MUFFIN-PTS trial, Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome: protocol of a randomised controlled trial

IntroductionAfter deep vein thrombosis, up to 50% of patients develop post-thrombotic syndrome (PTS). PTS is a chronic condition that reduces quality of life (QOL). Cornerstones of PTS treatment include the use of elastic compression stockings but this treatment is usually incompletely effective and is burdensome. Venoactive drugs have been reported to be effective to treat chronic venous insufficiency (CVI). However, the level of evidence supporting their use in CVI in general and in PTS in particular is low.Methods and analysisThe MUFFIN-PTS trial is an academic, publically funded, multicentre randomised placebo-controlled trial assessing the efficacy of micronised purified flavonoid fraction (MPFF, Venixxa), a venoactive drug, to treat PTS. Eighty-six patients with PTS (Villalta score (VS) ≥5) and experiencing at least two of the following PTS manifestations among daily leg heaviness, cramps, pain or oedema will be randomised to receive 1000 mg of oral MPFF or a similar appearing placebo for 6 months, in addition to their usual PTS treatment. Total study follow-up will be 9 months, with visits at inclusion/baseline, 3, 6 and 9 months. Primary outcome is the proportion of patients with improvement in VS in each group, where improvement is defined as a decrease of at least 30% in VS or a VS <5 in the PTS-affected leg. Main secondary outcomes include QOL and patient satisfaction.Ethics and disseminationPrimary ethics approval was received from Centre intégré universitaire de santé et de services sociaux (CIUSSS) West-Central Montreal Research Ethics Board. Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03833024); Pre-results.

Clinical effectiveness of bioflavonoids in the treatment of secondary lower limb lymphedema

AIM: This study aimed to investigate the effectiveness of the application of a combination of the preparation of micronized purified flavonoid fraction (MPFF) and elastic compression in patients with acquired lymphostasis. MATERIALS AND METHODS: Sixty patients with stage II secondary lower limb lymphedema according to М. Foeldi were included. The patients were divided into two groups through randomization with the envelope method. The first group (n = 30) was subjected to a conservative treatment (MPFF, 1000 mg/day) coupled with elastic compression (3rd class compression stockings). The second group was given compressive therapy (third-class compression stockings). The patients were physically examined through the measurement of the circumference of the limb at different levels. RESULTS: In the first group, the circumference of the lower third of the shin decreased by 8.15% (p = 0.005) after 1 month and by the end of treatment by 10.6% (p 0.001), of the middle third of shin by 3.15% (p = 0.001) and 4.78% (p 0.001), and of the upper thirdby 4.08% (p 0.001) and 5.99% (p 0.001). By the end of the observation period (3 months), the circumference of the lower third of the shin in the second group (29.68 4.67 cm) was significantly greater than that in the first group (26.65 2.92 cm, p = 0.035). No adverse reactions were observed in the MPFF group. CONCLUSIONS: The volume of the lower limbs of patients with acquired lymphedema decreased after using a combination of MPFF and elastic compression to a larger extent than after the isolated use of elastic compression. Patients taking MPFF had a positive clinical effect without adverse reactions. Therefore, MPFF could be used in the pharmacotherapy of secondary lymphedema of the lower limbs.

Study of the antioxidant status in patients with secondary lymphedema of the lower extremities under conservative treatment

Aim. To assess the antioxidant status in patients with secondary lymphedema of the lower extremities who undergo different types of conservative treatment. Methods. The study included 90 patients with secondary lymphedema of the lower extremities and 30 healthy volunteers. Group 1 participants (n=30) received compression therapy and Vitamin E at a dose of 400 IU/day, group 2 participants (n=30) compression therapy and a micronized purified flavonoid fraction 1000 mg/day, group 3 (n=30) compression therapy alone. Group 4 (n=30) comprised healthy volunteers. The level of malondialdehyde, the activity of superoxide dismutase, glutathione peroxidase, catalase, and the level of non-protein thiols (SH-groups) were determined at inclusion in the study and then after 1 and 3 months. Results. In patients with secondary lymphedema, the initial level of glutathione peroxidase was higher by 768.22%, catalase by 420.5%, malondialdehyde by 60%, and the level of SH-groups was lower by 65,71% compared with the group of volunteers. In the first group, there was a significant decrease of 36.1% in the level of superoxide dismutase and a significant increase of 89.9% in the level of glutathione peroxidase at the end of therapy when compared with the level after 1 month. In the second group, catalase level significantly increased by 33.3%, superoxide dismutase by 17.6%, and glutathione peroxidase by 61.3% compared to baseline values. The biochemical indicators of the endothelium significantly increased when using a combination of micronized purified flavonoid fraction and elastic compression in comparison with elastic compression alone and a combination with Vitamin E. In the third group, there were no significant differences in the levels of biochemical indicators of endothelial function. Conclusion. Increased formation of lipid peroxidation products along with a decrease in the activity of antioxidant systems was revealed in patients with lower extremity secondary lymphedema compared with healthy volunteers; the most effective therapy aimed at correcting endothelial cell dysfunction is the use of micronized purified flavonoid fraction and elastic compression.

Current indications for phlebotropic therapy and its duration

Phlebotropic therapy is an important component of the pathogenetic treatment of chronic venous insufficiency (CVI) of the lower extremities. Venoactive drugs, which have proven their effectiveness and safety in a variety of studies, are widely represented in international and Russian clinical guidelines and standards. However, there is no consensus on the regulation of phlebotropic therapy and, above all, its duration in different clinical classes of CVI. In addition, there are no clear indications on the methods of treatment efficacy monitoring, which can be used in real clinical practice. The presented systematized review of the literature data on micronized purified flavonoid fraction not only reveals the possibilities of phlebotropic therapy of different clinical classes and forms of CVI, but also suggests effective regulations for the use of this drug in specific situations. The data concerning the efficacy of phlebotropic therapy in real clinical practice at the initial stages of CVI (C0s-C1s), in the treatment of C2s (varicose superficial veins with venospecific symptoms), C3 (chronic venous edema), C4 (trophic skin disorders), as well as in stages C5-C6 and C6r (venous trophic ulcers) are presented in details. In addition, the results of studies on the use of micronized purified flavonoid fraction in phlebosclerosing treatment are presented. The duration of phlebotropic therapy is in direct relation to the severity of the disease and the response to the ongoing treatment. The important role is played not only by personalization of treatment according to specific symptoms and syndromes, but also, if possible, by objective control of their dynamics.

PHLEBOPROTECTORS BASED ON FLAVONOIDS: DOSAGE FORMS, BIOPHARMACEUTICAL CHARACTERISTICS, TECHNOLOGICAL FEATURES

Micronized purified flavonoid fraction (MPFF) is the original phlebotropic drug. Its marketed form (Detralex®) consists of 90% diosmin and 10% of other flavonoids. Calculated as hesperidin, it is the most widely used drug today. Diosmin and hesperidin, which are parts of the majority of venoactive drugs, are sparingly water-soluble compounds, and this feature can effect on their clinical efficacy. One of the ways to increase the solubility of these compounds leading to an increase in bioavailability, is the micronization of the active ingredients.The aim of the investigation is a comparative determination of the dynamics and dissolution efficiency of the drugs containing bioflavonoid fractions in the dissolution test, as well as the analysis of the micronization degree and its impact on technology and biopharmaceutical parameters.Materials and methods. A biopharmaceutical release profile was determined using HPLC. Disintegration, characteristics of the shape and size of the tablets’ particles were determined according to the methods of the State Pharmacopoeia of the XIV-th edition.Results. The objects created with the use of diosmin and hesperidin, have been considered in detail. The role of technological solutions in relation to the corresponding dosage forms is notified. Detailed biopharmaceutical characteristics have been established with a choice of HPLC-based release control methodology. All the drugs in this group have a low water solubility leading to the maximum bioavailability for Detralex® which is about 1.26%; and no more than 0.2% for other analyzed models.Conclusion. Detralex® dominates among the analyzed objects (tablets) in terms of the release rate. With regard to the overall quantitative indicators of release, the actual numbers are quite low, which is associated with the poor water solubility of the active substances.