Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7,8/NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu, and Tregs/Th17 balance.

Diosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug's bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.

Chemopreventive potential of Diosmin against benzo[a]pyrene induced lung carcinogenesis in Swiss Albino mice.

Lung cancer, one of the most common cancer is a cause of concern associated with cancer-related mortality. Benzo[a]pyrene [B(a)P], a potent carcinogen as well as an environmental contaminant is reported to be found in cigarette smoke among various sources. The present study focuses on the chemopreventive potential of Diosmin against B[a]P-induced lung carcinogenesis and its possible mechanism in male Swiss Albino mice (SAM). SAM were treated orally with Diosmin (200 mg/kg b.w.) for 16 weeks and/or B[a]P (50 mg/kg b.w) for a period of 4 weeks. B[a]P treated cancerous mice showed increased peroxidation of membrane lipid as well as a decrease in the level/activity of antioxidant proteins. Cancerous mice also showed an increased level of carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE). Diosmin treatment, however, leads to decreased peroxidation of lipids, increased antioxidant proteins as well decrease in the level of CEA and NSE. B[a]P-induced cancerous animals also exhibited increased expression of cyclic AMP response element-binding protein (CREB), COX2 as well as prostaglandin-E2 (PGE2) while Diosmin-treated mice were found to have an ameliorative effect. Histopathological results further confirm the protective effect of Diosmin in averting B[a]P-induced pathological alterations of lung tissue. Overall, our results suggest Diosmin exerts its chemopreventive potential possibly via targeting the CREB/cyclooxygenase-2 (COX-2)/PGE2 pathway thereby repressing inflammation.

Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence.

Flavonoids are oral venoactive drugs frequently prescribed to relieve the symptoms of chronic venous disorders (CVD). Among venoactive drugs, diosmin is a naturally occurring flavonoid glycoside that can be isolated from various plant sources; it can also be obtained after conversion of hesperidin extracted from citrus rinds. Micronized purified flavonoid fraction (MPFF) is a preparation that contains mainly diosmin and a small fraction of hesperidin. We performed a state-of-the-art literature review to collect and analyze well-conducted randomized clinical studies comparing diosmin - also called non-micronized or hemisynthetic diosmin - 600 mg a day and MPFF, 1000 mg a day. Three clinical studies met the criteria and were included for this literature review. These clinical studies showed a significant decrease of CVD symptom intensity (up to approximately 50%) and global patient satisfaction after one-to-six-month treatment with diosmin or MPFF, without statistical differences between these two forms of diosmin. Both treatments were well tolerated with few mild adverse drug reactions reported. Overall, based on this literature review, there is no clinical benefit to increase the dose of diosmin beyond 600 mg per day, to use the micronized form, or to add hesperidin, since clinical efficacy on venous symptomatology is achieved with 600 mg per day of pure non-micronized diosmin. This challenges the status of diosmin - 600 mg a day - in guidelines for the management of CVD, which is currently categorized 2C (weak recommendations for use and poor quality of evidence), while the most widely used and assessed preparation MPFF is rated 1B (strong recommendation for use and moderate quality of evidence).

Diosmin 600 in adjunction to rivaroxaban reduces the risk of post-thrombotic syndrome after femoropopliteal deep vein thrombosis: results of the RIDILOTT DVT study.

BACKGROUND: To assess the efficacy and safety of long-term diosmin 600 therapy added to rivaroxaban and elastic compression stockings (ECS) in patients with femoropopliteal deep vein thrombosis (DVT). METHODS: This single-center, open-label randomized clinical trial RIDILOTT DVT enrolled patients with their first femoropopliteal DVT confirmed by duplex ultrasound scan (DUS). Participants were randomly allocated to the control group (standard treatment with rivaroxaban for six months and ECS for 12 months) or the experimental group (standard treatment with the additional use of diosmin 600 mg once daily for 12 months). Patients were followed for 12 months. The primary outcome was post-thrombotic syndrome (PTS), according to the Villalta Score (≥5). The secondary outcomes were deep vein recanalization, chronic venous disease (CVD) progression, the severity of PTS (Villalta), and CVD (VCSS), quality of life (CIVIQ-20), venous thromboembolism recurrence, and adverse event (AE). RESULTS: Ninety patients were randomized (45 per group). There were 56 men and 34 women with a mean age of 57.8±13.4 years, and 69% had clinically unprovoked DVT. PTS frequency at 12 months was significantly lower (8.9% vs. 48.9%) in the experimental group compared with control one (relative risk, 0.14; 95% confidential interval, 0.04-0.43, P<0.001). Adding diosmin 600 was associated with quicker and complete vein recanalization, lower CVD progression rate, and lower Villalta, VCSS, and CIVIQ-20 scores. There was no difference in recurrent DVT or AE. CONCLUSIONS: Adjunctive use of diosmin 600 to rivaroxaban and ECS in patients with femoropopliteal DVT can improve the clinical and ultrasound outcomes after 12 months of treatment.

Diosmin Treats Lipopolysaccharide-Induced Inflammatory Pain and Peritonitis by Blocking NF-κB Activation in Mice.

Gram-negative bacterial infections induce inflammation and pain. Lipopolysaccharide (LPS) is a pathogen-associated molecular pattern and the major constituent of Gram-negative bacterial cell walls. Diosmin is a citrus flavonoid with antioxidant and anti-inflammatory activities. Here we investigated the efficacy of diosmin in a nonsterile model of inflammatory pain and peritonitis induced by LPS. Diosmin reduced in a dose-dependent manner LPS-induced inflammatory mechanical hyperalgesia, thermal hyperalgesia, and neutrophil recruitment to the paw (myeloperoxidase activity). Diosmin also normalized changes in paw weight distribution assessed by static weight bearing as a nonreflexive method of pain measurement. Moreover, treatment with diosmin inhibited LPS-induced peritonitis as observed by a reduction of leukocyte recruitment and oxidative stress. Diosmin reduced LPS-induced total ROS production (DCFDA assay) and superoxide anion production (NBT assay and NBT-positive cells). We also observed a reduction of LPS-induced oxidative stress and cytokine production (IL-1ß, TNF-α, and IL-6) in the paw. Furthermore, we demonstrated that diosmin inhibited LPS-induced NF-κB activation in peritoneal exudate. Thus, we demonstrated, using a model of nonsterile inflammation induced by LPS, that diosmin is a promising molecule for the treatment of inflammation and pain.

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

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

Conservative Treatment of Hemorrhoids: Results of an Observational Multicenter Study.

INTRODUCTION: This study was conducted to determine the frequency of complaints in a cohort of patients with symptomatic hemorrhoidal disease (HD) treated with micronized purified flavonoid fraction (MPFF, Detralex). MPFF was selected for conservative treatment in this population owing to its proven effects on hemorrhoidal symptoms in a large number of patients. METHODS: This multicenter, non-interventional study was part of the international CHORUS survey (Chronic venous and HemORrhoidal diseases evalUation for improvement of Scientific knowledge), conducted in nine centers in different regions of Russia with the participation of 80 coloproctologists. The study enrolled consecutive patients with complaints of hemorrhoids. All were prescribed MPFF-based conservative treatment. The effect of treatment on HD clinical signs and symptoms was assessed at two follow-up visits performed 5-7 days and 25-30 days after enrollment. Surgical and minimally invasive treatment could be performed from day 7 onwards if required. RESULTS: A total of 1952 patients were enrolled. Over the entire period of observation, MPFF-based conservative treatment was effective in 1489 (76.3%) patients in eliminating the main clinical manifestations of disease, i.e., bleeding and prolapse of internal nodes. Invasive treatment was performed in 68 (3.5%) patients with grade IV hemorrhoids and was combined with MPFF conservative treatment in 395 (20.2%) patients with grades I-III hemorrhoids. CONCLUSION: Conservative therapy with MPFF was beneficial for relieving hemorrhoidal symptoms in the majority of patients. MPFF-based treatment was most effective in patients with grade I and II hemorrhoids before irreversible degenerative changes in ligaments of the hemorrhoidal plexuses have occurred. It was also beneficial in preventing disease relapse in patients with more advanced HD and for promoting optimal conditions in the postoperative period. FUNDING: Servier.

Flavonoid mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) in the treatment of I-III degree hemorroidal disease: a double-blind multicenter prospective comparative study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

[Multicentre observational study of Phlebodia 600 in treatment of patients with CEAP class C0-C3 chronic venous diseases]. / Mnogotsentrovoe nabliudatel'noe issledovanie primeneniia Flebodia 600 u bol'nykh c khronicheskimi zabolevaniiami ven klassov C0-C3 po CEAP.

The purpose of the study was to evaluate efficacy of Diosmin (Phlebodia 600, Innothera, France) in treatment of patients presenting with class C0s-C3 chronic venous diseases (CVD) according to the CEAP classification. Presented herein are the results of a prospective observational study aimed at assessing the outcomes of two-month administration of Phlebodia 600 (600 mg diosmin) in patients suffering from class C0s-C3 CVD according to the CEAP classification. The study comprised a total of 868 patients, including 175 (20.2%) men and 693 (79.8%) women. Of these, 866 patients completed the study according to the protocol. Amongst the 868 followed-up patients, 851 (98.0%) subjects strictly adhered to the physician's prescription and stopped taking the drug without violation of the regimen and dosing of diosmin. The main drug dosage regimen of diosmin was 1 tablet once a day in 851/868 (98.04%) patients. Satisfaction with treatment with diosmin was reported as 'excellent' by 46.7 % of patients (95% CI: 43.3-50.0) and by 49.4% of physicians (95%: CI 46.1-52.7), being rated as 'good' by 45.0% of patients (95 % CI: 41.7-48.4) patients and by 43.6% of physicians (95% CI: 40.3-47.0). The score for the quality of life of patients according to the CIVIQ-20 scale at the first follow-up visit amounted to 45.4±15.4 points (median 43.0 points). At the second follow-up visit, this parameter improved dramatically, dropping to the level of 35.6±11.5 points (median 33.0 points). By the third follow-up visit, the positive dynamics of the parameters preserved continued, averagely amounting to 28.9±8.7 points (median 26.0 points). A decrease in the circumference of the left and right crura (by 0.39±0.74 and by 0.36±0.75 cm, respectively) was observed at the second follow-up visit. The difference of the malleolar measurements between the first and third follow-up visits amounted to 7.2±9.4 mm and 6.6±9.7 mm for the right and left crus, respectively (p<0.001). The number of patients with a reported feeling of heaviness in the legs statistically significantly decreased from 97.6% at the stage of enrollment into the study to 73.0% after 2 months of therapy, that of those with painful sensations from 84.5 to 55.3%, those with complaints of swelling (oedemas) of the lower limbs from 83.9 to 56.8%, with complaints of convulsions from 71.2 to 35.7%, with complaints of sensation of tingling from 63.4 to 34.1%, respectively. Hence, a statistically significant improvement of the patients' condition was observed as early as 30 days after the beginning of treatment. By day 60, the positive effect of the carried out therapy continued to grow. Safety and good tolerance of the drug were noted, which was confirmed by low incidence of undesirable events and high adherence to treatment.

Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials.

INTRODUCTION: The use of a venoactive drug is considered an important component of medical treatment of chronic venous disease (CVD), although the efficacy of certain venoactive drugs (VADs) on one or more individual leg symptoms or signs may have not been extensively studied to justify a strong recommendation in guidelines on CVD. The aim of this systematic review and meta-analysis was to study the effectiveness of the micronized purified flavonoid fraction (MPFF, Daflon®) across the spectrum of defined venous symptoms, signs, quality of life (QoL) and treatment assessment by the physician. EVIDENCE ACQUISITION: On September 9, 2017, a systematic review of the databases MEDLINE, Scopus and Cochrane Central was performed, supplemented by hand searching, to identify randomized double-blind placebo-controlled trials on MPFF in patients with CVD. EVIDENCE SYNTHESIS: The main outcome measures were the individual and global symptoms, leg edema and redness, skin changes, QoL and evaluation of the overall effectiveness of the treatment by the physician. The effectiveness of MPFF compared with placebo was expressed as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI). Trial quality of evidence was graded using the GRADE system. RESULTS: We identified 7 trials, mostly with low risk of bias, involving 1,692 patients. On qualitative analysis, MPFF significantly improved nine defined leg symptoms, including pain, heaviness, feeling of swelling, cramps, paresthesia, burning sensation, and pruritus (itching), but also functional discomfort compared with placebo, leg redness, skin changes and QoL. On quantitative analysis, MPFF compared with placebo, assessed as a categorical variable, reduced leg pain (RR 0.53, P=0.0001, NNT=4.2), heaviness (RR 0.35, P<0.00001, NNT=2.0), feeling of swelling (RR 0.39, P<0.00001, NNT=3.1), cramps (RR 0.51, P=0.02, NNT=4.8), paresthesia (RR 0.45, P=0.03, NNT=3.5), and functional discomfort (RR 0.41, P=0.0004, NNT=3.0). Similarly, MPFF compared with placebo, assessed as a continuous variable reduced pain (SMD -0.25, 95% CI -0.38 to -0.11), heaviness (SMD -0.80, 95% CI -1.05 to -0.54), feeling of swelling (SMD -0.99, 95% CI -1.25 to -0.73), burning sensation (SMD -0.46, 95% CI -0.78 to -0.14), cramps (SMD -0.46, 95% CI -0.78 to -0.14), and functional discomfort (SMD -0.87, 95% CI -1.13 to -0.61). Regarding objective assessments of leg edema, the use of MPFF compared with placebo reduced ankle circumference (SMD -0.59, 95% CI -1.15 to -0.02), and leg redness (SMD -0.32, 95% CI -0.56 to -0.07, RR 0.50, P=0.03, NNT=3.6), improved skin changes (RR 0.18, P=0.0003, NNT=1.6) and quality of life (SMD -0.21, 95% CI -0.37 to -0.04) and was associated with clinical improvement as assessed by the physician (RR 0.28, P<0.00001, NNT=2.5). Heterogeneity was mostly minimal. The existing evidence where sufficient was mostly of high quality. CONCLUSIONS: Based on high quality evidence, MPFF is highly effective in improving leg symptoms, edema and quality of life in patients with CVD.

A Randomized Controlled Trial Evaluating the Effects of Diosmin in the Treatment of Radicular Pain.

Diosmin has been widely used to treat patients with vascular pain for its potent anti-inflammatory and analgesic effects. To evaluate the therapeutic effects of Diosmin in the treatment of radicular pain, we conducted an investigator-initiated, randomized, active-controlled noninferiority trial between January 1, 2009, and December 1, 2010. Diosmin (50 mg/kg/day) was orally administered to treat the radicular pain in 150 patients for one month. Another 150 patients with the same symptom were given 20% 250 ml mannitol (1 g/kg/day) for 7 days and dexamethasone (10 mg/day) for 3 days intravenously guttae. Short-term relief and long-term relief were measured. Secondary outcomes include improvement in functional and psychological status, return to work, and reduction in anti-inflammatory analgesic drugs intake. Patients treated with oral Diosmin achieved reduction in radicular pain. The total satisfaction rate of Diosmin group was 84.7% [95% confidence interval (CI): 77.9%, 90.0%], and the complete satisfaction rate was 50.7% (95% CI: 42.4%, 58.9%). No statistically significant difference was found between the Diosmin group and the active-control group regarding patient satisfaction. No adverse effects were found during the study period. Our study suggests that clinical application of Diosmin with a dose of 50 mg/kg/day might reduce the radicular pain. This trial is registered with ISRCTN97157037.

Diosmin reduces cell viability of A431 skin cancer cells through apoptotic induction.

OBJECTIVES: Aim of the present study was to evaluate the in vitro cytotoxic potential of the diosmin in A431 skin cancer cells. MATERIALS AND METHODS: The cytotoxic (anti-cell proliferative) potential of diosmin in A431 cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (cell viability), dual staining (apoptotic induction), dichloro-dihydro-fluorescein diacetate assay (reactive oxygen species [ROS] generation), DNA fragmentation study, Western blotting analysis (apoptotic markers expression) and flow cytometry (cell cycle arrest). RESULTS: Diosmin reduced the cell viability of A431 cells in a dose-dependent fashion and the inhibitory concentration 50% value was attained at 45 µg/ml using MTT assay. Diosmin at a concentration of 45 µg/ml generated excessive ROS in A431 cells, as compared to untreated cells. Diosmin treated A431 cells also revealed multiple DNA fragments than the untreated cells. Diosmin upregulated the expression of p53, caspases 3 and 9 and downregulated the expression of Bcl-2, matrix metalloproteinases-2 and 9 in A431 cells. CONCLUSION: The cytotoxic or anti-cell proliferative potential of diosmin is due to its ROS-mediated apoptotic induction potential, as well as due to its role in the inhibition of invasion in the A431 cells.

Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice.

The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases.

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.

[Safety of use of micronized diosmin at daily doses up to 2000 mg per day]. / Bezpieczenstwo stosowania zmikronizowanej diosminy w dawkach dobowych do 2000 mg.

Formulations of micronized diosmin (MPFF) are widely used in the treatment of chronic venous disease, hemorrhoidal disease and other indications. The usual recommended dose of micronized diosmin is 1000 mg once daily. Numerous studies confirm the superior efficacy and safety of higher doses of diosmin up to 2000 mg per day in a few months therapy. AIM: The aim of the study was to observe the efficacy and safety of micronized diosmine used in a daily dose of 1000 and 2000 mg for 4 months. MATERIALS AND METHODS: The study involved 327 patients meeting the inclusion and exclusion criteria. The parameters were measured immediately prior to the first dose and at 2 and 4 months of therapy. The safety analysis was conducted and the results obtained from measured parameters are presented in tables. RESULTS: No significant abnormalities in the following parameters were observed: complete blood cell count, fibrinogen level, the level of alanine transaminase and aspartate, the level of urea and creatinine, urinalysis. The therapy did not affect the level of systolic and diastolic blood pressure. There was no significant adverse events in the study groups. CONCLUSIONS: Cited in this publication results of a clinical study support the use of micronized diosmin at doses up to 2000 mg per day.

[Recanalization of lower-limb deep veins as an index of efficacy of treatment for acute venous thrombosis]. / Rekanalizatsiia glubokikh ven nizhnikh konechnostei kak pokazatel' éffektivnosti lecheniia ostrogo venoznogo tromboza.

The authors analysed the results of examination and treatment of a total of 102 patients presenting with iliofemoral venous thrombosis. During treatment, ultrasonographic duplex scanning was used to determine the localization of the proximal margin of thrombotic masses, the time of appearing of the first signs of recanalization, its degree at various levels of the deep venous system, as well as alteration in velocity of the venous blood flow in the deep veins of the lower limbs. The dynamics of clinical symptoms was assessed by the visual analogue scale. Clinical and instrumental examination was performed on day 10, and then 1, 3, 6 and 12 months after the beginning of treatment. The patients were subdivided into three groups. Group One comprised 38 patients receiving therapy with low-molecular-weight heparin (enoxaprin) followed by switching to indirect anticoagulants (warfarin) combined with venotonics (original highly-purified diosmin 600 mg once daily). Group Two was composed of 33 patients receiving rivaroxaban at a dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily. Group Tree patients (n=31) were also given rivaroxaban according to the above-described standard regimen but in combination with venotonics (original highly-purified diosmin 600 mg once daily). The obtained findings showed that prescribing rivaroxaban to patients from the first day of the disease made it possible to considerably improve and accelerate the processes of restoration of patency of deep veins of lower extremities as compared with the patients taking vitamin K antagonists (warfarin). In patients receiving rivaroxaban, there were no cases of residual thrombotic occlusions of the major veins, and recanalization in three fourths of patients was assessed as good and in the remaining third as moderate. In the warfarin group, occlusion in the iliac veins was noted to persist persisted in 13% of patients, with good recanalization observed only in half of the patients. Addition of venotonics (original highly-purified diosmin) to anticoagulants from the first day demonstrated safety of this therapeutic regimen (with no cases of clinically significant haemorrhagic complications revealed) and its high efficacy as compared with monotherapy with rivaroxaban. A combination of diosmin with rivaroxaban turned out more efficient than a combination of diosmin with warfarin.

[Efficacy of Venarus in treatment of patients with post-thrombotic disease of lower limbs].

The authors studied efficacy of Venarus in comprehensive treatment of patients presenting with post-thrombotic disease. An open multicenter retrospective study included a total of 110 patients subdivided into two groups. Group One (Study Group) consisted of 51 patients with post-thrombotic syndrome, undergoing comprehensive medical treatment with the use of phlebotonic agent Venarus. Group Two (Control Group) comprised 59 patients with post-thrombotic syndrome undergoing similar conservative treatment but without taking phlebotonics. It was proved that Venarus included into comprehensive treatment of patients with post-thrombotic syndrome led to a statistically significant increase of both psychological and social activity and improved patients' quality of life. During the standard term of administration (2 months) Venarus levelled subjective symptoms and certain objective symptoms (according to the Villalta Scale) of post-thrombotic syndrome. After 2-month use Venarus demonstrated the highest efficacy in treating patients with mild-to-moderate post-thrombotic syndrome. The maximal efficacy was observed after 3 months of administration in standard doses. No side effects were noted during the whole period of the study.

Uncommon serum creatine phosphokinase and lactic dehydrogenase increase during diosmin therapy: two case reports.

INTRODUCTION: Short-term administration of diosmin is usually considered safe, with only minor side effects (stomach and abdominal pain, diarrhea, dermatological disorders, and headache) occasionally observed. Within a 4-year period, a general practitioner noticed 17 cases of mild, diosmin-induced side effects, two of which showed particular interest. CASES PRESENTATION: Case 1: A 55-year-old Caucasian woman presented with chronic leg venous insufficiency. She was prescribed diosmin 450 mg twice a day. After 5 days of therapy, she developed pain in the legs (myalgia), and diosmin therapy was suspended. She made a spontaneous attempt of drug rechallenge and her leg pain reappeared. Thus, she underwent blood analysis, which showed elevation of creatine phosphokinase levels. Creatine phosphokinase values normalized only after prolonged discontinuation of the therapy. Case 2: A 79-year-old Caucasian man, who was diagnosed with acute hemorrhoidal syndrome. After 21 days of continuous diosmin treatment, increased levels of serum lactic dehydrogenase were detected. In both cases a comprehensive analysis of all possible causes for enzyme elevation was made. CONCLUSIONS: A feasible hypothesis to explain these rare effects could be that exaggerated adrenergic activity occurred on microcirculation, leading to an excessive peripheral vasoconstriction and subsequent ischemic damage. An individual predisposition is strongly suggested. A concurrence of events was probably responsible for the elevation of nonspecific tissue necrosis markers. Physicians and patients must be aware of these rare, but possible, adverse drug reactions.

[Micronized purified flavonoid fraction in treatment of pelvic varicose veins].

Presented herein are the results of studying efficacy of micronized purified flavonoid fraction (MPFF) in treatment of pelvic varicose veins (PVV) using reference ray-tracing methods of study. We examined a total of 85 patients with PVV. Of these, 65 subjects were found to have isolated dilatation of pelvic venous plexuses (study group), and 20 were diagnosed as having combined dilation of gonadal veins and venous plexuses of the pelvis (control group). Besides clinical examination, the patients were subjected to ultrasonographic angioscanning (USAS) and emission computed tomography (ECT) of pelvic veins before treatment and 2, 6, 12, 24, 36 and 60 months after the beginning of phlebotrophic therapy. Based on the findings of the clinical and instrumental studies, it was determined that MPFF was most efficient in patients with isolated dilatation of uterine and parametrial veins. In this group of patients, pelvic pain and other symptoms of the disease disappeared completely and the clinical effect persisted for a long time (up to 6-9 months). In the control group, venotonic therapy had a positive effect which was less pronounced as compared to the control group, and pelvic pain reappeared in the nearest time (up to 3 weeks) after withdrawal of MPFF.

Spontaneous intraventricular hemorrhage associated with prolonged diosmin therapy.

BACKGROUND: The prevalent use of anticoagulation in a growing elderly population has led to an increasing incidence of intracerebral hemorrhage. Furthermore, the understanding of the interactions and adverse effects of oral anticoagulants when used with non-FDA approved drugs is limited. Diosmin is one such non-FDA approved drug which is a semisynthetic, phlebotropic supplement with multiple microcirculatory effects. We report a case of a patient on oral anticoagulation and diosmin, who presented with spontaneous intraventricular hemorrhage, and discuss the possible etiology behind this rare event. METHODS: A retrospective chart review and a comprehensive search of the literature using the PubMed database were performed. RESULTS: A 77-year old female with a 6 week history of warfarin therapy and a several year history of diosmin use presented with severe bitemporal headache. Computed tomography scan revealed an acute hemorrhage within the right ventricle without associated intraparenchymal hemorrhage. International normalized ratio measured 1.8 and was corrected using fresh frozen plasma and vitamin K. She was discharged without neurological deficits. CONCLUSIONS: Diosmin inhibits platelet aggregation and prolongs the effect of norepinephrine on venous tone, leading to increased venoconstriction. The combined effect of chronic microcirculatory hypertension and inhibition of platelet aggregation due to diosmin may have predisposed to spontaneous hemorrhage in this anticoagulated patient. Individual cases such as this serve as a reminder that over-the-counter dietary supplements may be associated with serious adverse events. The practicing clinician should be aware of this possible adverse event when evaluating patients on oral anticoagulation and chronic diosmin treatment.