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).

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.

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.

[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.

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.

[Results of a multicentre clinical trial studying efficacy and safety of Vasocet in patients with varicose disease and chronic venous insufficiency].

Presented in the article are the findings of a multicenter prospective clinical trial assessing quality of life of patients with chronic diseases of lower limb veins on the background of administration of nonmicronized diosmin (Vasocet). Specialized questionnaires (CIVIQ-2) appeared to be the most optimal evaluating tools, more precisely catching alterations in patients' quality of life on the background of drug therapy.

Micronized purified flavonidic fraction compared favorably with rubber band ligation and fiber alone in the management of bleeding hemorrhoids: randomized controlled trial.

PURPOSE: The aim of this study was to assess the role of micronized purified flavonidic fraction in the management of bleeding nonprolapsed hemorrhoids. METHODS: Patients were randomly assigned to receive ispaghula husk alone, rubber band ligation plus ispaghula husk, or micronized purified flavonidic fraction plus ispaghula husk. Other colorectal diseases were excluded by colonoscopy. Blinded observers noted the time for bleeding to stop completely, recurrences, and treatment complications. RESULTS: A total of 162 patients were randomly assigned with no significant differences in the age and gender distributions among the groups. Hemorrhoidal bleeding was relieved most expediently in the micronized purified flavonidic fraction plus ispaghula husk group (ispaghula husk alone n = 66, mean (standard error of the mean) 10.6 (2.3) days; rubber band ligation plus ispaghula husk n = 57, 5.6 (1.1) days; micronized purified flavonidic fraction plus ispaghula husk n = 39, 3.9 (1.2) days; P = 0.03). However, there were no significant differences in the recurrences at six months of follow-up (ispaghula husk alone n = 8 (12 percent); rubber band ligation plus ispaghula husk n = 12 (21 percent); micronized purified flavonidic fraction plus ispaghula husk n = 2 (5.1 percent); P = 0.075). No complications or side-effects were noted. CONCLUSIONS: micronized purified flavonidic fraction used with fiber supplements rapidly and safely relieved bleeding from nonprolapsed hemorrhoids.