Fruits and fruit rinds, especially citrus fruits and rinds (orange, grapefruit, lemon, lime).
Standardized hesperidin extracts used in antioxidant products and multivitamin and mineral supplements.
– Capillary Fragility
– Cellular Regeneration
– Chronic Venous Insufficiency
– Circulatory Disorders
– Cramps (legs)
– Diabetic Complications
– Free Radical Related Diseases
– Hay Fever
– Immune System
– Leg Vein Health
– Lower LDL Cholesterol
– Menopausal Symptoms
– Nocturnal Leg Cramps
– Non-healing Ulcers
– Pain (lower extremities)
– Prevention of abnormal growths
– Skin Ulcers
– Vascular Disorders
– Ulcers (external skin ulcers)
– Venous Insufficiency
The bioflavonoid, hesperidin, is a water-soluble antioxidant that is widely distributed in the plant kingdom. It is often found together with vitamin C in fruits and enhances vitamin C activity within the body. Hesperidin is particularly concentrated in citrus rinds as a non-bitter tasting flavonoid glycoside. Bioflavonoids, in general, are essential for the processing of vitamin C within the body, the maintenance of capillary walls and the fortification of collagen, the intercellular “cement” of the body. A deficiency of hesperidin in the diet has been linked with abnormal capillary leakiness as well as pain in the extremities causing aches, weakness and night leg cramps. Additionally, hesperidin and other flavonoids modulate the activity of various enzymes that positively influence normal as well as malignant cells and have noted anticancer activity. Supplemental hesperidin may also help reduce edema or excess swelling in the legs due to fluid retention. Like other bioflavonoids, hesperidin works best when given with vitamin C and other bioflavonoids. Hesperidin and other flavonoids are widely used for the treatment of chronic venous insufficiency (CVI). In clinical trials, a product containing hesperidin together with one other flavonoid (diosmin), has demonstrated its activity by improving venous tone and vein elasticity. Randomized, double-blind, placebo-controlled clinical studies have shown an improvement in signs and symptoms related to chronic venous insufficiency and a decrease in leg circumferences at the ankle and calf. Additionally, a randomized double-blind, placebo-controlled clinical study has shown that treatment with this flavonoid for 2 months, in addition to standard compression therapy, accelerates leg ulcer healing in patients with ulcers. These findings are of particular significance for diabetic patients. Studies show that hesperidin also improves lymph drainage and protects microcirculation. Hesperidin is also effective for treating pain, sensation of swelling, cramps, hemorrhoids, varicose veins and purplish spots (capillary bruising) on skin.
Hesperidin is a polyphenolic compound classified as a bioflavonoid that is widely distributed in the plant kingdom. Bioflavonoids are often found together with vitamin C in fruits. Hesperidin is found in citrus rinds as a non-bitter tasting flavonoid glycoside, along with rutoside, sinensetin, nobiletin, tangeretin, citrin and bitter flavonoids, neohesperidin and naringin; polymethoxylated flavones, numerous hydroxycinnamates and at least 44 different flavones. Popular flavonoid products standardized for hesperidin content often also contain the flavonoid, diosmin. The product, Daflon 500 mg, is a micronized purified flavonoid fraction, containing 90% w/w diosmin and 10% w/w of flavonoids expressed as hesperidin, used clinically in the treatment of chronic venous insufficiency and hemorrhoidal disease.
The recommended daily dose of hesperidin ranges from between 50mg daily, when taken together with diosmin (450mg), to over 1000mg daily when taken in the form of mixed citrus bioflavonoids.
Hesperidin and other bioflavonoids tend to reduce blood platelet stickiness in a beneficial way and therefore may reduce the dosage required for blood thinners.
Bioflavonoids, including hesperidin, tend to reduce blood platelet stickiness and therefore individuals taking blood thinners should consult with their physician prior to commencing supplementation. Pregnant and lactating women should notify their doctor prior to taking hesperidin supplements, or should get their flavonoids from natural food sources for maximum safety.
No signs of toxicity have been observed with the normal intake of hesperidin, nobiletin or other citrus flavonoids.
Garg A, Garg S, Zaneveld LJ, Singla AK. 2001. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res 2001 Dec; 15(8): 655-69.
Garner RC, Garner JV, Gregory S, Whattam M, Calam A, Leong D. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002 Jan; 91(1): 32-40.
Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids.
Angiology. 2002 May-Jun; 53(3): 245-56.
Manuel y Keenoy B, Vertommen J, De Leeuw I. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients. Diabetes Nutr Metab. 1999 Aug; 12(4): 256-63.
Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res. 1999; 36 Suppl 1:37-41. Review.
Hesperidin as a Component of 'Vitamin P'.
Citrus bioflavonoids were first identified by Albert Szent-Gyorgyi in 1936, winner of The Nobel Prize for the discovery of vitamin C. He reported that citrus bioflavonoids strengthened blood vessel walls and prevented capillary permeability in ways that vitamin C did not. Indeed, he called these bioflavonoids 'vitamin P' after the Permeability factor because they prevented the permeability of capillaries. It was in the course of isolating vitamin C that he came across the bioflavonoids. Certain vitamin C deficiency symptoms (i.e. easy bruising, bleeding gums) were found in early studies to be relieved by crude vitamin C extract but not by purified vitamin C. Szent-Gyorgyi had a friend with bleeding gums and thought this condition might have something to do with a vitamin C deficiency. He gave the man some raw, impure vitamin C, and sure enough the bleeding gums cleared up. Later on, confronted by a recurrence of bleeding gums, he decided to try again; this time with pure vitamin C. He expected to observe an even more dramatic result but it did not occur. The man's gums went right on bleeding. Szent-Gyorgyi re-examined his earlier preparation and decided that the effective impurity was bioflavonoids. He then tried these by themselves, and reported that they worked. He named these substances “vitamin P.” Bioflavonoids thus first came into use as protectors of capillaries, the tiniest blood vessels in the body. Later studies disputed his findings because a deficiency state could not be identified and so these compounds (including hesperidin) never actually attained full vitamin status. This is because there are over 4,000 different flavonoids with different properties and biological activities. Later studies done by Dr. Jacques Masquelier of France found that certain bioflavonoids called oligomeric proanthocyanidins (concentrated in grape seeds, grape skins, red wine, pine bark and many tree leaves) are the most effective components of the 'vitamin P' mixture that Szent-Gyorgyi spoke of. Clinical studies now confirm that hesperidin also has significant 'vitamin P' activity.
Positive Clinical Findings:
Struckmann JR. 1999. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res 1999; 36 Suppl 1: 37-41.
Flavonoids are widely used for the treatment of chronic venous insufficiency (CVI). In clinical trials, micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin, Daflon 500 mg) has demonstrated its activity in CVI by improving venous tone and vein elasticity assessed by plethysmography. Randomized, double-blind, placebo-controlled clinical studies have shown an improvement in signs and symptoms related to CVI and a decrease in leg circumferences at the levels of the ankle and calf. The effect of MPFF on microcirculatory parameters suspected of participating in the pathophysiological process of venous ulceration has been investigated in patients. These include hemorheological parameters and transcutaneous oxygen tension measurements, which were shown to improve after treatment with MPFF. Finally, a randomized double-blind, placebo-controlled clinical study has shown that MPFF treatment for 2 months, in addition to standard compression therapy, accelerates leg ulcer healing in patients with ulcers <=10 cm.
Ramelet AA. 2001. Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency. Angiology 2001 Aug; 52 Suppl 1: S49-56
Chronic venous insufficiency (CVI) affects a large number of people in Western countries, and is responsible for considerable inconvenience, discomfort, suffering, and costs. Micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin-Daflon 500 mg) is a potent venotropic drug used in the treatment of venous insufficiency. Pharmacological and clinical studies demonstrated the comprehensive mode of action of Daflon 500 mg: it increases venous tone, it improves lymph drainage, and it protects the microcirculation. Clinical international, prospective, multicenter, randomized, controlled studies versus placebo studies documenting the effects of Daflon 500 mg in CVI at advanced stages with edema, skin changes, and venous leg ulcer are reviewed. In edema, one of the most frequent complaints of patients, Daflon 500 mg brings about a significant reduction in leg circumference, thanks to its capacity to inhibit inflammatory reactions and to decrease capillary hyperpermeability. The rationale for the use of Daflon 500 mg for treatment of skin disorders and venous leg ulcer is its action on the microcirculation-damaging processes. Regarding skin changes, Daflon 500 mg has been shown to improve venous trophic disorders, like gravitational (stasis) dermatitis, and dermatofibrosclerosis. In venous leg ulcer, Daflon 500 mg's clinical efficacy has been demonstrated in addition to standard treatment or versus standard treatment alone. Daflon 500 mg, thanks to its comprehensive mode of action on the veins, lymphatics, and microcirculation, is the method of choice not only in the early stages of CVI treatment, but also in the severe stages of this condition, in combination with compression treatment, sclerotherapy, and surgery if appropriate.
Jantet G. 2002. Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids. Angiology 2002 May-Jun; 53(3): 245-56.
Chronic venous insufficiency (CVI) results in considerable morbidity and may seriously affect patients' quality of life. The RELIEF (Reflux assEssment and quaLity of life improvEment with micronized Flavonoids) Study was a prospective controlled study designed to assess differences in the severity and in the evolution of symptoms and signs of CVI according to presence or not of venous reflux. Patients were thus separated into 2 comparative groups: those presenting venous reflux and those without venous reflux. The design of the study was multicentric and international, carried out in 23 countries over 2 years, in which 5,052 symptomatic patients assigned to classes C0 to C4 (on the basis of CEAP clinical classification) were enrolled. Patients were treated with micronized purified flavonoid fraction (MPFF), consisting of 450 mg of micronized diosmin and 50 mg of flavonoids expressed in hesperidin over 6 months. In order to document changes in the quality of life of these patients during MPFF treatment, a new validated Quality of Life Questionnaire specific to CVI (CIVIQ) was used. The study also set out to gather epidemiologic data including the prevalence of venous reflux in symptomatic patients. The RELIEF study provided important information about the epidemiology and clinical manifestations of CVI. Of particular interest was the observation that venous reflux was found to be absent in 57% of patients diagnosed as suffering from CVI belonging to CEAP classes C0 to C4. A positive relationship between symptoms of CVI (pain, leg heaviness, sensation of swelling, and cramps) and presence of venous reflux was found in the RELIEF study: symptoms were more frequent and more severe at presentation in patients with venous reflux. Moreover, during MPFF treatment, all symptoms showed a greater decrease in the group without venous reflux compared with the other group. This difference in the evolution of symptoms between the 2 groups was significant for pain, sensation of swelling, and cramps. Regarding leg heaviness and signs such as edema (assessed by leg circumference), patients improved equally independently of the presence or not of venous reflux. The significant and progressive improvement in the signs of CVI was reflected in significant changes in the clinical class of the CEAP classification, ie, from more severe to less severe stages. Continuous clinical improvement was found throughout the study and after treatment with MPFF for 6 months, the clinical scores of all symptoms and signs had significantly decreased (p=0.0001 versus DO) in both groups. This improvement was also associated with a significant and continuous progression in the quality of life scores of all patients. Age of patients, average time since diagnosis, and presence of venous reflux increased with the severity of the disease. The relationship shown in this study between these parameters and clinical CEAP classification reflects the progressive nature of CVI. Despite obvious symptoms of CVI, a very low percentage (21.8%) of the “intention-to-treat” (ITT) population had previously been treated. This was the case whether venous reflux was present or not.
Manuel y Keenoy B, Vertommen J, De Leeuw I.. 1999. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients. Diabetes Nutr Metab 1999 Aug; 12(4): 256-63.
Amongst the numerous co-adjuvant therapies which could influence the incidence and progression of diabetic complications, antioxidants and flavonoids are currently being tested in several clinical trials. In this study we investigated the effects of Daflon 500, which is made up of the flavonoids diosmin (90%) and hesperidin (10%), in a group of 28 Type 1 diabetic patients in a double blind placebo-controlled study. Parameters of glycation and oxidative stress were measured before and after the intervention. Treatment with this flavonoid had no side effects and was followed by a decrease in HbA1c, from 8.85+/-1.57 to 8.47+/-1.40% (p=0.017). This decrease was more pronounced in the patients with higher initial HbA1c but was unrelated to glycaemic control as monitored by the mean and fluctuations of daily glycaemia. Decrease in HbA1c was accompanied by an increase in glutathione peroxidase activity, from 119+/-68 to 145+/-42 U/l haemolysate (p=0.015), a tendency for increase in plasma protein thiols and an increase in the lag time of the copper-induced in vitro oxidability of non-HDL lipoproteins, from 96+/-24 to 111+/-28 min (p=0.005). These parameters did not change significantly after receiving placebo. Other parameters of antioxidant capacity such as blood GSH, catalase and superoxide dismutase activities, as well as in vitro formation of thiobarbituric acid reactive substances (TBARS), were unaffected by either flavonoid or placebo. Our results suggest that the flavonoid-induced decrease in glycation is associated with an increase in the antioxidant component dependent on the levels and activities of thiol-containing proteins such as glutathione peroxidase. One mechanism which could explain these effects is the protection of vitamin C and E from consumption by oxidative processes.