PHARMACOLOGY

Elimination

In a study conducted by Oustrin and colleagues, 3H-labelled diosmin was administered both i.v. and orally to Wistar rats . Absorption by the GI track was rapid, and the peak plasma concentration was between 1 and 2 hours. Of the organs examined, almost all had 0.1% to 0.2% of the original activity after 48 hours, only the liver had a 1 % concentration. Elimination took place in the urine and in the faeces. After i.v. administration, elimination was predominantly in the urine, while after oral administration it was eliminated almost equally in the urine and in the faeces, during the first 24-hour period . In the following 24-hour periods, the faeces carried the greater portion of diosmin or its metabolites . Binding to the vascular wall was relatively late.

Mechanism of Action

Inflammatory reactions are trigged by chemical and biological mediators, such as arachidonic acid derivatives (prostaglandins, leukotrienes, or tromboxanes), vasoactive amines (histamine or serotonin), and oxygen free radicals (superoxideion, 02~, or hydrogen peroxide) . In venous inflammation, histamine causes vasodilatation ; and PGE2, histamine, and free radicals increase membrane permeability . Diosmin acts by inhibiting the enzyme phosphodiesterase, increasing intracellular cyclic adenosine monophosphate (cAMP) and consequently reducing the level of the main biochemical mediators of inflammation prostaglandin E2 and F2 (PGE2, PGF2), thromboxane B2 (TXB2), and oxygen free radicals" .

Diosmin reinforces venous tone by prolonging the activity of pariental norepinephrine. In experiments on the saphenous vein strips of dog, conducted by Heusser & Osswald, diosmin blocked the inactivation of exogenous noradrenaline and caused a slow and gradual contractile response of an oil-immersed strip, which was not attributable to the release of noradrenaline2' . Diosmin exerts a significant potentiation toward NE in both normal and varicose veins under acidotic conditions . Local acidosis depresses reactivity of vascular smooth muscle, especially the response of human isolated saphenous veins to exogenous norepinephrine . In a in vitro study, Juteau and colleagues used isolated varicose veins to test the effect of diosmin+h and norepinephrine on human rings of veins under acidosis conditions. Results showed that the diosmin+h combination induced a shift to the left of the concentration-response curves for norepinephrine. This potentiation was significant in both normal and varicose veins and was increased in proportion with the pathological status of the venous rings".

In an in vitro study, the cytvtoxic effect of lipopalysaccharide (LPS) on cultivated bovine aortic endothelial cells was attenuated by diosmin . Melzig and Loose speculated that the inhibition of LPS-induced cytotoxicity in bovine aortic endothelial cell cultures by diosmin may be mediated via inhibition of tyrosine kinases. Study data showed that the IC50-value of LPS in the combination with diosmin 8 gmol/l was shifted from 31 to 70 nglml in a concentration dependent manner". In another in vitro study conducted by Korthuis, diosmin prevented ischemia and reperfusion-induced leukocyte adhesion in skeletal muscle . This antiadhesive effect appeared to be mediated, in part, by inhibition of induced expression of ICAM-1'

When the lymphatic activity diosmin+h was tested in dogs and rats, diosmin induced a lymphatic flow increase that was correlated with the administered doses. The maximal 10 minute period flow after i.v. injection of D (12 .500 mg/kg) was 191% higher than the corresponding one in the control group . A correlation between lymphatic flow increase and pulsatility was demonstrated . Infusion of 14Clabelled-D evidenced a clear blood-lymph transfer of the drug : an active transport into the lymph was suggested during a 15 minute to 100 minute period from the concentration curves".

Daflon is a strong inhibitor of Cu(2+)-induced arachidonic acid peroxidation, as revealed by the inhibition of thiobarbituric acid- reactive substance formulation in mixed liposomes of phosphatidylcholine and arachidonic acid. Diosmin is a good complexant of Cu2+ ions but not of Fe2+ ions. The Cu2+ complex formulation may thus explain part of the antioxidant effect. However, Daflon is also a good quencher of the singlet oxygen-induced arachidonic acid peroxidation that does not involved metal ions"

Struckmann and colleagues carried out a review of the pharmacology and therapeutic efficacy of Daflon 5t?0 mg (diosmin + hesperidin) in patients with CVI and related disorders . The major pathologic event in CVI, whether it is due to obstruction, reflux, or both, is an inability to reduce venous pressure during ambulation . This results in abolition of the arteriovenous reflex, and extravasation of plasma proteins, which accumulate in the pericapillary space and which may take part in the pathogenic mechanism of venous ulceration . White blood cells marginate in the capillary bed, where they liberate cytotoxic substances that may induce an inflammatory reaction, cell death, and ulceration. Animal experiments have provided evidence of an effect of diosmin+h on venous tone, prostaglandin synthesis, free radicals, complement activity, and lymphatic drainage. These findings may explain, at the microvascular level, the observed clinical findings in placebo-controlled, double-blind trials, which have shown significant effects on edema reduction and improvement in subjective parameters coincident with reductions in venous capacitance, distensibility, and emptying times'.