Flavonoids

NOTICE: This health information was not created by the University of Michigan Health System (UMHS) and may not necessarily reflect specific UMHS practices. For medical advice relating to your personal condition, please consult your doctor. Complete disclaimer

Flavonoids

Uses

Flavonoids

Flavonoids are a class of water-soluble plant pigments. Flavonoids are broken down into categories, though the issue of how to divide them is not universally agreed upon. One system breaks flavonoids into isoflavones, anthocyanidins, flavans, flavonols, flavones, and flavanones.1 Some of the best-known flavonoids, such as genistein in soy, and quercetin in onions, can be considered subcategories of categories. Although they are all structurally related, their functions are different. Flavonoids also include hesperidin, rutin, citrus flavonoids, and a variety of other supplements.

What Are "Star" Ratings?

a7_3star   Reliable and relatively consistent scientific data showing a substantial health benefit.

a7_2star   Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.

a7_1star   For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support.

Our proprietary “Star-Rating” system was developed to help you easily understand the amount of scientific support behind each supplement in relation to a specific health condition. While there is no way to predict whether a vitamin, mineral, or herb will successfully treat or prevent associated health conditions, our unique ratings tell you how well these supplements are understood by the medical community, and whether studies have found them to be effective for other people.

For over a decade, our team has combed through thousands of research articles published in reputable journals. To help you make educated decisions, and to better understand controversial or confusing supplements, our medical experts have digested the science into these three easy-to-follow ratings. We hope this provides you with a helpful resource to make informed decisions towards your health and well-being.

This supplement has been used in connection with the following health conditions:


Used for Amount Why
Chronic Venous Insufficiency
 500 mg hydroxyethylrutosides twice per day 3 stars   Flavonoids strengthen capillaries. A flavonoid derived from rutin, called HR, has been shown to be effective in clearing leg swelling and reducing other CVI symptoms.

3 stars  Chronic Venous Insufficiency

500 mg hydroxyethylrutosides twice per day

Flavonoids promote venous strength and integrity. Most trials of flavonoids in patients with CVI have used a type of flavonoid called hydroxyethylrutosides (HR), which is derived from rutin. These double-blind and other controlled trials have consistently shown a beneficial effect of HR in clearing leg swelling and other signs of CVI.2 , 3 , 4 Positive results from a double-blind trial have been obtained using 500 mg of HR taken twice per day for 12 weeks.5 In this trial, the preparation was found to add further benefit to that provided by compression stockings commonly used to treat CVI. Similar results were obtained in another controlled trial.6 It is unclear whether other flavonoids are as effective as HR for CVI. HR has also been used successfully as a topical preparation for the treatment of CVI.7

Used for Amount Why
Hepatitis
 500 to 750 mg daily of catechins 3 stars   The flavonoid catechin has helped people with acute viral hepatitis, as well as people with chronic hepatitis.

3 stars  Hepatitis

500 to 750 mg daily of catechins

Catechin, a flavonoid, has helped people with acute viral hepatitis,8 as well as individuals with chronic hepatitis,9 though not all trials have found a benefit.10 A typical amount used in successful trials is 500–750 mg three times per day. Although catechin is found in several plants, none contain sufficient amounts to reach the level used in the trials; thus, catechin supplements are needed. However, because of its potential to cause side effects on rare occasions,11 catechin should be used only under medical supervision.

Used for Amount Why
Bruising
 400 to 800 mg hesperidin with vitamin C daily 2 stars   Flavonoids are often recommended with vitamin C. Flavonoids are vitamin-like substances that can help strengthen capillaries and therefore may also help with bruising.

2 stars  Bruising

400 to 800 mg hesperidin with vitamin C daily

Doctors often suggest that people who experience easy bruising supplement with 100 mg to 3 grams of vitamin C per day for several months. Controlled research is limited, but vitamin C supplements have been shown to reduce bruising in people with low vitamin C intake.12 Flavonoids are often recommended along with vitamin C. Flavonoids are vitamin-like substances that can help strengthen capillaries and therefore may also help with bruising.13 Flavonoids may also increase the effectiveness of vitamin C; citrus flavonoids, in particular, improve the absorption of vitamin C. Older preliminary research suggested that vitamin C, 400–800 mg per day, in combination with 400–800 mg per day of the flavonoid, hesperidin, reduced bruising in menopausal women.14 A small, preliminary trial in Germany gave three people with progressive pigmented purpura (a chronic bruising disorder) 1,000 mg per day of vitamin C and 100 mg per day of the flavonoid rutoside. After four weeks, noticeable bruising was no longer apparent and did not recur in the three month period after treatment was stopped.15 Controlled research is needed to better establish whether vitamin C and flavonoids are effective for easy bruising.

Used for Amount Why
Cold Sores
(Vitamin C)
 200 mg with 200 mg flavonoids, three to five times daily 2 stars   Vitamin C plus flavonoids may help speed cold sore healing.

2 stars  Cold Sores

200 mg with 200 mg flavonoids, three to five times daily

Vitamin C has been shown to inactivate herpes viruses in the test tube.16 In one study, people with herpes infections received either a placebo or 200 mg of vitamin C plus 200 mg of flavonoids, each taken three to five times per day. Compared with the placebo, vitamin C and flavonoids reduced the duration of symptoms by 57%.17

Used for Amount Why
Gingivitis
(Vitamin C)
 300 mg of vitamin C, plus 300 mg of flavonoids daily 2 stars   In one study, supplementing with vitamin C plus flavonoids improved gum health in a group of people with gingivitis.

2 stars  Gingivitis

300 mg of vitamin C, plus 300 mg of flavonoids daily

People who are deficient in vitamin C may be at increased risk for periodontal disease.18 When a group of people with periodontitis who normally consumed only 20–35 mg of vitamin C per day were given an additional 70 mg per day, objective improvement of periodontal tissue occurred in only six weeks.19 It makes sense for people who have a low vitamin C intake (e.g., people who eat few fruits and vegetables) to supplement with vitamin C in order to improve gingival health.

For people who consume adequate amounts of vitamin C in their diet, several studies have found that supplemental vitamin C has no additional therapeutic effect. Research,20 including double-blind evidence,21 shows that vitamin C fails to significantly reduce gingival inflammation in people who are not vitamin C deficient. In one study, administration of vitamin C plus flavonoids (300 mg per day of each) did improve gingival health in a group of people with gingivitis;22 there was less improvement, however, when vitamin C was given without flavonoids. Preliminary evidence has suggested that flavonoids by themselves may reduce inflammation of the gums.23

Used for Amount Why
Hemorrhoids
 600 to 4,000 mg hydroxyethylrutosides daily or 1 to 3 grams of a mixture of 90% diosmin and 10% hesperidin 2 stars   Supplementing with flavonoids may reduce symptoms. A number of flavonoids have been shown to have anti-inflammatory effects and to strengthen blood vessels

2 stars  Hemorrhoids

600 to 4,000 mg hydroxyethylrutosides daily or 1 to 3 grams of a mixture of 90% diosmin and 10% hesperidin

A number of flavonoids have been shown to have anti-inflammatory effects and/or to strengthen blood vessels. These effects could, in theory, be beneficial for people with hemorrhoids. Most,24 , 25 , 26 , 27 but not all,28 double-blind trials using a group of semisynthetic flavonoids (hydroxyethylrutosides derived from rutin) have demonstrated significant improvements in itching, bleeding, and other symptoms associated with hemorrhoids when people used supplements of 600–4,000 mg per day.

Other trials have evaluated Daflon, a product containing the food-derived flavonoids diosmin (90%) and hesperidin (10%). An uncontrolled trial reported that Daflon produced symptom relief in two-thirds of pregnant women with hemorrhoids.29 Double-blind trials have produced conflicting results about the effects of Daflon in people with hemorrhoids.30 , 31 Amounts of flavonoids used in Daflon trials ranged from 1,000 to 3,000 mg per day. Diosmin and hesperidin are available separately as dietary supplements.

Some doctors recommend flavonoid supplements for people with hemorrhoids. However, many different flavonoids occur in food and supplements, and additional research is needed to determine which flavonoids are most effective against hemorrhoids.

Used for Amount Why
Ménière’s Disease
 Refer to label instructions 2 stars   Certain flavonoids, known as hydroxyethylrutosides, have been reported to improve symptoms of Ménière’s disease, including hearing problems.

2 stars  Ménière’s Disease

Certain flavonoids, known as hydroxyethylrutosides (HR), have been reported to improve symptoms of MD in one double-blind study. In this study, 2 grams per day of HR for three months resulted in either stabilization of or improvement in hearing.32 Other types of flavonoids have not been studied as treatments for MD.

Some cases of MD are associated with otosclerosis,33 , 34 , 35 , 36 a disease affecting the small bones of the inner ear. Otosclerosis often goes undiagnosed in people with MD, although the coexistence is well documented.37 While preliminary reports suggest otosclerosis may be a cause of MD,38 , 39 the relationship between these two conditions remains unclear. Sodium fluoride, a mineral compound available only by prescription, is reported to improve otosclerosis.40 , 41 , 42 , 43 In a preliminary study,44 people with MD and otosclerosis were given supplements of 50 mg of sodium fluoride, 200 mg calcium carbonate, and a multiple vitamin supplying 400–800 IU of vitamin D per day, for periods ranging from six months to over five years. Many participants also had blood sugar abnormalities, and were asked to follow a modified hypoglycemia diet as described above. Significant improvement in vertigo was reported within six months, but improvements in hearing required one to two years. Because most participants used both diet and supplements, the importance of fluoride, calcium, and/or vitamin D to the overall results of this trial is unclear.

Used for Amount Why
Allergies and Sensitivities
 Refer to label instructions 1 star   Test tube and animal studies have found some effects from natural antihistamines such as flavonoids, though no clinical research has shown whether these substances can specifically reduce allergic reactions.

1 star  Allergies and Sensitivities

Many of the effects of allergic reactions are caused by the release of histamine, which is the reason antihistamine medication is often used by allergy sufferers. Some natural substances, such as vitamin C45 , 46 and flavonoids,47 including quercetin,48 , 49 have demonstrated antihistamine effects in test tube, animal, and other preliminary studies. However, no research has investigated whether these substances can specifically reduce allergic reactions in humans.

Used for Amount Why
Capillary Fragility
 Refer to label instructions 1 star   Flavonoids may help strengthen weakened capillaries, possibly by protecting collagen, one of the most important components of capillary walls.

1 star  Capillary Fragility

Compounds called flavonoids may help strengthen weakened capillaries. In test tube and animal studies, they have been shown to protect collagen, one of the most important components of capillary walls.50 , 51 A preliminary study found that proanthocyanidins (flavonoids extracted from grape seeds), 150 mg per day, increased capillary strength in people with hypertension and/or diabetes.52 A double-blind trial found a combination of two flavonoids (900 mg per day of diosmin and 100 mg per day hesperidin) for six weeks reduced symptoms of capillary fragility.53 Use of vitamin C with flavonoids, particularly quercetin, rutin, and hesperidin, is sometimes recommended for capillary fragility.54 Doctors often recommend 400 mg of rutin or quercetin three times per day or 1 gram of citrus flavonoids three times per day.

Used for Amount Why
Gingivitis
 Refer to label instructions 1 star   Shown to be effective against gingivitis when taken with vitamin C, flavonoids also appear to be effective by themselves at reducing gum inflammation.

1 star  Gingivitis

People who are deficient in vitamin C may be at increased risk for periodontal disease.67 When a group of people with periodontitis who normally consumed only 20–35 mg of vitamin C per day were given an additional 70 mg per day, objective improvement of periodontal tissue occurred in only six weeks.68 It makes sense for people who have a low vitamin C intake (e.g., people who eat few fruits and vegetables) to supplement with vitamin C in order to improve gingival health.

For people who consume adequate amounts of vitamin C in their diet, several studies have found that supplemental vitamin C has no additional therapeutic effect. Research,69 including double-blind evidence,70 shows that vitamin C fails to significantly reduce gingival inflammation in people who are not vitamin C deficient. In one study, administration of vitamin C plus flavonoids (300 mg per day of each) did improve gingival health in a group of people with gingivitis;71 there was less improvement, however, when vitamin C was given without flavonoids. Preliminary evidence has suggested that flavonoids by themselves may reduce inflammation of the gums.72

Used for Amount Why
Measles
 Refer to label instructions 1 star   Flavonoids are nutrients found in the white, pithy parts of fruits and vegetables. Certain flavonoids have been found to inhibit the infectivity of measles virus in the test tube.

1 star  Measles

Flavonoids are nutrients found in the white, pithy parts of fruits and vegetables. In preliminary laboratory research, certain flavonoids have been found to inhibit the infectivity of measles virus in the test tube.73 Whether flavonoid supplements could be effective in preventing or treating measles is unknown.

Used for Amount Why
Menopause
 Refer to label instructions 1 star   A preliminary trial reported that a combination of vitamin C and the flavonoid hesperidin helped relieve hot flashes in menopausal women.

1 star  Menopause

In 1964, a preliminary trial reported that 1,200 mg each of vitamin C and the flavonoid hesperidin taken over the course of the day helped relieve hot flashes.74 Although placebo effects are strong in women with hot flashes, other treatments used in that trial failed to act as effectively as the flavonoid/vitamin C combination. Since then, researchers have not explored the effects of flavonoids or vitamin C in women with menopausal symptoms.

Used for Amount Why
Menorrhagia
 Refer to label instructions 1 star   Flavonoids protect capillaries (small blood vessels) from damage. In so doing, they might protect against the blood loss of menorrhagia.

1 star  Menorrhagia

Both vitamin C and flavonoids protect capillaries (small blood vessels) from damage. In so doing, they might protect against the blood loss of menorrhagia. In one small study, 88% of women with menorrhagia improved when given 200 mg vitamin C and 200 mg flavonoids three times per day.75 In another study, 70% of women with excessive menstrual bleeding experienced at least a 50% reduction in bleeding after taking a flavonoid product.76 The preparation used in this study contained 90% diosmin and 10% hesperidin and was given in the amount of 1,000 mg per day, beginning five days prior to the expected start of menstruation and continuing until the end of bleeding for three cycles.

Used for Amount Why
Retinopathy
 Refer to label instructions 1 star   Quercetin has been shown to inhibit aldose reductase, an enzyme that appears to contribute worsen diabetic retinopathy. Another flavonoid, rutin, may also improve retinopathy.

1 star  Retinopathy

Quercetin (a flavonoid) has been shown to inhibit the enzyme, aldose reductase.77 This enzyme appears to contribute to worsening of diabetic retinopathy. However, because the absorption of quercetin is limited, it is questionable whether supplementing with quercetin can produce the tissue levels that are needed to inhibit aldose reductase. Although human studies have not been done using quercetin to treat retinopathy, some doctors prescribe 400 mg of quercetin three times per day. Another flavonoid, rutin, has been used with success to treat retinopathy in preliminary research.78

Used for Amount Why
Varicose Veins
 Refer to label instructions 1 star   Taking hydroxyethylrutoside may help reduce the size of varicose veins associated with pregnancy.

1 star  Varicose Veins

A controlled clinical trial found that oral supplementation with hydroxyethylrutosides (HR), a type of flavonoid that is derived from rutin, improved varicose veins in a group of pregnant women.79 Further research is needed to confirm the benefits observed in this preliminary trial. A typical amount of HR is 1000 mg per day.

How It Works

How to Use It

Flavonoid supplements are not required to prevent deficiencies in people eating a healthy diet. Healthcare practitioners commonly recommend 1,000 mg of citrus flavonoids taken one to three times per day. Alternatively, 240–600 mg of bilberry (standardized to 25% anthcyanosides) may be taken per day.

Where to Find It

Flavonoids are found in a wide range of foods. For example, flavanones are in citrus, isoflavones in soy products, anthocyanidins in wine and bilberry, and flavans in apples and tea.

Possible Deficiencies

Flavonoid deficiencies have not been reported.

Interactions

Interactions with Supplements, Foods, & Other Compounds

The flavonoids work in conjunction with vitamin C. Citrus flavonoids, in particular, improve the absorption of vitamin C.80 , 81

Interactions with Medicines

Certain medicines interact with this supplement.

May Be Beneficial: Some medicines may increase the need for this supplement.
Avoid: Some medicines interact with this supplement, so they should not be taken together.
Check: Some interactions between this supplement and certain medicines require more explanation. Click the link to see details.

Note: The following list only includes the generic or class name of a medicine. To find a specific brand name, use the Medicines Index.

May Be Beneficial: Acyclovir

Side Effects

Side Effects

No consistent side effects have been linked to the flavonoids except for catechin, which can occasionally cause fever, anemia from breakdown of red blood cells, and hives.82 , 83 These side effects subsided when treatment was discontinued.

In 1980, quercetin was reported to induce cancer in animals.84 Most further research did not find this to be true, however.85 , 86 While quercetin is mutagenic in test tube studies, it does not appear to be mutagenic in animal studies.87 In fact, quercetin has been found to inhibit both tumor promoters88 and human cancer cells.89 People who eat high levels of flavonoids have been found to have an overall lower risk of getting a wide variety of cancers,90 though preliminary human research studying only foods high in quercetin has found no relation to cancer risk one way or the other.91 Despite the confusion, in recent years experts have shifted their view of quercetin from concerns that it might cause cancer in test tube studies to guarded hope that quercetin has anticancer effects in humans.92

References

1. Peterson J, Dwyer J. Taxonomic classification helps identify flavonoid-containing foods on a semiquantitative food frequency questionnaire. J Am Diet Assoc 1998;98:682-5.

2. Rehn D, Brunnauer H, Diebschlag W, Lehmacher W. Investigation of the therapeutic equivalence of different galenical preparations of O-(s-hydroxyethyl)-rutosides following multiple dose per oral administration. Arzneimittelforschung 1996;46:488–92.

3. Bergqvist D, Hallbook T, Lindblad B, Lindhagen A. A double-blind trial of O-(s-hydroxyethyl)-rutoside in patients with chronic venous insufficiency. Vasa 1981;10:253–60.

4. Poynard T, Valterio C. Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa 1994;23:244–50.

5. Unkauf M, Rehn D, Klinger J, et al. Investigation of the efficacy of oxerutins compared to placebo in patients with chronic venous insufficiency treated with compression stockings. Arzneimittelforschung 1996;46:478–82.

6. Neumann HA, van den Broek MJ. A comparative clinical trial of graduated compression stockings and O-(beta-hydroxyethyl)-rutosides (HR) in the treatment of patients with chronic venous insufficiency. Z Lymphol 1995;19:8–11.

7. Frick RW. Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon. Angiology 2000;51:197–205 [review].

8. Blum AL, Doelle W, Kortum K, et al. Treatment of acute viral hepatitis with (+)-cyanidanol-3. Lancet 1977;2:1153–5.

9. Suzuki H, Yamamoto S, Hirayama C, et al. Cianidanol therapy for HBs-antigen-positive chronic hepatitis: a multicentre, double-blind study. Liver 1986;6:35–44.

10. Bar-Meir S, Halpern Z, Gutman M, et al. Effect of (+)-cyanidanol-3 on chronic active hepatitis: A double blind controlled trial. Gut 1985;26:975–9.

11. Conn HO. Cyanidanol: will a hepatotrophic drug from Europe go west? Hepatology 1983;3:121–3.

12. Schorah CJ, Tormey WP, Brooks GH, et al. The effect of vitamin C supplements on body weight, serum proteins, and general health of an elderly population. Am J Clin Nutr 1981;34:871–6.

13. Shamrai EF. Vitamin P. Its chemical nature and mechanism of physiologic action. Uspekhi Sovremennoi Biologii 1968;65:186–201.

14. Horoschak A. Nocturnal leg cramps, easy bruisability and epistaxis in menopausal patients: treated with hesperidin and ascorbic acid. Delaware State Med J 1959;Jan:19–22.

15. Reinhold U, Seiter S, Ugurel S, Tilgen W. Treatment of progressive pigmented purpura with oral bioflavonoids and ascorbic acid: an open pilot study in 3 patients. J Am Acad Dermatol 1999;41:207–8.

16. Holden M, Molloy E. Further experiments on the inactivation of herpes virus by vitamin C (l-ascorbic acid). J Immunol 1937;33:251–7.

17. Terezhalmy GT, Bottomley WK, Pelleu GB. The use of water-soluble bioflavonoid-ascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surg 1978;45:56–62.

18. Vaananen MK, Markkanen HA, Tuovinen VJ, et al. Periodontal health related to plasma ascorbic acid. Proc Finn Dent Soc 1993;89:51–9.

19. Aurer-Kozelj J, Kralj-Klobucar N, Buzina R, Bacic M. The effect of ascorbic acid supplementation on periodontal tissue ultrastructure in subjects with progressive periodontitis. Int J Vitam Nutr Res 1982;52:333–41.

20. Woolfe SN, Kenney EB, Hume WR, Carranza FA Jr. Relationship of ascorbic acid levels of blood and gingival tissue with response to periodontal therapy. J Clin Periodontol 1984;11:159–65.

21. Vogel RI, Lamster IB, Wechsler SA, et al. The effects of megadoses of ascorbic acid on PMN chemotaxis and experimental gingivitis. J Periodontol 1986;57:472–9.

22. El-Ashiry GM, Ringsdorf WM, Cheraskin E. Local and systemic influences in periodontal disease. II. Effect of prophylaxis and natural versus synthetic vitamin C upon gingivitis. J Periodontol 1964;35:250–9.

23. Carvel I, Halperin V. Therapeutic effect of water soluble bioflavonoids in gingival inflammatory conditions. Oral Surg Oral Med Oral Pathol 1961;14:847–55.

24. Sinnatamby CS. The treatment of hemorrhoids. Role of hydroxyethylrutosides, troxerutin (Paroven; Varmoid; Venoruton). Clin Trials J 1973;2:45–50.

25. Clyne MB, Freeling P, Ginsborg S. Troxerutin in the treatment of haemorrhoids. Practitioner 1967;198:420–3.

26. Annoni F, Boccasanta P, Chiurazzi D, et al. Treatment of acute symptoms of hemorrhoid disease with high-dose oral O-(beta-hydroxyethyl)-rutosides. Minerva Med 1986;77:1663–8 [in Italian].

27. Wijayanegara H, Mose JC, Achmad L, et al. A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992;20:54–60.

28. Thorp RH, Hughes ESR. A clinical trial of trihydroxyethylrutoside (“Varemoid”) in the treatment of hemorrhoids. Med J Aust 1970;2:1076–8.

29. Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. Int J Gynaecol Obstet 1997;57:145–51.

30. Cospite M. Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids. Angiology 1994;45:566–73.

31. Thanapongsathorn W, Vajrabukka T. Clinical trial of oral diosmin (Daflon) in the treatment of hemorrhoids. Dis Colon Rectum 1992;35:1085–8.

32. Moser M, Ranacher G, Wilmot TJ, Golden GJ. A double-blind clinical trial of hydroxyethylrutosides in Meniere’s disease. J Laryngol Otol 1984;98:265–72.

33. Franklin DJ, Pollak A, Fisch U. Meniere’s symptoms resulting from bilateral otosclerotic occlusion of the endolymphatic duct: an analysis of a causal relationship between otosclerosis and Meniere’s disease. Am J Otol 1990;11:135–40.

34. Liston SL, Paparella MM, Mancini F, Anderson JH. Otosclerosis and endolymphatic hydrops. Laryngoscope 1984;94:1003–7.

35. Freeman J. Otosclerosis and vestibular dysfunction. Laryngoscope 1980;90:1481–7.

36. Sismanis A, Hughes GB, Abedi E. Coexisting otosclerosis and Meniere’s disease: a diagnostic and therapeutic dilemma. Laryngoscope 1986;96:9–13.

37. Sismanis A, Hughes GB, Abedi E. Coexisting otosclerosis and Meniere’s disease: a diagnostic and therapeutic dilemma. Laryngoscope 1986;96:9–13.

38. Franklin DJ, Pollak A, Fisch U. Meniere’s symptoms resulting from bilateral otosclerotic occlusion of the endolymphatic duct: an analysis of a causal relationship between otosclerosis and Meniere’s disease. Am J Otol1990;11:135–40.

39. Brookler KH, Glenn MB. Meniere’s syndrome: an approach to therapy. Ear Nose Throat J 1995;74:534–8, 540, 542.

40. Freeman J. Otosclerosis and vestibular dysfunction. Laryngoscope 1980;90:1481–7.

41. Bretlau P, Hansen HJ, Causse J, Causse JB. Otospongiosis: morphologic and microchemical investigation after NaF-treatment. Otolaryngol Head Neck Surg 1981;89:646–50.

42. Causse JR, Causse JB, Uriel J, et al. Sodium fluoride therapy. Am J Otol 1993;14:482–90 [review].

43. Sismanis A, Hughes GB, Abedi E. Coexisting otosclerosis and Meniere’s disease: a diagnostic and therapeutic dilemma. Laryngoscope 1986;96:9–13.

44. Brookler KH, Glenn MB. Meniere’s syndrome: an approach to therapy. Ear Nose Throat J 1995;74:534–8, 540, 542.

45. Johnston CS, Retrum KR, Srilakshmi JC. Antihistamine effects and complications of supplemental vitamin C. J Am Diet Assoc 1992;92:988–9.

46. Johnston S, Martin LJ, Cai X. Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. J Am Coll Nutr 1992;11:172–6.

47. Gabor M. Anti-inflammatory and anti-allergic properties of flavonoids. Prog Clin Biol Res 1986;213:471–80 [review].

48. Middleton E, Drzewieki G. Naturally occurring flavonoids and human basophil histamine release. Int Arch Allergy Appl Immunol 1985;77:155–7.

49. Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Medica 1985;51:16–20.

50. Schlebusch H, Kern D. Stabilization of collagen by polyphenols. Angiologica 1972;9:248–56 [in German].

51. Monboisse J, Braquet P, Randoux A, Borel J. Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion: protective effect of flavonoids. Biochem Pharmacol 1983;32:53–8.

52. Lagrue G, Olivier-Martin F, Grillot A. A study of the effects of procyanidol oligomers on capillary resistance in hypertension and in certain nephropathies. Sem Hop 1981;57:1399–401 [in French].

53. Galley P, Thiollet M. A double-blind, placebo-controlled trial of a new veno-active flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility. Int Angiol 1993;12:69–72.

54. Bruneton J. Pharmacognosy Phytochemistry Medicinal Plants. Andover: Intercept Ltd., 1995, 277.

55. Becker HM, Niedermaier G, Orend KH. Benzopyrone in the therapy of postreconstructive edema. A clinical double-blind study. Fortschr Med 1985;103:593–6 [in German].

56. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo- [a]-pyrone. N Engl J Med 1993;329:1158–63.

57. Chang TS, Gan JL, Fu KD, Huang WY. The use of 5,6 benzo-[alpha]-pyrone (coumarin) and heating by microwaves in the treatment of chronic lymphedema of the legs. Lymphology 1996;29:106–11.

58. Casley-Smith JR, Wang CT, Casley-Smith JR, Zi-hai C. Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin). BMJ 1993;307:1037–41.

59. Loprinzi CL, Kugler JW, Sloan JA, et al. Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 1999;340:346–50.

60. Wadworth AN, Faulds D. Hydroxyethylrutosides. A review of its pharmacology, and therapeutic efficacy in venous insufficiency and related disorders. Drugs 1992;44:1013–32 [review].

61. Renton S, Leon M, Belcaro G, Nicolaides AN. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. Int Angiol 1994;13:259–62.

62. Piller NB, Morgan RG, Casley-Smith JR. A double-blind cross over trial of o-beta-hydroxyethyl-rutosides (benzopyrones) in the treatment of lymphoedema of the arms and legs. Br J Plast Surg 1988;41:20–7.

63. Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res 1999;36 Suppl 1:37–41 [review].

64. Pecking AP, Fevrier B, Wargon C, Pillion G. Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology 1997;48:93–8.

65. Griffith JQ. Clinical application of quercetin: preliminary report. J Am Pharm Assoc 1953;42:68–9.

66. Shanno RL. Rutin: a new drug for the treatment of increased capillary fragility. Am J Med Sci 1946;211:539–43.

67. Vaananen MK, Markkanen HA, Tuovinen VJ, et al. Periodontal health related to plasma ascorbic acid. Proc Finn Dent Soc 1993;89:51–9.

68. Aurer-Kozelj J, Kralj-Klobucar N, Buzina R, Bacic M. The effect of ascorbic acid supplementation on periodontal tissue ultrastructure in subjects with progressive periodontitis. Int J Vitam Nutr Res 1982;52:333–41.

69. Woolfe SN, Kenney EB, Hume WR, Carranza FA Jr. Relationship of ascorbic acid levels of blood and gingival tissue with response to periodontal therapy. J Clin Periodontol 1984;11:159–65.

70. Vogel RI, Lamster IB, Wechsler SA, et al. The effects of megadoses of ascorbic acid on PMN chemotaxis and experimental gingivitis. J Periodontol 1986;57:472–9.

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