Selective PPARγ modulator diosmin improves insulin sensitivity and promotes browning of white fat.

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.

Effect of Diosmin on Selected Parameters of Oxygen Homeostasis.

Chronic venous disease (CVD) is a condition characterized by functional disturbances in the microcirculation of the superficial and deep veins, affecting up to 30% of the global population. Diosmin, a phlebotropic drug, is commonly used in the treatment of CVD, and its beneficial effects have been described in numerous clinical studies. However, the precise molecular mechanism underlying the activity of diosmin is not yet fully understood. Therefore, the objective of our study was to investigate whether diosmin has an impact on oxygen management, as cardiovascular diseases are often associated with hypoxia. In our study, patients were administered a daily dosage of 2 × 600 mg of diosmin for 3 months, and we evaluated several factors associated with oxygen management, angiogenesis, and inflammation using biochemical assays. Our findings indicate that diosmin reduced the levels of fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF-C), while increasing endostatin and angiostatin levels, suggesting a potential influence on angiogenesis regulation. Furthermore, diosmin exhibited anti-inflammatory properties by suppressing the levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), and interleukin 6 (IL-6), while promoting the production of interleukin 12 (IL-12). Additionally, diosmin significantly decreased the levels of hypoxia-inducible factor (HIF), anion gap (AG), and lactate, indicating its potential influence on the hypoxia-inducible factor pathway. These findings suggest that diosmin may play a crucial role in modulating oxygen management and inflammation in the context of chronic venous disease.

Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies.

Novel coronavirus SARS-CoV-2continues tospread rapidly worldwide and causing serious health and economic loss. In the absence of any effective treatment, various in-silico approaches are being explored towards the therapeutic discovery against COVID-19. Targeting multiple key enzymes of SARS-CoV-2 with a single potential drug could be an important in-silico strategy to tackle the therapeutic emergency. A number of Food and Drug Administration (FDA) approved drugs entered into clinical stages were originated from multi-target approaches with an increased rate, 16-21% between 2015 and 2017. In this study, we selected an FDA-approved library (Prestwick Chemical Library of 1520 compounds) and implemented in-silico virtual screening against multiple protein targets of SARS-CoV-2 on the Glide module of Schrödinger software (release 2020-1). Compounds were analyzed for their docking scores and the top-ranked against each targeted protein were further subjected to Molecular Dynamics (MD) simulations to assess the binding stability of ligand-protein complexes. A multi-targeting approach was optimized that enabled the analysis of several compounds' binding efficiency with more than one protein targets. It was demonstrated that Diosmin (6) showed the highest binding affinity towards multiple targets with binding free energy (kcal/mol) values of -63.39 (nsp3); -62.89 (nsp9); -31.23 (nsp12); and -65.58 (nsp15). Therefore, our results suggests that Diosmin (6) possesses multi-targeting capability, a potent inhibitor of various non-structural proteins of SARS-CoV-2, and thus it deserves further validation experiments before using as a therapeutic against COVID-19 disease.

Selected polyphenolic compounds and their use as a supportive therapy in metabolic syndrome.

Metabolic syndrome is diagnosed mainly in people of economically developed parts of the world and it affects 20-25% of the adult population worldwide. Nowadays, it is also more frequently diagnosed in children and adolescents. In addition to standard treatment that often involves polypharmacotherapy, and thus increases risk of side effects caused by drugdrug interactions, it is appropriate to look for alternative tools to support the treatment of metabolic syndrome components. Natural polyphenolic compounds, usually present in the so-called functional foods, are suitable candidates for that matter, due to the bioactivity and beneficial effects on the human body. Quercetin, troxerutin, diosmin, hesperidin or silybin are among the currently studied and used natural polyphenolic compounds with a positive effect on aspects of the metabolic syndrome. In addition to their antioxidant and anti-inflammatory effects, these compounds have other positive properties that very often outweigh their side effects whilst their usage in the pharmacotherapy.

[Non-drug methods of treatment of post-thrombophlebitic syndrome]. / Nemedikamentoznye metody lecheniya posttromboflebiticheskogo sindroma.

Postthrombophlebitic syndrome (PTPS) develops in 20-50% of patients who have had deep vein thrombosis (DVT). Patients with chronic venous insufficiency (CVI) of class C4-C5 according to the CEAP clinical classification, which developed as a result of DVT of the lower extremities, including those who underwent endovascular treatment (iliac vein stenting), are subject to staged medical rehabilitation. In this regard, the development of personalized complex technologies for the sanatorium treatment of patients with PTPS is an important medical and social problem. PURPOSE OF THE STUDY: Study of clinical efficacy and identification of the mechanisms of action of a new complex of spa treatment of patients with PTPS of the lower extremities using supravenous laser radiation, low-frequency magnetotherapy, dry-air carbon dioxide baths and structured therapeutic exercises in the gym. MATERIAL AND METHODS: 60 patients with PTPS of the lower extremities (CVI C4-C5 according to CEAP) were under observation. All patients were randomly divided into 2 groups: first group (main group) included 30 patients who received a treatment, including procedures for supravascular laser blood irradiation, pulsed magnetotherapy and dry-air carbon dioxide baths, as well as structured therapeutic exercises in gym under the supervision of an exercise therapy instructor; second group (control group) included 30 patients who received standard elastic compression (compression class 2-3) while taking lymphovenotonics (a combination of diosmin and hesperidin) and therapeutic exercises in the gym. RESULTS: Against the background of the course of treatment in patients of the main group, to a greater extent than in the control group, a decrease in the clinical symptoms of the disease was noted: a more pronounced regression of edema, a decrease in heaviness in the legs, as evidenced by the data of anthropometric studies and questionnaires on the CIVIQ-2 scale. Positive dynamics in the microcirculation system (MC) was established, which was confirmed by the data of laser Doppler flowmetry. In patients with spastic-congestive type of MC, a decrease in the initially increased myogenic and neurogenic tone of arterioles was registered. There was a decreasing of stagnation in the venular link. In patients with hyperemic-congestive type of MC, the initially reduced tone of arterioles increased, which contributed to the improvement of blood flow in the capillaries. There was also a decrease in congestion in the venular link of the microvasculature. CONCLUSION: A new effective complex method for the rehabilitation of patients with PTPS has been developed, including laser exposure according to the general method, pulsed magnetotherapy and dry-air carbon dioxide baths, which have a multifocal effect on different links in the pathogenesis of PTPS.

'de Novo' repurposing of Daflon as anti-intestinal parasitic drug in experimental giardiasis.

BACKGROUND: There is a necessity to develop or discover an alternative drug to combat the drug resistance by Giardia duodenalis and minimize the multiple doses and frequency of the conventional drug administration. Progressive repositioning or 'repurposing' of drugs has become widespread due to economic circumstances and medical emergency needs. Daflon 500 mg (DFL) is a natural product used safely as a nutrient supplement and an antidiabetic drug in many European countries and the US. OBJECTIVE: This study aimed at investigating the efficiency of DFL, in vivo, in a murine model as a safe alternative or co-drug for giardiasis. MATERIALS AND METHODS: Swiss Albino mice (n = 32) were inoculated with 1X104Giardia cysts and assigned to four groups: One group was the infected non-treated control mice and three experimental groups that were treated differently, either with Metronidazole (MTZ), DFL, or combined therapy of DFL/MTZ. Also, eight normal mice served as a control group. All mice were sacrificed 13 days post-infection for the parasitic, histopathological, and oxidative stress analysis. RESULTS: MTZ, DFL, and the combined therapy significantly reduced the number of trophozoites and cysts compared to their counterparts of the infected mice. The histopathological analysis of the small intestines of the mice treated with the combined therapy retained typical intestinal architecture and normal levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione. CONCLUSION: This study indicated promising actions of Daflon 500 as an anti-giardial drug, and the results demonstrated its potential effect in improving the intestinal epithelial tissue and disturbing the Giardia stages when it was taken collectively with Metronidazole.

Diosmin Inhibits Glioblastoma Growth through Inhibition of Autophagic Flux.

Diosmin, a natural flavone glycoside acquired through dehydrogenation of the analogous flavanone glycoside hesperidin, is plentiful in many citrus fruits. Glioblastoma multiforme (GBM) is the most malignant primary brain tumor; the average survival time of GBM patients is less than 18 months after standard treatment. The present study demonstrated that diosmin, which is able to cross the blood-brain barrier, inhibited GBM cell growth in vitro and in vivo. Diosmin also impeded migration and invasion by GBM8401and LN229 GBM cells by suppressing epithelial-mesenchymal transition, as indicated by increased expression of E-cadherin and decreased expression of Snail and Twist. Diosmin also suppressed autophagic flux, as indicated by increased expression of LC3-II and p62, and induced cell cycle arrest at G1 phase. Importantly, diosmin did not exert serious cytotoxic effects toward control SVG-p12 astrocytes, though it did reduce astrocyte viability at high concentrations. These findings provide potentially helpful support to the development of new therapies for the treatment of GBM.

Diosmin Mitigates Cyclophosphamide Induced Premature Ovarian Insufficiency in Rat Model.

The current study was designed to investigate the protective role of diosmin against cyclophosphamide-induced premature ovarian insufficiency (POI). Female Swiss albino rats received a single intraperitoneal dose of cyclophosphamide (200 mg/kg) followed by 8 mg/kg/day for the next 15 consecutive days either alone or in combination with oral diosmin at 50 or 100 mg/kg. Histopathological examination of ovarian tissues, hormonal assays for follicle stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH), assessment of the oxidative stress status, as well as measurement of the relative expression of miRNA-145 and its target genes [vascular endothelial growth factor B (VEGF-B) and regulator of cell cycle (RGC32)] were performed. Diosmin treatment ameliorated the levels of E2, AMH, and oxidative stress markers. Additionally, both low and high diosmin doses significantly reduced the histopathological alterations and nearly preserved the normal ovarian reserve. MiRNA-145 expression was upregulated after treatment with diosmin high dose. miRNA-145 target genes were over-expressed after both low and high diosmin administration. Based on our findings, diosmin has a dose-dependent protective effect against cyclophosphamide-induced ovarian toxicity in rats.

Diosmin ameliorates inflammation, insulin resistance, and fibrosis in an experimental model of non-alcoholic steatohepatitis in rats.

Non-alcoholic steatohepatitis (NASH) is becoming of increasing significance due to its growing global prevalence and risk of progression to end-stage liver disease. This study was carried out to investigate the potential anti-inflammatory, insulin sensitizing, and antifibrotic effects of diosmin in an experimental model of NASH induced in rats using high-fat diet (HFD) and 30 mg/kg streptozotocin (STZ). Diosmin was administered orally at dose of 100 mg/kg for 8 weeks. Stained tissue sections were examined for histopathological signs of NASH, collagen deposition, and alpha smooth muscle actin (α-SMA) expression. In addition, insulin resistance, dyslipidemia, inflammation, and fibrosis markers were assessed. HFD/STZ successfully induced different NASH features such as insulin resistance seen by elevated fasting blood glucose levels and homeostasis model assessment for insulin resistance. Moreover, induced rats demonstrated dyslipidemia, a significant elevation in tumor necrosis factor alpha (TNF-α) and interleukin-6 levels, and an imbalance in the oxidative status of the liver. Those events altogether precipitated initiation of liver fibrosis as confirmed by elevated transforming growth factor beta (TGF-ß) levels. Treatment with diosmin demonstrated multiple beneficial effects as it significantly ameliorated histopathological NASH findings, lowered TNF-α, interleukin-6, and malondialdehyde levels, improved lipid and glucose metabolism, and lowered hepatic TGF-ß, α-SMA, and collagen content compared to untreated rats. The present study represents a drug repositioning scenario as diosmin is widely used for management of blood vessel disorders and is known to be well tolerated. This encourages the extension of our study to the clinical setting to explore diosmin effects in NASH patients.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.

The chondroprotective effect of diosmin on human articular chondrocytes under oxidative stress.

Excessive oxidative stress, which can amplify inflammatory responses, is involved in the pathologic progression of knee osteoarthritis. Diosmin is known to possess a variety of biological functions such as antiinflammatory and antioxidant activities. We therefore demonstrated the chondroprotective potentials of diosmin on human articular chondrocytes under oxidative stress. The cytotoxicity of diosmin (5, 10, 50, and 100 µM) to chondrocytes was first evaluated. Subsequently, the cells were treated with diosmin (5 and 10 µM) after hydrogen peroxide (H2 O2 ) exposure. We found that the cytotoxicity of diosmin occurred in a dose-dependent manner (10, 50, and 100 µM), and low-dose diosmin (5 µM) slightly impaired cell viability. Diosmin supplementations (5 and 10 µM) did not show beneficial effects on mitochondrial activity, cytotoxicity, proliferation, and survival and the cell senescence was ameliorated in H2 O2 -exposed chondrocytes. On the other hand, diosmin down-regulated the mRNA levels of iNOS, COX-2, IL-1ß, COL1A1, MMP-3, and MMP-9; up-regulated TIMP-1 and SOX9; and improved COL2A1 in chondrocytes under oxidative stresses. Furthermore, diosmin also regulated glutathione reductase and glutathione peroxidase of H2 O2 -exposed chondrocytes. In conclusion, diosmin displayed a remarkable antiinflammatory effect compared with the antioxidant capacity on human chondrocytes. Diosmin can maintain the homeostasis of extracellular matrix of articular cartilage.

Diosmin - still an important modality in the treatment of venous insufficiency.

Chronic venous insufficiency is a highly prevalent disease in the western population. Unfortunately, there is no causal treatment yet. A key role in the recommended therapeutic approaches, especially in the early stages, is the compression therapy accompanied by pharmacotherapy. This includes, inter alia, micronized diosmin. The following text summarizes the basic knowledge of its properties that determine its clinical use.

[Diosmin-containing phlebotropic drugs in varicose eczema]. / Diosminsoderzhashchie flebotropnye lekarstvennye preparaty pri varikoznoi ékzeme.

AIM: The purpose of the study was to examine the effect of diosmine-based phlebotropic drugs on dynamics of regress of varicose eczema in patients with chronic venous diseases, to compare their objective complaints and subjective symptoms before and after treatment, to determine the time of improvement. PATIENTS AND METHODS: The study enrolled a total of 80 patients presenting with chronic venous diseases complicated by varicose eczema (CEAP class C4A). The patients of the Study Group received combined treatment: elastic compression of lower extremities, phlebotropic agents (diosmin 450 mg + hesperidin 50 mg, 'Venarus' (manufactured by the Limited Liability Company 'Obolenskoe', Russia) and a dermatologist's prescribed topical treatment. The patients of the Comparison Group received similar treatment with the exception of phlebotropic drugs, however taking penoxiphylline at a daily dose of 1200 mg. RESULTS: The obtained findings demonstrated a decrease in pain intensity, lowered exudation, achievement of complete remission and reduced area of eczema with statistically significant differences in the groups. CONCLUSION: Modern phlebotropic drugs based on diosmin proved to be effective agents in comprehensive treatment of chronic diseases of lower-limb veins and varicose eczema.

[Pharmacology of the drugs prescribed for chronic venous diseases]. / Farmakologiia preparatov, primeniaiushchikhsia pri khronicheskikh zabolevaniiakh ven.

The main groups of the drugs used for pharmacotherapy of chronic venous disease are considered. The main therapeutic targets of the drugs including their effect on venous wall tone, permeability and inflammation are described.

Hyaluronan as a mediator for the hepatoprotective effect of Diosmin/Hesperidin complex.

Daflon is a phlebotonic drug widely used in chronic venous or lymphatic insufficiency. This study designed to investigate the relation of daflon with hyaluronan as a mediator for the hepatoprotective effect against Carbon tetrachloride (CCl4) and/or γ-radiation induced liver damage. Animals of this study were administered CCl4 (1 ml/kg b.wt.), exposed to γ-radiation (1Gy) and treated with daflon (100 mg/kg/day). Our results showed the ameliorative effect of daflon on cytochrome P450 (CYT P450), lipid peroxidation (MDA), liver enzymes (aspartate amino transferase; AST, alanine aminotransferase; ALT and gamma glutamyl transferase; γ-GT), antioxidant capacity (reduced glutathione; GSH and glutathione per oxidase; GPx), inflammatory markers (C-reactive protein; CRP and interlukin- 6; IL-6), alpha-fetoprotein (AFP) and extra cellular matrix proteins (hyaluronan; HA and hyaluronidase; HAase) which was supported by histopathological examination of liver sections compared to the damage induced in CCL4 and/or rats exposed to radiation. It could be concluded that the hepatoprotective effect of daflon is mediated via antioxidant and anti-inflammatory activity in addition to preserving native tissue hyaluronan by preventing its degradation.

Effect of a mixture of diosmin, coumarin glycosides, and triterpenes on bleeding, thrombosis, and pain after stapled anopexy: a prospective, randomized, placebo-controlled clinical trial.

PURPOSE: We evaluated the efficacy of oral administration of a mixture of diosmin, coumarin glycosides, and Centella asiatica (Venoplant®) in preventing bleeding, pain, and thrombosis of internal and external hemorrhoids after stapled anopexy (SA). METHODS: SA was conducted in 182 patients with third-degree hemorrhoids. Preoperatively, patients were randomized evenly into two groups. Group A patients were administered Venoplant for 30 days post-SA, and group B received a placebo for 30 days post-SA. Patients received paracetamol for postoperative pain. Visit (v)1, v2, and v3 took place 7, 15, and 30 days postoperatively, respectively; bleeding (clinical examination), visual analog scale (VAS), thrombosis (clinical examination), and pain (paracetamol dosage, VAS) were evaluated. RESULTS: At v1, v2, and v3, the numbers of patients with bleeding in groups A and B were 21 and 46, 3 and 25, and 1 and 5, respectively (p < 0.05). At v1, v2, and v3, the numbers of patients in groups A and B with thrombosed internal hemorrhoids were 3 and 13, 2 and 11, and 1 and 8, respectively (p < 0.05). The number of patients who took at least one paracetamol tablet was similar in both groups at v1 but was significantly greater in group B than group A at v2 and v3 (p < 0.05); pain VAS scores were equivalent at v1 and significantly greater in group B than group A at v2 and v3 (p < 0.05). CONCLUSIONS: Venoplant effectively reduced bleeding after SA, decreased the incidence of thrombosed internal hemorrhoids, and decreased postoperative pain.

Antihyperglycaemic action of diosmin, a citrus flavonoid, is induced through endogenous ß-endorphin in type I-like diabetic rats.

Diosmin is one of the flavonoids contained in citrus and has been demonstrated to improve glucose metabolism in diabetic disorders. However, the mechanism(s) of diosmin in glucose regulation remain obscure. Therefore, we investigated the potential mechanism(s) for the antihyperglycaemic action of diosmin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Diosmin lowered hyperglycaemia in a dose-dependent manner in STZ-diabetic rats. This action was inhibited by naloxone at a dose sufficient to block opioid receptors. Additionally, we determined the changes in plasma ß-endorphin-like immunoreactivity (BER) using enzyme-linked immunosorbent assay (ELISA). Diosmin also increased BER dose-dependently in the same manner. Repeated treatment of STZ-diabetic rats with diosmin for 1 week resulted in an increase in the expression of the glucose transporter subtype 4 (GLUT 4) in the soleus muscle and a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver. These effects were also inhibited by naloxone at a dose sufficient to block opioid receptors. Bilateral adrenalectomy in STZ-diabetic rats eliminated the actions of diosmin, including both the reduction in hyperglycemia and the elevation of plasma BER. In conclusion, our results suggest that diosmin may act on the adrenal glands to enhance the secretion of ß-endorphin, which can stimulate the opioid receptors to attenuate hepatic gluconeogenesis and increase glucose uptake in soleus muscle, resulting in reduced hyperglycemia in STZ-diabetic rats.

Effect of Pycnogenol on the Healing of Venous Ulcers.

BACKGROUND: Venous ulcers are common complications of chronic venous insufficiency that result in severe physical and mental suffering to patients. The oral administration of diosmin/hesperidin has been used as adjuvant therapy in the treatment of chronic venous insufficiency. The purpose of this study was to evaluate and compare the effect of pycnogenol and diosmin/hesperidin on the healing of venous ulcers. METHODS: This longitudinal, prospective, randomized clinical trial was conducted with 30 adult patients with venous ulcers from a vascular surgery outpatient clinic of a university hospital. The patients were randomly allocated to 2 groups: Group 1 (n = 15) was treated with pycnogenol (50 mg orally, 3 times daily) and Group 2 (n = 15) was treated with diosmin/hesperidin (450/50 mg orally, twice daily). They were assessed every 15 days for 90 days. During follow-up visits, photo-documentation was obtained and the ulcer area and circumference of the affected limb were measured. Friedman's test and Mann-Whitney test were used to compare ulcer areas and circumference of affected limbs between and within groups at different time points. The level of significance was set at 5% (P < 0.05) for all tests. RESULTS: Both the pycnogenol and diosmin/hesperidin treatments had a similar effect on the healing of venous ulcers and led to a significant decrease in the circumference of affected limbs (P < 0.0001). CONCLUSION: The results suggest that pycnogenol has an adjuvant effect on the healing of venous ulcers, similar to diosmin/hesperidin.

[The effects of diosmin and hesperidin on capillary blood flow of upper limbs in patients with secondary Raynaud's syndrome]. / Vozdeistvie diosmina i gesperidina na kapilliarnyi krovotok verkhnikh konechnostei u patsientov s vtorichnym sindromom Reino.

The article discusses the effects of diosmin and hesperidin on capillary blood flow in patients with secondary Raynaud's syndrome (RS). Raynaud's syndrome a difficult problem of modern angiology, since in its development there is a large range of disorders of the capillary blood flow of the limbs. Currently, the main way of therapy in patients with secondary Raynaud's syndrome is the use of either calcium channel blockers (if angiospastic stage of the disease), or prostaglandins of group E1 (with tropho-paralytic stage of secondary RS). However, pharmacological effects of calcium channel blockers (vasodilation) and prostaglandins (vasodilation, antiproliferative, anti-inflammatory etc.) do not allow impact on all violations of capillary blood flow, occurs when the Raynaud's syndrome. In this regard, the task was to study the reaction of capillary blood flow of the fingers of the hands on the concomitant use of drugs based on diosmin and hesperidin. A prerequisite for the use of a combination of diosmin and hesperidin in the treatment of RS was based on data about their impact on the state of the venous segment of the capillary bed and perivascular oedema. To conduct the study was established two groups of patients (22 in each group). The main criterion for inclusion of patients in the study was the presence of newly identified Raynaud's syndrome of angiospastic or tropho-paralytic stage of the disease. The main exclusion criteria was the presence of necrotic stage of the disease. In the first group of patients therapy was carried out using only vasodilators. In the second group (comparison group) with the addition of a combination of diosmin and hesperidin (tablets Venarus used in a dose 500 mg 2 times per day). The condition of capillary blood flow in this study was estimated by the method of videocapillaroscopy (VCS). Statistical data processing was performed using a criterion of statistical significance (P-value). The study revealed the significant impact of a combination of diosmin and hesperidin for parameters of capillary blood flow that correlated with clinical improvements - reduction of oedema of the fingers of the hands.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses. MAIN RESULTS: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.