Micronised Purified Flavonoid Fraction

Abstract

Micronised purified flavonoid fraction (MPFF) [Daflon® 500mg¹], an oral phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its micronisation to particles with a diameter <2μm. Compared with placebo, MPFF 500mg twice daily significantly decreased ankle or calf circumference, and improved many symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial. Significantly more venous leg ulcers ≤10cm in diameter completely healed with MPFF 500mg twice daily plus standard management (compression and local treatment) for 2–6 months than with standard management alone or with placebo in a nonblind and a double-blind trial. The addition of MPFF to standard management was cost effective in a retrospective pharmacoeconomic analysis of the 6-month trial. Compared with placebo, the duration and/or intensity of individual symptoms of grade 1 or 2 acute internal haemorrhoids improved significantly with 3 tablets of MPFF 500mg twice daily for 4 days then 2 tablets of MPFF 500mg twice daily for 3 days. Two tablets of MPFF 500mg daily for 60 or 83 days reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids compared with placebo. Compared with a control group, MPFF significantly reduced the risk of secondary bleeding after elective haemorrhoidectomy. In clinical trials, MPFF had a tolerability profile similar to that of placebo; the most frequently reported adverse events were gastrointestinal and autonomic in nature. In conclusion, MPFF is a well established and well tolerated treatment option in patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids. MPFF is indicated as a first-line treatment of oedema and the symptoms of CVI in patients in any stage of the disease. In more advanced disease stages, MPFF may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible. The healing of venous ulcers ≤10 cm in diameter is accelerated by the addition of MPFF to standard venous ulcer management. MPFF may reduce the frequency, duration and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids, and also the severity of the signs and symptoms of chronic haemorrhoids. MPFF, an oral phlebotropic and vascular protective agent consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, increases venous tone, improves lymphatic drainage and reduces capillary hyperpermeability. By reducing the expression of some endothelial adhesion molecules, MPFF inhibits the activation, migration and adhesion of leukocytes, which leads to a reduction in the release of inflammatory mediators and thereby a reduction in capillary hyperpermeability. Two tablets of MPFF 500mg daily reduced venous distensibility and capacitance, and improved venous tone in patients with various types of venous insufficiency. Several indices of inflammation in the microcirculation are reduced by MPFF. Plasma levels of some markers of endothelial activation (intercellular adhesion molecule-1 and vascular cell adhesion molecule) and surface expression of some leukocyte adhesion molecules (monocyte or neutrophil CD62L) were significantly reduced from baseline with 2 tablets of MPFF 500mg daily for 60 days in patients with CVI. Capillary hyperpermeability decreased with 2 or 3 tablets of MPFF 500mg daily resulting in a decrease in oedema in patients in two trials. Daily administration of 1–4 tablets of MPFF 500mg for 1–3 months had beneficial effects on venous oximetry measurements (e.g. increases from baseline in oxygen pressure, oxygen saturation or pH, and decreases from baseline in carbon dioxide pressure) in patients with mild to moderate CVI in two studies. In patients with CVI, 2 tablets of MPFF 500mg daily for 4 weeks increased red blood cell velocity in capillaries; however, relative capillary packed cell volume also increased. In patients with severe CVI, 2 tablets of MPFF 500mg daily for 28 days decreased intralymphatic pressure and the diameter of lymphatic capillaries and increased the number of functional lymphatic capillaries compared with baseline. Most information on the pharmacokinetics of oral MPFF relates to the diosmin portion of the drug. Diosmin is rapidly transformed in the intestine by intestinal flora and absorbed as its aglycone, diosmetin; the unchanged form of diosmin does not appear to be absorbed. Approximately half of an oral 500mg dose of radiolabelled MPFF was absorbed within 48 hours of administration in healthy volunteers. Micronisation of diosmin increased oral absorption compared with nonmicronised diosmin (57.9 vs 32.7% of a radiolabelled dose was absorbed 0–168 hours postdose). Diosmetin has a rapid distribution period followed by a slower elimination period. Animal studies have demonstrated that radiolabelled diosmetin and/or its metabolites are widely distributed throughout the body. Diosmetin is rapidly and extensively degraded to phenolic acids or their glycine conjugate derivatives, which are eliminated in the urine; unmetabolised diosmin and diosmetin are not excreted in the urine. The predominant metabolite, 3-hydroxy-phenylpropionic acid, is mainly eliminated in its conjugated form. Unidentified metabolites may be responsible for the pharmacological activity of diosmin. Approximately half of a radiolabelled dose of diosmin was eliminated in the faeces as unchanged diosmin and diosmetin....