IngredientesRutosides are a group of naturally occurring flavonoid glycosides whose principal member is rutin (also called rutoside). Rutin (rutoside, quercetin-3-O-rutinoside, or sophorin) is the glycoside combining the flavonol quercetin and the disaccharide rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranose). The term "rutosides" is used both for this compound specifically and as a collective name for a class of related flavonoid glycosides, including semi-synthetic derivatives such as hydroxyethylrutosides (also called oxerutins or oxerutins), which are widely used in clinical and pharmaceutical contexts.
The name "rutin" comes from the plant Ruta graveolens, which also contains rutin. Other synonyms include quercetin-3-rutinoside, sophorin, and vitamin P. The chemical formula of rutin is C27H30O16, and its molecular weight is approximately 610.5 g/mol. The common pharmaceutical salt form, rutoside trihydrate (C27H40O21), has a CAS number of 250249-75-3.
Hydroxyethylrutosides (HR), also known as oxerutins, are semi-synthetic derivatives of rutin and a mixture of mono-, di-, tri-, and tetra-O-β-hydroxyethyl rutosides, which are derivatives of rutin, flavonoids extracted from Sophora japonica, a plant used in traditional Chinese medicine. Oxerutins are used for the treatment of chronic venous disease. Hydroxyethylrutosides were obtained through hydroxylation of the natural flavonols, rutin; a standardized mixture contains mainly monohydroxyethyl rutosides (5%), dihydroxyethylrutosides (34%), trihydroxyethylrutosides (46%), and tetrahydroxyethylrutosides (5%). Commercially available products include Relvene, Venoruton, and Paroven.
Rutin is a flavonoid glycoside found in a wide variety of plants, including citrus. It is one of the more abundant dietary flavonoids. Key botanical sources include:
Historically, rutosides have been used in traditional medicine for their purported ability to strengthen blood vessels and support vascular health. Early use in Europe and Asia focused on addressing symptoms of venous insufficiency, bruising, and hemorrhoids.
Traditionally, rutin is used to prevent mucositis due to cancer treatment, to treat blood vessel disease such as varicose veins, bleeding, and hemorrhoids. It has been used therapeutically to decrease capillary fragility.
Sophora japonica, a primary commercial source of rutin, is listed as a top-grade herb in Shen Nong's Classic Materia Medica, one of the oldest Chinese pharmacopoeias. Flavonoids extracted from Sophora japonica are a plant used in traditional Chinese medicine.
Rutin was historically used in traditional medicines to treat conditions associated with poor blood flow, chronic pain, and high cholesterol. In folk remedies, rutoside-rich plants like buckwheat tea were often recommended for bruising. Traditionally, rutin is used to prevent mucositis due to cancer treatment, to treat blood vessel diseases such as varicose veins, bleeding, and hemorrhoids.
Chemically, rutin is a glycoside comprising the flavonolic aglycone quercetin along with the disaccharide rutinose. Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside) is a flavonol found abundantly in plants such as the flowers of pagoda tree, buckwheat seeds, tea, and berries. The attachment of the sugar moiety (rutinose) to the flavonol backbone quercetin at the 3-O position is what distinguishes rutin from quercetin and determines many of its pharmacokinetic properties.
The low water solubility of rutin limits its expansion into food and pharmaceutical applications. Various studies have been conducted to increase the water solubility and efficacy of rutin. Rutin encapsulated with β-cyclodextrin has been studied for its solubility and biological activity.
Rutin is not well absorbed in the small intestine of humans, and thus is transported into the colon and metabolized by the gut microbiota into quercetin-3-glucoside and then quercetin, or directly into quercetin. The glyco-conjugates of quercetin are poorly absorbed in the upper intestinal tract and accumulate in the large intestine. In the colon, members of the gut microbiota can hydrolyze rutin or other glyco-conjugates, removing the sugar moiety and permitting the absorption of the aglycone. Therefore, the colonic microbiota is responsible for the extensive breakdown of the original flavonoid structures into low-molecular-weight phenolic metabolites.
The gut microbiota, including strains of Streptococcus, Lactobacillus, Bifidobacterium, and Bacteroides, produces α-rhamnosidases and β-glucosidases that perform deglycosylation of rutin to form the aglycone, which is later passed into circulation for further catabolic reactions to form lower molecular weight compounds. Absorption of quercetin is followed by phase II metabolism within the small intestine, which involves reactions mediated by sulfotransferases (SULTs), uridine-5′-diphosphate glucuronosyl transferases (UGTs), and catechol-O-methyl transferases (COMTs).
The recovery of rutin (97%) in the luminal fluid strongly suggested that rutin was metabolized in the colon. Another study in Sprague-Dawley rats showed that after oral administration of rutin, only sulfates and glucuronides of quercetin were present in the circulatory system whereas parent rutin was absent, suggesting that rutin itself cannot enter the bloodstream and undergoes extensive degradation.
Rutosides exert their biological effects through multiple, partially overlapping mechanisms. The best-documented mechanisms are:
Rutin is also known as vitamin P and has antiplatelet, antiviral, and antihypertensive properties. It strengthens capillaries due to its high radical scavenging activity and antioxidant capacity. Rutin has been reported to strengthen the capillaries of blood vessels, which is the result of its high reactive oxygen species (ROS) scavenging activity and antioxidant capacity.
Rutin expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor.
Available preclinical evidence suggests that rutin, through its strong antioxidant properties, can effectively ameliorate inflammation by reducing the levels of pro-inflammatory markers such as tumor necrosis factor-α, interleukin (IL)-6, cyclooxygenase-2 (COX-2), and IL-1β. This includes blocking the associated inflammatory pathways such as NF-κB, MAPK, and JAK/STAT. The activation of NRF2 enhances intracellular antioxidant responses and alleviates inflammation.
The aglycone part of rutin can block both COX and LOX pathways at high concentration; furthermore, the lipoxygenase pathway is primarily the target of inflammation inhibition at low concentrations of rutin.
Rutosides and escin are known as "venoactive" or "phlebotonic" remedies. In chronic venous insufficiency (CVI) patients, white blood cells accumulate in the affected limbs, resulting in activation of enzymes which degrade the protein within the capillary walls. Studies have shown that escin inhibits these enzymes, thereby preventing fluid leakage and swelling due to loss of capillary wall patency.
Rutosides inhibit erythrocyte and platelet aggregation, improve erythrocyte deformability and aggregation, and improve plasma viscosity and retinal microcirculation. Many pharmacological and clinical studies have shown the influence of troxerutin (a rutoside derivative) on disturbances of capillary permeability, antiedematous actions, inhibition of prostaglandin synthesis, and reduction in venous hypertension.
Rutin and rutin glycoside derived from rutin showed dose-dependent reduction effects on the level of NO or PGE2, and pro-inflammatory cytokines TNF-α and IL-6. Rutin and rutin glycoside did not show much difference in the anti-inflammatory effects, although they showed differences in antioxidant activity.
Rutin, a natural flavonoid glycoside widely distributed in various plants including buckwheat, citrus fruits, and onions, has garnered significant attention as a promising neuroprotective agent. Research comprehensively evaluates rutin's multifaceted neuroprotective mechanisms, which encompass antioxidant, anti-inflammatory, anti-apoptotic, antidepressant, anticonvulsant, and analgesic effects, as well as its role in enhancing neural signal transduction, improving learning and memory, and protecting the blood-brain barrier. Rutin can regulate capillary permeability, improve cerebral microcirculation and metabolic environment, and provide stable nutritional support for the brain.
This is the area with the most substantial clinical evidence for rutosides. Rutoside (rutin; quercetin rutinoside) is a glycoside found in various plant products, including apples, citrus fruits, and cranberries. Hydroxyethylrutosides (HR) are semi-synthetic derivatives sold as standardized products for the treatment of chronic venous insufficiency (CVI). Commercially available products include Relvène (France), Venoruton (Switzerland), and Paroven (United Kingdom).
A major Cochrane review included 69 RCTs of oral phlebotonics, of which 56 studies (7,690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics: 28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract, and one on grape seed extract.
A Cochrane review and meta-analysis of phlebotonics for venous insufficiency, published in 2020, analyzed 56 randomized, double-blind, placebo-controlled trials involving 7,690 participants. The meta-analysis suggests that oral venoactive drugs as a whole reduce lower leg oedema (risk ratio 0.70, 95% CI 0.63 to 0.78) and ankle circumference (mean difference −4.27 mm, 95% CI −5.61 to −2.93 mm) compared with placebo. Little or no effect was evidenced for ulcer healing (RR 0.94, 95% CI 0.79 to 1.13).
Phlebotonics present limited efficacy for oedema and for some signs and symptoms related to CVI. There is moderate-certainty evidence that phlebotonics probably slightly reduce oedema compared to placebo; moderate-certainty evidence of little or no difference in quality of life (QoL); and low-certainty evidence indicates that these drugs do not influence ulcer healing. Moderate-certainty evidence shows that phlebotonics are probably associated with higher risk of adverse events than placebo, especially in the subgroup analysis of the rutoside group.
Studies included in this Cochrane Review provided only short-term efficacy and safety data; therefore, the middle- and long-term efficacy and safety of phlebotonics could not be estimated. Based on the results of subgroup analysis, some phlebotonics were effective for certain symptoms and signs; however, given the limited number of studies and the differences between them, further high-quality evidence is needed.
A systematic review published in the Journal of Clinical Pharmacy and Therapeutics (2015) focused specifically on hydroxyethylrutosides for CVI. The search identified 1,474 records and only 15 trials involving 1,643 participants met the inclusion criteria. A meta-analysis based on similar studies that compared HR with placebo showed that HR significantly improved outcomes.
Evidence strength summary for CVI: Moderate-certainty evidence that rutosides (as part of the phlebotonics class) probably slightly reduce oedema in CVI. Evidence for ulcer healing is low-certainty. Long-term data are absent.
Post-thrombotic syndrome is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years.
Overall, there is currently limited low-quality evidence that "venoactive" or "phlebotonic" remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in the Cochrane review provide no evidence to support the use of rutosides in the treatment of PTS.
No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ("mild side effects" reported in 7/41 and 5/42 respectively). In the study comparing rutosides with elastic compression stockings, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. There was no evidence that rutosides were superior to the use of placebo or elastic compression stockings (ECS).
Regarding prevention of PTS after DVT, a separate Cochrane review found that no studies were identified comparing rutosides versus any alternative in the prevention of PTS.
A 2020 review indicated that oral rutosides may reduce leg edema by a small amount in people with post-thrombotic syndrome, but the risk of adverse effects was higher.
Evidence strength summary for PTS: The evidence is low-quality and insufficient to support use; no superiority over placebo or elastic compression stockings has been demonstrated.
In a study of 37 pregnant women given 300 mg rutoside three times daily for 8 weeks versus placebo, rutoside reduced symptom scores for pain, feelings of leg heaviness and tiredness, nocturnal cramps, and paraesthesias associated with varicosities, compared with placebo, in women with visible varices and these symptoms after 28 weeks' gestation. Rutosides also led to reduction of ankle size compared with placebo, in whom ankle size increased.
Evidence strength: This is a single small study (n=37); findings are preliminary and cannot form the basis of a definitive efficacy claim.
Rutin inhibits Aβ aggregation and cytotoxicity, attenuates oxidative stress, and decreases in vitro production of NO and proinflammatory cytokines. Neuroprotective properties of rutin (or rutin metabolites) were demonstrated in a number of in vivo and in vitro studies.
Rutin, a natural flavonoid glycoside widely distributed in various plants including buckwheat, citrus fruits, and onions, has garnered significant attention as a promising neuroprotective agent. Research evaluates rutin's multifaceted neuroprotective mechanisms, which encompass antioxidant, anti-inflammatory, anti-apoptotic, antidepressant, anticonvulsant, and analgesic effects, as well as its role in enhancing neural signal transduction, improving learning and memory, and protecting the blood-brain barrier.
Evidence strength: Preclinical (in vitro and animal model) evidence only. No clinical trials in humans have been completed to establish neuroprotective efficacy.
Findings from preclinical studies indicate that rutin has a significant positive impact on various indicators of intestinal disease caused by IBD. Key results include reduced weight loss, lower disease activity index (DAI), decreased inflammatory markers, reduced oxidative stress markers, and increased antioxidant defenses. Its mechanism of action involves anti-inflammatory, antioxidant, inhibition of inflammatory signaling pathways, barrier protection, inhibition of adaptive immune responses, restoration of intestinal permeability, and regulation of the microbiota.
Preclinical evidence suggests that rutin can significantly alleviate the abnormal indicators of intestinal inflammation. In experiments, the performance of rutin in various indicators is very close to existing positive control drugs such as sulfasalazine and budesonide, with similar therapeutic effects.
Evidence strength: Preclinical evidence only (animal models and in vitro); no human clinical trials have demonstrated efficacy in IBD.
Rutin (also known as rutoside) is a natural flavonoid glycoside widely distributed in Sophora japonica, buckwheat, and various citrus fruits. Accumulating evidence indicates that rutin, owing to its superior antioxidant, anti-inflammatory, anti-apoptotic, and immunomodulatory properties, exhibits significant protective potential in ischemia-reperfusion injury (IRI) models across multiple organs—including the heart, brain, kidney, liver, intestine, and skeletal muscle.
Evidence strength: Entirely preclinical; no human clinical trials have investigated rutosides for ischemia-reperfusion injury.
As a component of the dietary supplement Phlogenzym, rutin is used for the treatment of osteoarthritis. For osteoarthritis, a dosage of 2 tablets of a combination product (Phlogenzym), which contains 100 mg of rutin, 48 mg of trypsin, and 90 mg of bromelain, 3 times daily, has been used. However, because rutin is combined with other bioactive enzymes in this formulation, attribution of benefit to rutin specifically cannot be made from these trials.
Evidence strength: Available only in combination formulations; the independent contribution of rutin is unclear. Evidence strength is low.
Rutin is also used for treatment of post-surgical swelling of the arm after breast cancer surgery. This application has been explored in clinical settings but high-quality, large-scale evidence is lacking.
Most clinical studies have used hydroxyethylrutosides (HER), a standardized mixture of rutinosides. The following dosages have been reported in clinical literature:
Dosage forms available in commerce and studied include oral tablets, oral capsules, and topical gels. Oxerutins are semi-synthetic derivatives of rutin used for the treatment of chronic venous disease. Brand-name oral products studied include Venoruton and Paroven.
Adverse effects are rare and transient. The most commonly reported adverse effects include dizziness, headache, dry mouth, tiredness, nausea, dyspepsia, diarrhea, constipation, and skin rash.
Moderate-certainty evidence shows that phlebotonics are probably associated with higher risk of adverse events than placebo, especially in the subgroup analysis of the rutoside group. This finding from a large Cochrane meta-analysis is an important consideration.
No clear evidence of a difference in adverse effects between the rutosides and placebo/no-treatment groups was seen ("mild side effects" reported in 7/41 and 5/42 participants respectively) in the Cochrane review of PTS trials. A meta-analysis combining two rutoside studies reported a non-significant increased risk with rutoside use (RR 2.04, 95% CI 0.76 to 5.51) for adverse effects.
Rutin appears to be safe during pregnancy. Its safety after 28 weeks of gestation has been confirmed in two human trials. Scientific evidence for the safe use of rutin during lactation is not available. Given the uncertainty of the safety of rutoside preparations, it is recommended that pregnant women consume foods rich in rutin and take a complete vitamin supplement with bioflavonoids, including rutin, rather than a rutoside product.
One of the primary interaction concerns is rutin's interaction with anticoagulant and antiplatelet drugs such as warfarin, aspirin, and clopidogrel. Since rutin can inhibit platelet aggregation and enhance blood flow, taking it alongside these medications may amplify their effects, increasing the risk of bleeding.
A pharmacokinetic study in rats found that concurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half-life of the more potent S-enantiomer. This finding (from an animal study) suggests the interaction between rutin and warfarin may be complex and not unidirectional; clinical data in humans remain limited.
Studies included in the major Cochrane review provided only short-term efficacy and safety data; therefore, the middle- and long-term efficacy and safety of phlebotonics could not be estimated. This represents a significant gap in the safety evidence base for rutosides.
Rutin (rutoside or rutinoside) and other dietary flavonols are under preliminary clinical research for their potential biological effects, such as in reducing post-thrombotic syndrome, venous insufficiency, or endothelial dysfunction, but there remains no high-quality evidence for their safe and effective uses, as of 2018.
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Rutosides are a class of flavonoid glycosides derived from rutin, comprising the oxerutins (hydroxyethylrutoside mixture) used extensively in Europe for varicose veins and CVI. Multiple double-blind, placebo-controlled trials support their use, and they are covered by the 2020 Cochrane review on phlebotonics for venous insufficiency. They reduce leg aching, swelling, and fatigue, and have been shown effective for pregnancy-related varicosities.
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