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Hydroxyethylrutosides. A review of its pharmacology, and therapeutic efficacy in venous insufficiency and related disorders.

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.

Animals↗

The effect of hydroxyethylrutoside and its combination with acetylsalicylic acid in patients with obliterative atherosclerosis.

The effect of 7-mono-hydroxyethylrutoside and its combination with acetylsalicylic acid was evaluated in a controlled clinical trial, performed in 105 patients with obliterative atherosclerosis of the lower limbs, and using non-invasive measurement of peripheral haemodynamic parameters--blood flow during reactive hyperaemia and ankle systolic blood pressure. Patients, randomized into three groups, received either placebo or 7-mono-hydroxyethylrutoside alone or in combination with acetylsalicylic acid for 12 months. The placebo group showed a decrease in maximum calf blood flow and a decrease in ankle systolic pressure. Administration of 7-mono-hydroxyethylrutoside did not lead to any significant changes in systolic pressure but there was a decrease in the maximum calf blood flow. There were no statistically significant changes in patients receiving the 7-mono-hydroxyethylrutoside and acetylsalicylic acid combination who, by contrast, showed a tendency to increased values of the parameters measured.

Adult↗

Acute effects of hydroxyethylrutosides on capillary filtration in normal volunteers, patients with venous hypertension and in patients with diabetic microangiopathy (a dose comparison study).

The acute effects of hydroxyethylrutosides on capillary filtration were studied in 12 normal subjects, 25 patients with venous hypertension and 22 diabetics with microangiopathy. The two groups of patients randomly received a single oral dose (500 or 1000 mg) of hydroxyethylrutosides. A single dose of 500 mg was used for normal volunteers. In the following 6 hours capillary filtration was studied with straingauge plethysmography. The decrease in capillary filtration was evident within the first hour and was at its peak between the second and fourth hour. After 6 hours it was still significantly below baseline values in patients. The 1000 mg dose was significantly more effective in both groups of patients. This study confirms the efficacy of hydroxyethylrutosides in decreasing capillary filtration. It suggests that the effect of one dose lasts at least 6 hours and also that the higher dose is more effective.

Adult↗

The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study.

The aim of this study was to evaluate the effect of hydroxyethylrutosides on capillary filtration in subjects with mild to moderate venous incompetence--superficial varicose veins and/or deep venous disease and ankle oedema--using the vacuum suction chamber (VSC) device applied to the internal perimalleolar region and the wheal vanishing (WV) time. Subjects entered in to the study were randomised to receive either hydroxyethylrutosides (1 g twice daily for 4 weeks) or placebo for four weeks. The two groups entering and completing the study were comparable. Microcirculatory parameters (laser-Doppler resting flux, the venoarteriolar response, transcutaneous PO2 and PCO2) remained constant during the four week study in both groups. The WV time, which was comparable in the two groups at the beginning of the study decreased significantly [from a median 55 min (interquartile 955 min), to a median 45 minutes (interquartile 65-40 min) in the treated group, p < 0.01]. No change was observed in the WV time in the placebo group. Subjective symptoms measured with an analogue scale improved following treatment with hydroxyethylrutosides [foot oedema (p < 0.005), ankle oedema (p < 0.001), and paraesthesia (p < 0.01)]; only night cramps were reported less in patients receiving the placebo (p < 0.05). In conclusion, the WV time can be used to assess the beneficial effect of therapy on capillary filtration in subjects with mild-moderate venous hypertension, even after a short period of treatment, and before other microcirculatory parameters change. Furthermore, the changes observed in WV time correlate well with an improvement in patients symptoms.

Ankle↗

Metabolism of hydroxyethylrutosides (HR): metabolism of [14C]-HR in man.

1. following oral administration of a [14C]-hydroxyethylrutoside (Paroven, Venoruton) preparation (HR) to three subjects, 3.05--5.97% of the administered [14C] was excreted in urine. Unchanged urinary [14C]-hydroxyethylrutosides represented 1.57--1.96% of the total dose. 2. Significant levels of [14C] were detected in plasma within 1 h of oral administration of HR. Peak levels were observed from 2--9 h. 3. The presence in urine of [14C]-3',4',5,7-tetra-O-(beta-hydroxyethyl)rutoside, [14C]-3',4',7-tri-O-(beta-hydroxyethyl)rutoside and [14C]-4',7-di-O-(beta-hydroxyethyl)rutoside was shown by radioscanning and/or spectal methods. 4. Administration of a second oral dose of [14C]-HR to each of the three subjects following extended dosage of nonlabelled HR did not result in any increase in urinary [14C] excretion over that observed after administration of a single oral dose. 5. Observations on urinary excretion in man are compatible with the finding in experimental animals that the major route of hydroxyethylrutoside excretion is via the biliary-enteric route.

Administration, Oral↗

Treatment of erythropoietic protoporphyria with hydroxyethylrutosides.

BACKGROUND: Assuming that flavonoids have anti-oxidative properties and may protect against abnormal skin reactions in erythropoietic protoporphyria (EPP), we investigated whether systemic treatment with hydroxyethylrutosides (2.7 g/day) could decrease skin sensitivity to blue light in a 37-year-old female patient who suffered from EPP. DESIGN AND RESULTS: Before treatment, skin exposure during 5 min to a xenon high-pressure gas discharge lamp with filter was sufficient to produce intense erythema, irritation and later swelling. After 1, 2 and 3 months of treatment, the exposure times, necessary to produce similar effects, gradually increased. This improvement coincided with an increased tolerability to sunlight. No adverse effects were observed. CONCLUSION: These results encourage the set-up of a more systematic, placebo-controlled study of the protective effects of hydroxyethylrutosides in EPP.

Adult↗

Effect of hydroxyethylrutosides on blood oxygen levels and venous insufficiency symptoms in varicose veins.

Oxygen levels (tension, saturation, and content) in blood from varicose leg veins were found to be significantly lower than those in blood from normal leg veins at the same site on the limb under the same laboratory conditions. Treatment with hydroxyethylrutosides significantly increased the oxygen levels in blood from varicose veins, and this was associated with an improvement in leg symptoms attributable to venous insufficiency. Hydroxyethylrutosides have been shown to have a beneficial effect on capillary dysfunction in venous stasis.

Adult↗

Inhibition of beta-aminopropionitrile (beta APN)-induced skeletal teratogenesis by the flavonoid beta-hydroxyethylrutosides (HR) in hamster fetuses.

Since biochemical studies have shown that flavonoids such as beta-hydroxyethylrutosides (HR) protect against the damage to collagen induced by lathyrogens in adult rats, this compound was given to pregnant hamsters in order to determine its effects on the teratogenicity induced by beta-aminopropionitrile (beta APN). A dose of 2,500 mg/kg of beta APN alone given by gavage on day 11 produced a high frequency (69.5%) of skeletal anomalies in the offspring of hamsters. Administration of HR immediately following beta APN to pregnant animals resulted in a significantly decreased teratogenic response (P less than 0.05). These data provide evidence to support the view that the primary mechanism for the beta APN-induced skeletal dysmorphogenesis is the inhibition of cross linking during the maturation of collagen fibers.

Abnormalities, Drug-Induced↗

Hepatic clearance and disposition of hydroxyethylrutosides.

Although salts of rutin on i-v admin. undergo insolubilization giving rise to concretions and suppurative inflammation in the liver this was not observed in respect of the vaso-active hydroxyethylrutosides (Pfeifer et al., 1970). I-v admin. of 3',4',7-tri0-(beta-hydroxy[14C]ethyl)-rutoside (tri-HR) and 7-mono0-(beta-hydroxy[14C]ethyl)rutoside (mono-HR) to mice showed rapid biliary excretion (approx. 71% within 24 h). Approx. 2/3 of the dose was subsequently excreted in faeces and ca. 25% in urine over 72 h. Autoradiography and scintilation counting showed short term concentration in the liver over the initial 4 h period but at 72 h less than 0.22% of tri-HR and 0.59% of mono-HR was detectable in hepatic tissue. Carcasses of mice killed at 72 h contained less than 7% of the initial dose which was mainly present in intestinal contents.

Animals↗

The effect of hydroxyethylrutosides on capillary filtration rate in the lower limb of man.

The rate of capillary filtration in the lower limbs after hydroxyethylrutosides administered in various doses and by different routes was studied in patients with chronic venous insufficiency. Capillary filtration rate decreased immediately after intravenous and from 55 to 85 minutes after oral administration, depending on the dose. The slow-release tablets produced a definite falt in capillary filtration 240 minutes after administration.

Administration, Oral↗

Effect of hydroxyethylrutosides on hypoxial-induced neutrophil adherence to umbilical vein endothelium.

A clinically available mixture of hydroxyethylrutosides (HR) was examined as a protector against endothelial cell activation by hypoxia in perfused human umbilical vein. The results showed that 500 micrograms/mL HR totally inhibited the adherence of human unstimulated neutrophils to the endothelium of umbilical vein incubated in hypoxic conditions. This inhibition was confirmed by a morphological study performed by scanning electron microscopy. In addition, neutrophils adherent to the hypoxic umbilical vein endothelium became activated, as evidence by the increased release of superoxide anions and synthesis of leukotriene B4. These processes could also be inhibited by HR. In conclusion, the results of this study suggest that the improvement in venous insufficiency observed clinically with HR could, in part, be the result of their ability to inhibit the recruitment and activation of neutrophils by endothelium activated during blood stasis.

Cell Adhesion↗

Effects of hydroxyethylrutosides on the permeability of microvessels in the frog mesentery.

1. We have investigated the effects of a standardised mixture of hydroxyethylrutosides (HR, Venoruton), a mixture of five of its main components (M) and each of the five components separately (7-mono-HR, 7,4'-di-HR, 7,3',4'-tri-HR, 5,7,3',4'-tetra-HR and 7,3'4'-tri HQ) upon the permeability of single perfused capillaries and venules in the mesenteries of pithed frogs. 2. In each experiment, the hydraulic permeability (Lp) of a single perfused microvessel and the effective osmotic pressure (sigma delta pi) exerted by macromolecules across its walls were estimated by a microcclusion technique, first during control perfusion and then in the presence of a known concentration of test substance. 3. HR, M and 7,4'-di-HR reduced Lp in a similar concentration-dependent manner over the range of 1 microgram ml-1 to 1 mg ml-1 (maximum reduction was to 40% of control Lp at 1 mg ml-1). At perfusate concentrations greater than 1 mg ml-1, these substances reduced Lp to a lesser extent. While the four other test substances reduced Lp significantly when their perfusate concentrations equalled or exceeded 100 micrograms ml-1, they were all less potent than 7,4'-di-HR. 4. The reduction in Lp induced by the mixture of flavonoids was only slightly reversed by subsequent perfusion with flavonoid-free solutions. 5. When permeability was increased by perfusing with protein-free solutions, both HR and 7,4'-di-HR reduced and then reversed the increase in Lp in a concentration-dependent manner over the range of 1 microgram ml-1 to 100 micrograms ml-1. None of the other component flavonoids was effective in restoring Lp under these conditions.

Animals↗

Effects of hydroxyethylrutosides on hypoxia-induced activation of human endothelial cells in vitro.

1. A clinically available mixture of hydroxyethylrutosides (HR) was examined as inhibitors of endothelial cell activation by hypoxia in vitro. Thus, the effects of HR on ATP depletion, phospholipase A2 activation and neutrophil adherence were investigated in hypoxia-activated human umbilical vein endothelial cells in primary cell culture. 2. Our results show that HR inhibited two important steps of the activation of endothelial cells by hypoxia: the decrease in ATP content, which is the starting point of the process, and the activation of phospholipase A2 one enzyme responsible for the release of inflammatory mediators. This inhibition was dose-dependent with 70 to 90% inhibition at 500 micrograms ml-1 of HR. 3. In addition, hypoxia-activated endothelial cells increased their adhesiveness for neutrophils. This process could also be prevented in a dose-dependent manner if endothelial cells were incubated in the presence of HR. This inhibition was confirmed by a morphological study. 4. In conclusion, the results of this study suggest that a possible explanation for the improvement in venous insufficiency by HR observed clinically could be their ability to inhibit the activation of endothelial cells during blood stasis.

Adenosine Triphosphate↗

Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon.

Escin, hydroxyethylrutoside (HR), and Daflon have been shown to be safe and effective for the treatment of chronic venous insufficiency (CVI). They seem to work differently than compression therapy, suggesting that they would usefully augment this therapy. All three phlebotonics attenuate the drop in adenosine triphosphate in venous endothelial cells during hypoxia. This attenuates (1) the inflammation response, (2) the attraction of neutrophils, (3) damage to the veins, and (4) the release of growth factors. These factors otherwise would perpetuate venous insufficiency and contribute to varicose veins. Additional independent effects that would be useful for the treatment of CVI are that they reduce permeability and fragility; HR, Daflon, and perhaps escin increase venous tone; escin inhibits hyaluronidase; Daflon and probably HR are attracted to the veins. With regard to similarity, no differences in effect have been established among these phlebotonics.

Chronic Disease↗

Improvement of subcutaneous nutritional blood flow in the forefoot by hydroxyethylrutosides in patients with arterial insufficiency: case studies.

Four patients with bilateral arterial insufficiency were treated with i.v. hydroxyethylrutoside for three days (1.5 grs twice a day). All patients experienced relief of symptoms. By continuous registration of subcutaneous nutritional blood flow in the forefoot (by 133Xenon clearance technique) a significant increase in nutritional blood flow of 33% on the average during the second and third hour after medication could be demonstrated. The drug seems to be of use in treating subacute occlusions and thrombosis of arteries in the lower extremity.

Aged↗

Intravenous hydroxyethylrutosides combined with long-term oral anticoagulation in atherosclerotic nonreconstructable critical leg ischemia: a retrospective study.

OBJECTIVE: To evaluate in a group of seriously diseased patients with nonreconstructable chronic critical leg ischemia (CLI), treated by a combination of i.v. hydroxyethylrutosides (HR)* and oral anticoagulation (AC) by warfarin, the short-term effects on the cutaneous microvascular blood perfusion of the soles of feet and especially the long-term clinical outcome in terms of amputation and death. DESIGN: A retrospective comparison between two groups of patients, HR + AC and a comparable reference group, fulfilling the same inclusion and exclusion criteria corresponding to the definition of CLI according to the Second European Consensus Document (1991). Clinical follow-up in both groups was made after 1, 3, 6, 12, and 24 months. SETTING: Patients were examined at university departments of clinical physiology with special interest in peripheral vascular disease, in cooperation with colleagues at university departments of surgery, internal medicine and dermatology of Karolinska Hospital, Södersjukhuset and Huddinge Hospital. PATIENTS: A total of seventy patients with CLI according to the definition of the Second European Consensus Document, 1991, ie, besides severe rest pain or ischemic lesions also a toe blood pressure < 30 mg Hg. Group with HR + anticoagulation (AC): 42 patients (19 diabetics, 23 nondiabetics). Reference group: 28 patients (18 diabetics, 10 nondiabetics). For distribution of age and toe blood pressure at baseline, see Table I. INTERVENTIONS: Therapy group: besides ordinary standard therapy, daily HR infusions for a mean period of 3.6 weeks + oral anticoagulation continued to the end of the study at 24 months. A comparable reference group on the same basic therapy but without the combination HR + AC. PARAMETERS IN EVALUATION: Short-term parameters: clinical data, skin temperature, and fluorescein imaging. Long-term outcome: amputation or death. RESULTS: Short-term and long-term results with HR + AC indicated that patients with severe CLI and very poor prognosis benefited in terms of survival and limb salvage from initial therapy with HR infusion combined with long-term oral anticoagulation. Results of this combined treatment seem at least comparable with those with i.v. prostacyclin analogies.

Administration, Oral↗

Hydroxyethylrutosides during extracorporeal circulation: effect on erythrocyte deformability.

The effect of hydroxyethylrutosides (HR) on erythrocyte deformability was studied in 13 adult patients subjected to extracorporeal circulation, in seven cases for single valve replacement and in six for coronary bypass operations. A single dose of 1.5 g HR was given by slow intravenous injection immediately before the cardiopulmonary bypass. The controls were 13 patients undergoing the same operations but without HR. In the HR-medicated valve group there was only 3% decrease in erythrocyte deformability following extracorporeal circulation, in contrast to a 41% (p less than 0.01) decrease in the control valve group. Among the coronary patients there was no such difference between the HR and the control groups, with deformability decreasing by 21 and 26%, respectively (both significant, p less than 0.05). HR administered before extracorporeal circulation thus had significant prophylactic effect on red cell deformability in patients undergoing valve replacement. Such beneficial action may improve nutritional blood flow, thereby reducing the number of postoperative complications in various organs. With higher doses and/or longer periods of administration, a favorable effect of HR might be possible also in patients subjected to coronary surgery.

Aged↗