Hydroxyethylrutosides

Abstract

Hydroxyethylrutosides is a standardised mixture of semisynthetic flavonoids, mainly mono-, di-, tri-, and tetrahydroxyethylrutosides, which acts primarily on the microvascular endothelium to reduce hyperpermeability and oedema. In patients with chronic venous insufficiency or diabetes, hydroxyethylrutosides improves microvascular perfusion and microcirculation, and reduces erythrocyte aggregation. The preparation also has a possible protective effect on the vascular endothelium. In short to medium term placebo-controlled studies (up to 6 months) hydroxyethylrutosides therapy improved signs and symptoms of chronic venous insufficiency, including venous insufficiency associated with pregnancy and lymphoedema, and was well tolerated. However, the long term effects of hydroxyethylrutosides administration have yet to be demonstrated. The preparation also alleviated symptoms in patients with severe haemorrhoids, although there were no corresponding objective improvements. Hydroxyethylrutosides administration has been associated with reductions in retinal vascular permeability in patients with diabetic retinopathy but has no apparent effect on signs of retinal haemorrhage, although a reduction in oedema and haemorrhage has been reported in other patients receiving oral hydroxyethylrutosides in the acute phase of central retinal vein occlusion. There are only limited effective pharmacological treatment options for patients with chronic venous insufficiency or lymphoedema, and hydroxyethylrutosides clearly improves signs and symptoms of these disorders. While its role in diabetic retinopathy and haemorrhoids requires some clarification, hydroxyethylrutosides therapy shows promise as a useful additional option for the management of oedema and other symptoms of chronic venous insufficiency. Hydroxyethylrutosides is a standardised mixture of semisynthetic flavonoids, comprised mainly of mono-, di-, tri-, and tetrahydroxyethylrutosides. It acts mainly on the microvascular endothelium where it reduces hyperpermeability and oedema. In healthy volunteers, and patients with chronic venous insufficiency, lower limb oedema, idiopathic oedema or diabetic microangiopathy, single doses of hydroxyethylrutosides (0.3 to 1g orally or intravenously) reduce capillary filtration rate. In addition, oral dosages of 1 to 3g daily have improved parameters of microvascular perfusion, including transcutaneous partial oxygen pressure (pO₂), and have reduced oedema formation in patients with chronic venous insufficiency. Oral and intravenous administration of 3 g/day decreases microvascular permeability in patients with severe venous hypertension and patients with diabetic microangiopathy. Hydroxyethylrutosides inhibits erythrocyte aggregation in healthy volunteers and preserves erythrocyte deformability in patients undergoing cardiac valve replacement. Hydroxyethylrutosides attenuates nicotine-induced endothelial cell damage in healthy volunteers, and in animals, it has inhibited free radical scavenging. The preparation also appears to have an affinity for vein walls with a possible protective effect against endothelial cell damage and hydroxyl radical formation. There are limited data available on the pharmacokinetic properties of hydroxyethylrutosides in humans and none in special patient groups such as pregnant women, diabetics or elderly patients. Data from studies in healthy volunteers show that the proportion of a dose of hydroxyethylrutosides reaching the systemic circulation is low; about 10% of an orally administered dose is absorbed. In healthy volunteers peak plasma hydroxyethylrutosides concentrations are reached within 1 to 6 hours of oral administration. A maximum plasma concentration of 142 μg/L was reached following a single oral 900mg dose. The plasma elimination half-life ranges from 10 to 25 hours after oral administration and is approximately 1 hour after intravenous administration. The components undergo degradation by intestinal flora to aglycones, although mono-, di- and trihydroxyethylrutosides may undergo hepatic metabolism and are eliminated primarily via the bile. Three to 6% of an orally administered dose is excreted in the urine. In patients with chronic venous insufficiency, hydroxyethylrutosides 0.6 to 1.2 g/day for up to 6 months significantly improves objective and subjective measures of lower limb venous insufficiency. In most placebo-controlled studies the improvements in leg volume, calf and/or ankle circumference, and relief from symptoms of pain, tired legs, night cramps, and restless legs achieved during hydroxyethylrutosides therapy were significantly greater than those reported during placebo therapy. The wearing of supportive elastic hosiery did not appear to affect response. Overall, 73 to 100% of patients had some improvement during hydroxyethylrutosides therapy and 25 to 90% responded to placebo treatment. Response rates (percentage of patients with improvements) for individual symptoms during hydroxyethylrutosides therapy ranged from 54 to 82% for pain, 35 to 55% for restless legs, 64 to 68% for tired ‘heavy’ legs and 59 to 91% for cramps. Improvements in signs and symptoms of venous insufficiency (including cramps, irritation, swelling and pain) and reductions in accumulation of extravascular fluid correlated with improvements in microcirculatory parameters. Reductions in ankle circumference, and improvements in symptoms of pain, night cramps and paraesthesia were achieved in patients with varicosis of pregnancy treated with hydroxyethylrutosides 0.3 to 1.8 g/day. However, effects on the healing rate of leg ulcers have been equivocal. Signs and symptoms of haemorrhoids, including haemorrhoids of pregnancy, have been improved by oral therapy with hydroxyethylrutosides (0.6 to 2g daily for up to 3 to 4 weeks), although in most studies the response of hydroxyethylrutosides-treated patients was significantly greater than that of placebo recipients only in patients with severe symptoms, and objective measures of haemorrhoid severity were not altered. Signs and symptoms of lymphoedema have been alleviated by hydroxyethylrutosides treatment (3 g/day for 6 months), and radiotherapyinduced damage to skin and/or mucosa has also been reduced using concomitant hydroxyethylrutosides therapy (0.6 to 2g daily). In addition, hydroxyethylrutosides has reduced foot swelling rates and reduced retinal vascular permeability of patients with diabetic microangiopathy and retinopathy, respectively, although it does not appear to have any effect on existing retinal haemorrhage in these patients. However, oedema and haemorrhage were reduced in patients receiving oral hydroxyethylrutosides early in the acute phase of central retinal vein occlusion. Administration of hydroxyethylrutosides in clinical trials has generally been well tolerated. The incidence of adverse events reported by patients receiving treatment with hydroxyethylrutosides was similar to that reported by placebo recipients. Gastrointestinal disturbances, headache, dizziness and/or pruritus were the effects most frequently associated with either active or placebo therapy in most studies of patients with chronic venous insufficiency. In studies of patients with haemorrhoids, gastrointestinal disturbances were the most frequently reported adverse events. Hydroxyethylrutosides had no effect on glycaemic control in patients with diabetes. The recommended hydroxyethylrutosides dosage is 0.9 to 1.2 g/day orally, for patients with venous insufficiency and those with haemorrhoids, and 3g/day orally, for patients with lymphoedema. A dosage of 1.2 to 2.4g daily has been used in patients with diabetic retinopathy and dosages of 0.6 to 2 g/day have been administered to patients with skin and/or mucosal damage associated with radiotherapy. Hydroxyethylrutosides should not be administered during the first 3 months of pregnancy.