Diosmin

Diosmin: A Comprehensive Reference

1. Identity: Chemical Names, Botanical Sources, and Forms

1.1 Chemical Identity

Diosmin (diosmetin 7-O-rutinoside), a flavone glycoside of diosmetin, is manufactured from citrus fruit peels as a phlebotonic non-prescription dietary supplement. Its systematic chemical names include 3′,5,7-trihydroxy-4′-methoxyflavone-7-rutinoside and 3′,5,7-trihydroxy-4′-methoxyflavone-7-ramnoglucoside. Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is constituted by a sugar moiety (rutinoside disaccharides) linked to the aglycone diosmetin; it can be obtained by extracting hesperidin from citrus rinds through iodine-assisted oxidation.

Diosmin is extracted from plants (Rutaceae) or obtained by synthesis, as with another bioflavonoid, hidrosmin. The half-life of diosmin is 8 to 12 hours, with its elimination renal (65%) and biliary (35%).

1.2 Botanical Sources

In nature, large concentrations of this flavonoid are found mainly in citrus fruits, notably oranges, grapefruits, and tangerines, as well as in certain shrubs, such as Ruta graveolens and Barosma betulina. Citrus fruits, especially lemons, are rich sources of diosmin. Lemons produce a number of useful flavonoids, including diosmin, in both the mature fruit and the leaves. Members of the Vicia (vetch) genus also contain diosmin, including Asian and Caucasian vetch species. Vetches are native to North America, Europe, Africa, and Asia, and are related to peas and lentils.

In 1925, diosmin was first isolated from Scrophularia nodosa L. (figwort). The plant Hyssopus officinalis (hyssop) has also been identified as a botanical source; Ivashev and colleagues reported the isolation of diosmin from plants of the genus Vicia and Hyssopus officinalis and its influence on blood coagulation, published in the Pharmaceutical Chemistry Journal, 1995.

1.3 Commercial Forms and Preparations

Various specialties containing diosmin are available, including micronized purified flavonoid fraction (MPFF) which contains 90% diosmin and 10% hesperidin. Diosmin is commercially available in the United States and Europe as a nonprescription dietary supplement (e.g., DiosVein). It is most often combined in a micronized form with hesperidin (diosmin 90% plus hesperidin 10%), referred to as micronized purified flavonoid fraction (MPFF), and marketed in the United States as Daflon 500 (diosmin 450 mg/hesperidin 50 mg). Diosmin is distributed in the U.S. as a dietary supplement called Daflon. It is not approved as a prescription drug in the United States, although it is available as an over-the-counter or prescription-only drug in Europe, sold under names such as Detralex among others.

The benefits of diosmin make it an ideal ingredient for products for external use, such as ointments, creams, or gels to be applied directly to the skin, as well as for products for internal use, such as supplements and medicines. The micronization process is a key manufacturing development: the micronization process enhances absorption of diosmin by reducing particle size to less than 2 micrometers.

2. Historical and Traditional Use

Diosmin is a herbal substance first isolated in 1925. In 1925, diosmin was first isolated from Scrophularia nodosa L. (figwort). It was introduced as a therapeutic agent in 1969 and has been widely used in Europe as a phlebotonic and vascular protector for the treatment of venous leg ulcers and hemorrhoids. Since 2005 it has been used to treat vascular diseases.

Diosmin has been widely used since 1969 as a phlebotonic and vascular protector for venous leg ulcers and hemorrhoids. Since the late 1960s, diosmin has been widely used as a therapeutic remedy against numerous problems, including haemorrhoids, swollen legs, varicose veins, and many others.

In Europe, diosmin has been widely used for a long time as a phlebotonic and vascular protector for oral use in different types of pharmaceutical and nutritional products. The compound belongs to the broader class of phlebotonics: diosmin is included among a small class of agents called "phlebotonics," having heterogeneous composition and consisting partly of citrus peel extracts (flavonoids, such as hesperidin) and synthetic compounds, which are used to treat chronic venous insufficiency or hemorrhoids.

3. Key Constituents, Active Compounds, and Mechanisms of Action

3.1 Relationship to Diosmetin

Following oral administration, diosmin is not directly absorbed but must first be hydrolyzed into its aglycone, diosmetin, which is then absorbed into the systemic circulation. Intestinal microflora enzymes rapidly hydrolyze diosmin into its aglycone form, diosmetin, which is easily absorbed and dispersed throughout the body, according to previous pharmacokinetic studies. Diosmin and diosmetin are therefore closely related: diosmin is the glycosylated prodrug, and diosmetin is its biologically active aglycone.

3.2 Venotonic and Microcirculatory Mechanisms

The mechanisms of venotonic action of diosmin include increased lymphatic drainage, inhibition of inflammatory reactions, reduced capillary permeability, improvement of venous tone, and protection of capillary bed microcirculation. At the cellular level, diosmin directly acts on venous tone by enhancing sympathetic-mediated venous contractibility and increasing calcium sensitivity and contractility.

Diosmin and its aglycone diosmetin are polyphenols with a confirmed wide range of biological activities. In vivo studies have evidenced that diosmin has a strong protective effect on blood vessels via an increase in the elasticity of vessel walls and a reduction in venous pressure and venous stasis. It is also effective in facilitating lymph flow and reduces the permeability of capillary walls, hence its anti-edematous effect. Moreover, it alleviates oxidative stress linked with the inflammation process.

3.3 Anti-inflammatory Mechanisms

MPFF and non-micronized diosmin have demonstrated a broad anti-inflammatory activity through the inhibition of leukocyte adhesion to the vascular endothelium and the reduction of pro-inflammatory factor expression (e.g., TNF-α, IL-6). Some flavonoids, including diosmin, are promising inhibitors of thromboxane A2 (TxA2) and prostaglandin E2 (PGE2); they also showed inhibition of leukocyte migration, activation, and adhesion. An in vitro study confirmed that both diosmin and diosmetin reduced the levels of IL-6, IL-1β, COX-2, and PGE2, but had no impact on IL-10; the addition of the compounds prior to LPS stimulation was more effective, and diosmetin modulated the proinflammatory factors more strongly than diosmin.

3.4 Antioxidant Mechanisms

Diosmin scavenges free radicals and enhances the antioxidant defense mechanism by upregulating the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx). Diosmin is a natural flavonoid applied in vascular system disorders, especially in chronic venous insufficiency, and it plays a significant part in the alleviation of CVI symptoms. Due to its antioxidant activity, it also has the ability to scavenge oxygen free radicals and hence decreases the level of oxidative stress biomarkers, such as prostaglandins and their precursors—isoprostanes.

3.5 Lymphatic System Effects

Diosmin also impacts the lymphatic system, which is crucial for maintaining fluid balance in the body. It enhances lymphatic drainage by increasing the frequency and intensity of lymphatic contractions and reducing lymphatic capillary permeability. This action is particularly beneficial in conditions like lymphedema, where there is an accumulation of lymphatic fluid in tissues causing swelling.

3.6 Enzyme Inhibition

Diosmin has been found to inhibit the activity of certain enzymes such as hyaluronidase and collagenase, which are involved in the breakdown of connective tissues. By inhibiting these enzymes, diosmin helps in preserving the structural integrity of blood vessels and surrounding tissues.

3.7 Note on Defined Drug Targets

No specific drug targets for diosmin are reported, although some potential factors have been involved in screening, such as P-glycoprotein (P-gp), IKKβ, and acetylcholinesterase (AChE). The mechanism of action of diosmin and other phlebotonics is undefined, and clinical evidence of benefit is limited.

4. Scientific Evidence by Area of Use

4.1 Chronic Venous Insufficiency (CVI) and Chronic Venous Disease (CVD)

Diosmin is a dietary supplement used to aid treatment of hemorrhoids and venous diseases, i.e., chronic venous insufficiency including spider and varicose veins, leg swelling (edema), stasis dermatitis, and venous ulcers.

Clinical and meta-analytic evidence: 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. Ten trials with MPFF out of forty using flavonoids were included. The meta-analysis suggests that oral venoactive drugs considered as a whole reduce lower leg oedema (risk ratio [RR] 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.

There is moderate-quality evidence that diosmin or other phlebotonics improved leg and ankle swelling and lower leg pain. A clinical study examined whether angiogenesis-related factors were modulated: the study assessed the correlation between diosmin administration (2 × 600 mg daily) in patients suffering from CVD and the levels of selected factors influencing angiogenesis, which are involved in CVD pathophysiology. Thirty-five CVD patients were examined. The evidence concerning microcirculation improvement is also corroborated by a clinical biomarker study: a statistically significant decrease of isoprostane content after 3 months of treatment was observed within the studied group. The mean T0 value was 39.65 ± 42.1, and after 3 months, it decreased to 23.97 ± 31.3 pg/mL (the difference was statistically significant). The most significant changes were observed in patients who smoke, where the level of isoprostanes decreased from 42.96 to 7.74 pg/mL. The obtained results confirmed the ability of diosmin to alleviate oxidative stress.

In 2017, the American Working Group in Chronic Venous Disease recommended use of micronized purified flavonoid fraction (diosmiplex) as a medical food for chronic venous disease symptoms and venous ulcers, having "beneficial outcomes without serious adverse events," alone or combined with compression therapy, concurring with the previous guidance of the International European Society for Vascular Surgery. The German Dermatological Society indicated that diosmin may be used with other treatments for symptoms of chronic venous diseases.

Evidence strength: Moderate quality, primarily based on meta-analyses of randomized controlled trials. Venoactive drugs in CVD have been assessed in clinical studies that were generally small in size. Therefore, conclusions on the efficacy of these treatments are mainly based on meta-analyses and expert consensus statements.

4.2 Hemorrhoids

Previous non-systematic reviews have found evidence for the efficacy of MPFF not only in reducing pain, bleeding, anal discharge, and prolapse in acute hemorrhoid disease (HD), but also in preventing relapse and reducing the duration and severity of acute attacks in chronic HD. A 2006 meta-analysis of 14 studies investigating flavonoid treatment (MPFF, diosmin, or rutosides) for hemorrhoids reported that flavonoids reduced the risk of not improving globally by 58%, with apparent reductions in the risks of bleeding, pain, itching, and recurrences.

The American Society of Colon and Rectal Surgeons mentions phlebotonics as a possible treatment for symptoms of hemorrhoid grades I to II, as there is only moderate-quality evidence.

Evidence strength: Low-quality evidence for treating hemorrhoids as classified in recent assessments, though multiple RCTs show consistent symptomatic benefit.

4.3 Venous Leg Ulcers

The effect of MPFF (Detralex) on venous trophic ulcers was assessed in a meta-analysis of 5 large randomized controlled trials conducted in Russia (N = 616). In these trials, 75% of patients had reflux in the superficial venous system alone or in both superficial and deep veins. The standard dose of 1,000 mg was administered for 2 months, or for 6 months when given as an adjunct to conventional therapy. Complete ulcer healing was achieved in 61.3% of diosmin-treated patients compared with 47.7% in control groups, and diosmin treatment led to shorter healing time (38% less than in the control group; mean of 16 weeks with diosmin vs. 21 weeks with control). The benefit of diosmin treatment was present from week 8 of treatment.

Subanalysis revealed that the benefit of MPFF was significant only in patients with an ulcer history of less than 5 years, in patients with mid-sized ulcers between 5 and 10 cm², and in patients with ulcers that persisted for 6 to 12 months.

Evidence strength: Moderate, based on meta-analysis of RCTs. The benefit appears confined to specific patient subgroups.

4.4 Post-Surgical Outcomes (Knee Arthroplasty)

A randomized, controlled multicenter trial registered in the Cochrane Central Register investigated the efficacy of diosmin in reducing lower-extremity swelling and pain after total knee arthroplasty, published in the Journal of Bone and Joint Surgery (American volume), 2024. This represents a newer clinical application with emerging but limited data.

4.5 Pelvic Venous Disorders, Varicocele, and Post-Cardiac Surgery

Diosmin has also been used to improve postoperative cardiac function and outcomes in adults undergoing coronary artery bypass grafting (CABG) surgery, for pelvic congestion caused by pelvic varicose veins in men and women, and for varicoceles in men; however, few large-scale quality clinical trials support these uses.

4.6 Anticancer Properties (Predominantly Preclinical)

Diosmin's anticancer mechanisms are multifaceted, involving apoptosis induction, angiogenesis inhibition, and metastasis prevention. At the molecular level, diosmin induces cell cycle arrest by upregulating tumor suppressors like p53, p27, and p21, particularly at the G2/M checkpoint, and promotes DNA damage through increased double-strand breaks. It triggers apoptosis via caspase activation, mitochondrial damage, and ROS generation, leading to the release of cytochrome c.

In MCF-7, MDA-MB-231, and SKBR-3 breast cancer cells, as well as DU145 prostate cancer cells, A431 skin cancer cells, and colon, oral, urinary bladder, and esophageal carcinogenesis, diosmin has been found to trigger apoptosis. The anticancer mechanisms of diosmin involve stimulating receptors, increasing ROS, and inducing cell death via the PI3K/Akt pathway.

Evidence strength: Preliminary studies have shown encouraging results in the inhibition of tumor growth and progression in various cancer cell lines, suggesting a potential role for diosmin as an adjunct in oncology treatment regimens. The evidence is predominantly in vitro and animal-based; large human clinical trials are lacking.

4.7 Antidiabetic and Metabolic Effects

Diosmin has been found to have anti-diabetic properties. Diosmin has therapeutic effects in the event of diabetes and associated complications, such as neuropathy and dyslipidemia. Animal data shows that diosmin was found to modulate the NF-κB pathway and decrease oxidative stress markers in the kidney of alloxan-induced diabetic rats.

Evidence strength: Primarily preclinical (animal models and in vitro). Human data are limited and preliminary.

4.8 Neuroprotection

Diosmin exhibits anti-inflammatory activity by suppression of overexpressed nuclear factor κB, cyclooxygenase-2, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase. Its potential in treating diabetic neuropathy and neuropathic pain was reported in many studies recently, and it proved to have neuroprotective activity in peripheral neurons. Still, a lack of research was found in the area of diosmin activity on the central nervous system.

Evidence strength: Predominantly preclinical. Human clinical data in the neuroprotective domain are limited.

4.9 Hepatoprotective and Renoprotective Effects

In animal models, diosmin (100 and 200 mg/kg) treatments significantly reduced elevated levels of kidney function test parameters and restored structural changes in the kidney in cisplatin-induced nephrotoxic animals. Administration significantly reduced lipid peroxidation levels, increased GSH content, and showed improvements in antioxidant enzymes. Markers of inflammatory cytokines such as IL-1β, IL-6, and TNFα were significantly reduced. These findings demonstrate the nephroprotective effect of diosmin against cisplatin-induced kidney damage.

Histopathological examination showed that diosmin significantly minimized methotrexate-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues, suggesting diosmin may be a promising agent for protection against methotrexate-induced cytotoxicity.

Evidence strength: Entirely preclinical (rodent models). No human clinical trials have yet validated these organ-protective effects.

4.10 Antimicrobial Activity

Some evidence of a weak antimicrobial action was also found. This area of investigation remains at an early, largely preclinical stage with no established clinical use.

5. Bioavailability and Pharmacokinetics

Due to its low water solubility, diosmin is dramatically limited in clinical application. Many potential strategies have been developed for improving its pharmacokinetic values and bioavailability. The development of micronized formulations represents the primary clinical solution to this challenge. The micronization process enhances absorption of diosmin by reducing particle size to less than 2 micrometers.

A comparative bioavailability study in 16 healthy volunteers using a crossover design found that the tested buffered micronized diosmin formulation (µSmin® Plus) showed higher plasmatic concentrations of diosmetin in comparison to those obtained after the administration of unformulated micronized diosmin. The relative bioavailability was 9.4 times greater for the tested formulation than for micronized diosmin. These data indicate that µSmin® Plus was rapidly and well absorbed into systemic circulation.

In one study, patients were administered a daily dosage of 2 × 600 mg of diosmin for 3 months, and several factors associated with oxygen management, angiogenesis, and inflammation were evaluated. Findings indicate that diosmin reduced the levels of fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF-C), while increasing endostatin.

6. Dosage Forms and Doses Reported in Clinical Studies

The following dosages are reported as used in clinical studies and practice; they are not recommendations:

• Chronic venous insufficiency: Diosmin 1,000 mg/day for 60 days; MPFF 500 mg twice daily or 1,000 mg once daily for up to 6 months.
• Hemorrhoidal crisis (acute): Loading dose of MPFF 1,000 mg 3 times daily for 4 days, then 1,000 mg twice daily for 3 days.
• Prevention of relapse of internal hemorrhoids: 450 mg of diosmin plus 50 mg of hesperidin twice daily for 3 months of therapy.
• Venous stasis ulcers: The combination of 900 mg of diosmin and 100 mg of hesperidin daily has been used for up to 2 months.
• Chronic venous disease (non-micronized diosmin): 2 × 600 mg daily has been used in clinical studies for 3 months.
• Venous leg ulcers ≤10 cm² diameter: 1,000 mg daily (two 500 mg tablets) in combination with standard compression therapy and local wound management. Treatment duration typically ranges from 2–6 months, with MPFF significantly accelerating ulcer healing compared to standard management alone.
• Comparative dosing note: Non-micronized (pure) diosmin 600 mg daily is clinically equivalent to MPFF 1,000 mg daily. No clinical benefit exists for doses exceeding 600 mg per day when using pure non-micronized diosmin.

This compound has been explored as the major component of Daflon and micronized purified flavonoid fraction (MPFF), which have been used in clinics to improve micro-circulation.

7. Body Systems and Health Areas

Extensive study has indicated that diosmin possesses diverse pharmacological activities, including anti-inflammation, anti-oxidation, anti-diabetes, anti-cancer, anti-microorganism, liver protection, neuro-protection, cardiovascular protection, renoprotection, and retinal protection activities. In terms of established clinical use, diosmin is a dietary supplement used to aid treatment of hemorrhoids and venous diseases, i.e., chronic venous insufficiency including spider and varicose veins, leg swelling (edema), stasis dermatitis, and venous ulcers.

• Venous and circulatory system: The primary clinical domain. Varicose veins, CVI, venous ulcers, and leg edema.
• Anorectal system: Hemorrhoid disease (acute and chronic), post-hemorrhoidectomy recovery.
• Lymphatic system: Lymphedema following surgery for breast cancer, when used in combination with hesperidin.
• Ophthalmologic: Bleeding (hemorrhage) in the eye is listed as an area of use, though evidence is limited.
• Metabolic/endocrine: Antidiabetic effects and protection against diabetic complications in preclinical models.
• Neurological: Neuroprotective activity in peripheral neurons, primarily in preclinical settings.
• Oncology: Anticancer and chemotherapy-adjunct potential, currently limited to preclinical data.
• Hepatic and renal: Organ-protective effects demonstrated in animal models only.

8. Safety Considerations and Drug Interactions

8.1 General Tolerability

In clinical trials, two patients discontinued treatment with non-micronized diosmin because of palpitations, abdominal pain, diarrhoea, and/or dyspepsia. In the MPFF group, one patient stopped treatment due to vertigo and weight decrease. The most commonly reported adverse effects are gastrointestinal in nature: potential side effects associated with diosmin and hesperidin include headache, stomach pain, nausea, and diarrhea.

8.2 Contraindications and Special Populations

Diosmin is not recommended for treating the rectal mucosa, skin irritations, or wounds, and should not be used to treat dermatitis, eczema, or urticaria. Diosmin is not recommended for use in children or women during pregnancy.

Pregnancy: Diosmin is not intended for use in pregnant or breast-feeding women unless the benefit outweighs the risk of therapy. Clinical data are limited; however, in a safety and efficacy study of MPFF for the treatment of internal hemorrhoids of pregnancy (N=50), MPFF was found to be safe, acceptable, and effective when used for a median of 8 weeks before delivery and for 4 weeks afterwards. Pregnancy, fetal development, birth weight, infant growth, and feeding were not affected by treatment.

The safety of diosmin during pregnancy and lactation has not been established. It is not known if diosmin passes into breast milk.

Bleeding risk: Diosmin may worsen bleeding in people with bleeding disorders.

Duration of use: Diosmin should not be taken for more than three months without medical supervision.

8.3 Documented Drug Interactions

Several pharmacokinetic interactions have been identified in clinical studies:

• Chlorzoxazone (CYP2E1 substrate): Serum levels of chlorzoxazone, a CYP2E1 substrate, may be increased in the presence of diosmin.
• Diclofenac sodium (CYP2C9 substrate): Bioavailability and serum levels of diclofenac sodium, a CYP2C9 substrate, may be increased in the presence of diosmin.
• Fexofenadine (P-glycoprotein substrate): Bioavailability and serum levels of fexofenadine, a P-glycoprotein substrate, may be increased in the presence of diosmin.
• Anticoagulants and antiplatelets: Anticoagulants such as warfarin and heparin increase the chances of bruising and bleeding. Antiplatelet agents, such as clopidogrel and aspirin, also increase bleeding risk.
• NSAIDs: Extra care is warranted when taking drugs to help with swelling or inflammation — including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, diclofenac, ibuprofen, or naproxen.

The interactions between diosmin and medicines are not fully understood. As with most dietary supplements, the research on drug interactions with diosmin is incomplete.

8.4 Regulatory Status

The FDA has not reviewed diosmin for safety and effectiveness, and it is not approved by the FDA. In Europe, diosmin-containing products are registered as over-the-counter or prescription medications in several countries. It is available as an over-the-counter or prescription-only drug in Europe, sold under names such as Detralex, among others.

References

• Wikipedia — Diosmin
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• Teng et al. (2020). Metabolism and pharmacological activities of the natural health-benefiting compound diosmin. PubMed.
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• Feldo et al. (2019). Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. PMC.
• Feldo et al. (2018). Influence of Diosmin Treatment on the Level of Oxidative Stress Markers in Patients with Chronic Venous Insufficiency. PMC.
• Effect of Diosmin on Selected Parameters of Oxygen Homeostasis. PMC, 2023.
• Modulatory Effect of Diosmin and Diosmetin on Metalloproteinase Activity and Inflammatory Mediators in Human Skin Fibroblasts Treated with LPS. PMC, 2022.
• Alonso-Coello et al. Micronized Purified Flavonoid Fraction in Hemorrhoid Disease: A Systematic Review and Meta-Analysis. PMC, 2020.
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• Therapeutic potential of diosmin against arsenic-induced neurotoxicity via suppression of NOX 4. PMC, 2021.
• Nephroprotective Effect of Diosmin against Cisplatin-Induced Kidney Damage. PMC, 2023.
• Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury. PMC, 2017.
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• ScienceDirect Topics — Diosmin overview.
• Bogucka-Kocka et al. (2013). Diosmin – Isolation Techniques, Determination in Plant Material and Pharmaceutical Formulations, and Clinical Use. Natural Product Communications.
• Huwait & Mobashir (2022). Potential and Therapeutic Roles of Diosmin in Human Diseases. Biomedicines (MDPI).