administration of OFRS in a dose which was also effective in the hydrogen peroxide model.

Topics: alpha-Tocopherol; Animals; Anticoagulants; Ascorbic Acid; Aspirin; Coronary Disease; Endothelium; Female; Femoral Artery; Free Radicals; Heparin; Hydrogen Peroxide; Hydroxyethylrutoside; Kinetics; Lactates; Lactic Acid; Perfusion; Pyruvates; Pyruvic Acid; Rats; Rats, Inbred Strains; Rutin; Tocopherols; Vitamin E

Two highly sensitive models of arterial and venous thrombosis forming with the test of endothelial stability a complementary system with a maximum stress on the role of vascular lesion were used to test a series of four antithrombotic drugs (heparin, acetylsalicylic acid, dipyridamole, sulfinpyrazone) and four drugs with other indications but with an antithrombotic activity in experiment (prenylamine, troxerutin, ketanserin and pizotifen). All drugs, except heparin, were given orally. Whereas heparin, aspirin and prenylamine had mixed effects on both arterial thrombosis (i.e. mostly on platelet functions) as well as on endothelial stability, ketanserin and pizotifen had a predominant effect on the former while dipyridamole, troxerutin and sulfinpyrazone influenced mostly the latter function.

Topics: Animals; Anticoagulants; Arteries; Aspirin; Dipyridamole; Female; Hydroxyethylrutoside; Ketanserin; Piperidines; Pizotyline; Prenylamine; Rats; Rats, Inbred Strains; Sulfinpyrazone; Thrombophlebitis; Thrombosis

A series of drugs representing several groups of antithrombotics was tested in a new model of arterial thrombosis in rats. Thrombosis was produced in the aorta by the combination of local partial obstruction and systemic administration of hypotonic saline with serotonin. High efficacy was demonstrated with heparin, acetylsalicylic acid, troxerutin, prenylamine, antiserotonin agents /pizotifen, ketanserin/ and particularly with the combinations of antiserotonins and the above mentioned antithrombotic drugs. The model showed high sensitivity to all tested drugs in the clinical dose range.

Topics: Animals; Aspirin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Heparin; Hydroxyethylrutoside; Prenylamine; Rats; Serotonin; Serotonin Antagonists; Thrombosis

Deformability of red cells and plasma levels of cAMP and cGMP were studied in patients with arteriosclerosis obliterans of lower limbs. Deformability of red cells and plasma levels of cAMP were found to be decreased in these patients. Venous injection of HR (Venoruton) in one dose (1,000 mg) to patients, led to an increase of red cell deformability and normalisation of cAMP plasma level. The plasma level of cGMP was not changed. The beneficial effect of HR in arteriosclerosis obliterans depends, first of all, on improving the deformability of red cells. The decreased deformability observed in arteriosclerosis seems to be a result of disturbances in the rate of spectrin phosphorylation of the erythrocyte membrane. By normalising the plasma level of cAMP HR had a considerable influence on the appropriate state of elasticity of the red cell membrane.

Topics: Aged; Arteriosclerosis Obliterans; Erythrocyte Deformability; Female; Humans; Hydroxyethylrutoside; Leg; Male; Middle Aged; Rutin

Topics: Adult; Aged; Female; Humans; Hydroxyethylrutoside; Male; Middle Aged; Retinal Vein Occlusion; Rutin

Topics: Aged; Anticoagulants; Arteriosclerosis Obliterans; Cell Adhesion; Female; Humans; Hydroxyethylrutoside; Leg; Leukocytes; Male; Middle Aged; Rutin

Topics: Adult; Coumarins; Drug Combinations; Dysgerminoma; Humans; Hydroxyethylrutoside; Lymphography; Lymphoma; Male; Middle Aged; Neoplasms; Rutin

Adriamycin (Adriablastine), administered weekly at the dose of 5 mg/kg i.p. for 3 weeks in rats, produced a general decrease of vitality associated with a decrease of body weight, hypothermia, decreases of stroke volume and cardiac output. Hematocrit was decreased. Renal blood flow decreased whereas pulmonary blood flow increased. Mean blood pressure and heart rate remained unaffected. Biochemical evaluations revealed a decrease of blood urea and serum creatinine, which might be related to decreased food intake and protein metabolism. Morphological changes in the heart tissue could not be appreciated. Venoruton (HR), administered at the dose of 300 mg/kg p.o. daily for 28 days (5 days before and 23 days after the first injection of adriamycin), improved adriamycin-induced clinical signs and symptoms (loss of body weight, hypothermia and decreased general vitality). It tended to increase cardiac output and stroke volume.

Topics: Animals; Blood Chemical Analysis; Body Weight; Cardiac Output; Doxorubicin; Hemodynamics; Hydroxyethylrutoside; Male; Myocardium; Rats; Rats, Inbred Strains; Regional Blood Flow; Rutin

A high-performance liquid chromatographic method (HPLC) is described for the analysis of 3',4',7-tri-O-(beta-hydroxy-ethyl)-rutoside (troxerutin) in human plasma and urine. After separation of interfering substances on XAD-2 trihydroxyethylrutoside is converted to tetrahydroxyethylrutoside by 2-chlorethanol in alkaline medium. After HPLC-separation tetrahydroxyethylrutoside is quantified by fluorescence detection. The pharmacokinetics of troxerutin were measured in plasma after oral administration to man. The relative bioavailability of the drug from Venelbin was 97.8 +/- 37.1% compared to an aqueous standard solution.

Topics: Anticoagulants; Chromatography, High Pressure Liquid; Humans; Hydroxyethylrutoside; Rutin

Clobenoside (1-O-ethyl-3-O-propyl-5,6-di-O-chlorbenzyl-D-glucofuranose, CL) and Venoruton [O-(beta-hydroxyethyl)-rutosides, HR] did not cause supersensitivity to either exogenous or endogenous (stimulation-released) noradrenaline, in strips of the saphenous vein of the dog. Both drugs caused a significant blockade of the inactivation of noradrenaline, in oil immersion experiments. In incubation experiments with 3H-isoprenaline, CL and HR (100 to 900 mumol/l) caused a dose-dependent inhibition of O-methylation; they had additive effects with the COMT inhibitor, U-0521 and their effects were abolished in the presence of hydrocortisone. In incubation experiments with 3H-adrenaline, formation of metanephrine was inhibited, neuronal uptake and oxidative deamination remaining unaffected. After intravenous administration of HR (100 mg/kg), the O-methylating capacity of blood vessels was similarly reduced. It is concluded that CL and HR affected exclusively the extraneuronal O-methylating system (probably both by inhibiting COMT and depressing uptake) and that this effect may contribute to their therapeutic actions.

Topics: Animals; Anticoagulants; Catechol O-Methyltransferase Inhibitors; Catecholamines; Dogs; Electric Stimulation; Glucose; Hydroxyethylrutoside; In Vitro Techniques; Isoproterenol; Methylation; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Rutin; Saphenous Vein

O-(beta-hydroxyethyl)-rutoside (Venoruton) has been reported to alleviate edema formation in chronic venous insufficiency. In an attempt to elucidate Venoruton's potential as an antiinflammatory agent, we infused Venoruton (20 mg/minute) intraarterially into the canine forelimb perfused at constant flow during the simultaneous intraarterial infusion of histamine (4 micrograms base/minute) or bradykinin (2 micrograms/minute). The infusion of Venoruton alone for forty minutes resulted in a small but significant increase in forelimb arterial pressures but no change in systemic pressure or forelimb skin lymph flow, protein concentration or protein transport. Subsequent infusion of either histamine or bradykinin resulted in a significant decrease in forelimb arterial pressures and a marked increase in skin lymph flow, lymph total protein concentration and lymph total protein transport. The changes in forelimb vascular pressures and skin lymph parameters were similar to those seen during the infusion of either histamine or bradykinin alone. These data indicate that the intraarterial infusion of Venoruton at this dosage does not inhibit the ability of simultaneously infused histamine or bradykinin to increase transvascular fluid and macromolecular efflux in the canine forelimb perfused at constant arterial inflow.

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Bradykinin; Capillary Permeability; Dogs; Edema; Female; Forelimb; Histamine; Hydroxyethylrutoside; Infusions, Intra-Arterial; Lymph; Male; Perfusion; Proteins; Rutin; Skin

Topics: Aluminum Hydroxide; Benzocaine; Diet; Drug Combinations; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hydroxyethylrutoside; Hypertension, Portal; Magnesium Hydroxide; Sclerosing Solutions; Sorbitol

Topics: Adult; Aged; Anticoagulants; Arteriosclerosis; Humans; Hydroxyethylrutoside; Middle Aged; Platelet Aggregation; Rutin

Topics: Aging; Animals; Capillaries; Hydroxyethylrutoside; Rats; Rats, Inbred Strains; Rutin; Skin; Vascular Resistance

Electron microscopy was used to examine the status of the juxtaglomerular apparatus (JGA) and interstitial cells (IC) 3 and 24 hours after administration of furosemide (10 mg/kg), indomethacin (10 mg/kg), venoruton (500 mg/kg) and trental (100 mg/kg), and after 1,6 an 12 sessions of hyperbaric oxygenation. To evaluate objectively the results of examining the JGA, use was made of a method devised by the authors of a mathematical appraisal of granulation from the density of the epithelioid cells. Granulation of 50 IC from each animal was calculated on semi-thin araldite sections stained methylene blue-azur II-fuchsin. The results indicate that all the types of exposure including hyperbaric oxygenation produced JGA activation whose degree varied depending on the time elapsed after exposure. An apparently great increase in the JGA activity was detected after injection of furosemide and indomethacin. All the drugs with the exception of furosemide entailed granule accumulation after 3 hours, followed by the recovery of their amount after 24 hours. Furosemide injection produced a reverse effect.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Furosemide; Hydroxyethylrutoside; Hyperbaric Oxygenation; Indomethacin; Juxtaglomerular Apparatus; Kidney Medulla; Rabbits

Topics: Cellulose; Delayed-Action Preparations; Drug Compounding; Hydroxyethylrutoside; Rutin

The effects of 2,5-dihydroxybenzene-1,4-disulphonic acid-bisdiethylamine salt (263-E) and trihydroxyethylrutoside (Vitamin P4) on capillary permeability have been compared in the rabbit. Both drugs were administered by intradermal and intravenous routes. Histamine and bradykinin were injected intradermally to increase permeability. 263-E was sown to be a potent inhibitor of permeability changes induced by histamine and bradykinin intravenous routes. Vitamin P4 maximally inhibited permeability at the lowest intravenous dose level but with increasing dose the inhibition became negligible. After intradernal administration, vitamin P4 did not inhibit permeability but potentiated the permeability response induced by histamine and bradykinin.

Topics: Animals; Benzenesulfonates; Bradykinin; Capillary Permeability; Histamine; Hydroxyethylrutoside; Injections, Intradermal; Injections, Intravenous; Male; Rabbits

Topics: Blindness; Burns; Contraceptives, Oral, Hormonal; Diabetic Retinopathy; Drug Antagonism; Humans; Hydroxyethylrutoside; Rutin; Shock, Hemorrhagic; Vascular Diseases

Methionine administered orally to rats produced a prolonged dose-dependent increase in endothelemia. The increase was observed after doses exceeding 100 mg/kg and was inhibited by a simultaneous administration of pyridoxine. The effect of methionine was also inhibited by trihydroxyethylrutoside and acetylsalicyclic acid. Endothelemia was increased furthermore by oral administration of cysteine and cystine and this increase was again inhibited by pyridoxine.

Topics: Animals; Aspirin; Dose-Response Relationship, Drug; Drug Antagonism; Endothelium; Female; Homocystinuria; Humans; Hydroxyethylrutoside; Methionine; Pyridoxine; Rats

Pain in the legs is a common diagnostic problem. Diagnosis is made on an anatomical basis and by a process of exclusion. Deep vein thrombosis is still an exceedingly difficult condition to diagnose; however, investigation by ultrasound with the Doppler Flow Meter often provides a definite answer. There is a large group of patients, nearly always female and in their twenties and thirties, in whom chronic leg pain without demonstrable underlying cause poses a problem. These cases respond very favourably to Paroven 250 mg three or four times daily, as well as light support pantyhose.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Doppler Effect; Female; Humans; Hydroxyethylrutoside; Joint Diseases; Male; Medical History Taking; Pain; Pain Management; Physical Examination; Physicians, Family; Sex Factors; Thrombophlebitis; Wounds and Injuries

Topics: Humans; Hydroxyethylrutoside; Varicose Veins

Topics: Dermatitis; Drug Therapy; Erythema Nodosum; Humans; Hydroxyethylrutoside; Leg Ulcer; Ointments; Phlebitis; Rutin; Thrombosis; Varicose Veins

Topics: Allergy and Immunology; Antimalarials; Collagen Diseases; Flavonoids; Geriatrics; Humans; Hydroxyethylrutoside; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Prednisone; Rutin

Topics: Capsules; Hemorrhoids; Humans; Hydroxyethylrutoside; Phlebitis; Rutin; Varicose Ulcer; Varicose Veins

Topics: Capsules; Flavonoids; Hemorrhoids; Humans; Hydroxyethylrutoside; Rutin

Topics: Aesculus; Hydroxyethylrutoside; Plants, Medicinal; Rutin

Topics: Disease; Flavonoids; Hydroxyethylrutoside; Nutrition Therapy; Vascular Diseases; Veins; Vitamins