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.

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.

TREATMENT OF VENOUS INSUFFICIENCY EMERGING AFTER COVID-19 DISEASE

COVID-19 disease caused by the virus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious disease leading to hyperinflammation. Lockdown measures implemented due to COVID-19 can lead to weakness in the calf muscles of the elderly individuals who stay at home for a long time and in those receiving COVID-19 treatment in intensive care unit. Thus, venous insufficiency may develop in these circumstances. It is important to treat these patients without delay, as it may prevent the progression to chronic venous insufficiency. Our study includes eight patients who were diagnosed with COVID-19 and were discharged after being treated in various centers, but later developed venous insufficiency. Two of the patients were women and six were men. Their ages ranged from 43 to 70, and the mean age was 56.87 ± 9.70 years. The main complaints of the patients were pain, swelling, itching, tingling, burning, edema, cramping, feeling of heaviness and discoloration in the legs. All patients were hypertensive and five patients were using tobacco products. In addition, two patients had diabetes and one patient had concomitant coronary artery disease. All patients had weak calf muscles and high D-dimer levels. Venous insufficiency was diagnosed because reflux was detected in the deep veins of both lower extremities in the color venous Doppler ultrasonographic examination of the patients. Considering that venous insufficiency may be seen after recovery in COVID-19 patients, intermittent control of these patients should be done after discharge. It is important to closely monitor patients who develop venous insufficiency after COVID-19 treatment, and to strengthen the weakened calf muscles with exercises in addition to medical treatment with venoactive drugs. Since venous insufficiency may regress as a result of the strengthening of calf muscles, it should not be rushed for invasive procedures.

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.

Micronized purified flavonoid fraction in the treatment of hemorrhoidal disease

Hemorrhoidal disease (HD) is common in adults. Treatment is largely conservative, although more invasive procedures may be required. Venoactive drugs such as micronized purified flavonoid fraction (MPFF) are widely used, but a recent and comprehensive review of supporting evidence is lacking. In acute HD, MPFF can reduce HD symptoms such as bleeding, pain, anal discomfort, anal discharge and pruritus. In patients undergoing surgery, postoperative adjunct MPFF consistently reduces pain, bleeding duration and use of analgesia. MPFF treatment is appropriate and effective both as a first-line conservative treatment and as a postoperative adjunct treatment. MPFF reduces the duration of hospital stay following surgery, facilitating a return to normal activity and improving quality of life. MPFF may also prevent HD recurrence.

The Significance of Pain in Chronic Venous Disease and its Medical Treatment

Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression. </P><P> General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease.

Pharmacotherapy of chronic venous insufficiency of the lower extremities

Chronic venous insufficiency (CVI) is the most common pathology of the peripheral vascular system. One of the main principles of conservative treatment for both small and complicated forms is pharmacotherapy with the use of venoactive drugs. The effectiveness of therapy is largely associated with the choice of phlebotrophic drug. The article discusses approaches to systemic and topical drug therapy depending on the form and stage of CVI.