Diosmin/hesperidin: a cooperating tandem, or is diosmin crucial and hesperidin an inactive ingredient only?

Česká verze

Authors: Debora Karetová ¹; Josef Suchopár ²; Jan Bultas ³
Authors place of work: II. interní klinika kardiologie a angiologie 1. LF UK a VFN Praha ¹; INFOPHARM, Praha ²; Farmakologický ústav 3. LF UK Praha ³
Published in the journal: Vnitř Lék 2020; 66(2): 97-103
Category: Přehledové články

Summary

With the advent of novel monocomponent venoactive drugs containing the flavonoid diosmin, the need has arisen to answer the question of therapeutic equivalence of the widely used micronized purified flavonoid fraction (MPFF) contained in Detralex and of the currently introduced monocomponent venoactive drugs.

Experimental work provides evidence that each of the two dominant components, i.e. diosmin and hesperidin, has its specific and distinctive pharmacodynamic effect. There is also evidence of a mutual synergistic effect, e.g. in antiexudative action. Clinical studies have been carried out with MPFF for the most part, and effect has clearly been established in this particular form. Conversely, the results of studies documenting the effect of diosmin alone have been conflicting. Mutual comparisons failed to confirm equivalence of MPFF and monocomponent diosmin in any of the studies. This fact is clearly reflected in the relevant guidelines where the use of MPFF in chronic venous disease is recommended unequivocally (level of evidence 1 and strength of evidence B) while, in the case of monocomponent diosmin, it is stated that treatment can be considered (2C). It can be concluded that both experimental and clinical studies document that only a complex of biologically active flavonoids – a micronized purified flavonoid fraction – has evidence of effect and is recommended by relevant guidelines.

Keywords:

equivalence – diosmin – micronized purified flavonoid fraction – hesperidin – chronic venous disease

Zdroje

1. Ligi D, Croce L, Mannello F. Chronic venous disorders: The dangerous, the good, and the diverse. Int. J. Mol. Sci. 2018; 19: 2544,

2. Wittens C, et al. Management of Chronic Venous Disease. Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2015; 49: 678–737.

3. Nicolaides A, Kakkos S, Baekgaard N, et al. Management of chronic venous disorders of the lower limbs. Guidelines according to scientific evidence. Part I. Int Angiol 2018, June 37(3): 232–254.

4. Karetová D. Chronická žilní onemocnění končetin ve světle mezinárodních doporučení publikovaných v roce 2018 (Guidelines for the management of chronic venous disorders of the lower limbs, Int Angiol, 2018), Postgraduální medicína 2019, ročník 21, č. 1: 52–57.

5. Ding Z, Sun G, Zhu Z. Hesperidin attenuates influenza A virus (H1N1)-induced lung injury in rats through its anti‑inflammatory effect. Antivir Ther. 2018 Apr 6. doi: 10.3851, IMP3235.

6. Lee HJ, Im AR, Kim SM et al. The flavonoid hesperidin exerts anti‑photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways. BMC Complement Altern Med. 2018 Jan 30;18(1):39. doi: 10.1186/s12906-017-2058-8.

7. Tejada S, Pinya S, Martorell M et al. Potential anti‑inflammatory effects of hesperidin from the genus Citrus. Curr Med Chem. 2017 Jul 18. doi: 10.2174/0929867324666170718104412

8. Parhiz H, Roohbakhsh A, Soltani F, et al. Antioxidant and anti‑inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res. 2015 Mar;29(3): 323–331. doi: 10.1002/ptr.5256

9. Milenkovic D, Deval C, Dubray C, et al. Hesperidin displays relevant role in the nutrigenomic effect of orange juice on blood leukocytes in human volunteers: a randomized controlled cross‑over study. PLoS One. 2011; 6(11): e26669.

10. Salden BN, Troost FJ, de Groot E, et al. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals. Am J Clin Nutr. 2016 Dec;104(6): 1523–1533.

11. Haidari F, Heybar H, Jalali MT, et al. Hesperidin supplementation modulates inflammatory responses following myocardial infarction. J Am Coll Nutr. 2015; 34(3): 205–211.

12. Rizza S, Muniyappa R, Iantorno M, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011; 96(5): E782–792.

13. Morand C, Dubray C, Milenkovic D, et al. Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am J Clin Nutr. 2011; 93(1): 73–80.

14. Takase S, Pascarella L, Lerond L, Bergan JJ Schmid‑Schonbein GW. Venous hypertension, inflammation and valve remodeling. Eur. J. Vasc. Endovasc. Surg. 2004; 28: 484–493.

15. Das Gracas CDSM, Cyrino FZ, de Carvalho JJ, Blanc‑Guillemaud V, Bouskela E. Protective Effects of Micronized Purified Flavonoid Fraction (MPFF) on a Novel Experimental Model of Chronic Venous Hypertension. Eur. J. Vasc. Endovasc. Surg. 2018;55: 694–702.

16. Laurent R, Gilly R, Frileux C. Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg. Int. Angiol. 1988; 7: 39–43.

17. Efficacy and Safety of Diosmin 600 mg Versus Placebo on Painful Symptomatology in Patients With Chronic Venous Disease of Lower Limbs (EDEN), ClinicalTrials.gov Identifier: NCT01532882.

18. Feldo M, Wójciak‑Kosior M, Sowa I, et al. Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules. 2019; 24(18): 3316.

19. Paysant J, Sansilvestri‑Morel P, Bouskela E, et al. Different flavonoids present in the micronized purified flavonoid fraction (Daflon 500 mg) contribute to its anti‑hyperpermeability effect in the hamster cheek pouch microcirculation. Int Angiol. 2008; 27(1): 81–85.

20. Amato C. Advantage of a micronized flavonoidic fraction (Daflon 500 mg) in comparison with a nonmicronized diosmin. Angiology 1994; 45: 531–536.

21. Cospite M, Dominici A. Advantage of micronisation of Daflon 500 mg compared with a simple diosmine in the treatment of venous insufficiency. Double blind study. Phlebologie 1998; 51: 243–247.

22. Henriet J‑P. Insuffisance veineuse fonctionnelle: essai clinique comparatif d’une seule prise par jour de Diovenor® 600 mg (600 mg de diosmine d’hémisynthèse) versus 2 prises par jour d’un mélange de 500 mg de flavonoides (900 mg de diosmine). Phlebologie 1995; 48: 285–290.

23. Clinical Non‑inferiority Study Between Diosmin 600 mg & Diosmin + Hesperidin in Symptomatic Chronic Venous Insufficiency. ClinicalTrials.gov Identifier: NCT03471910.

24. Nicolaides A, Kakkos S, Baekgaard N, et al. Management of chronic venous disorders of the lower limbs. Guidelines According to Scientific Evidence. Int Angiol. 37(3): 181–254. doi: 10.23736/S0392-9590.18.03999-8.

25. Jantet G. RELIEF study: first consolidated European data. Reflux assEssment and quaLity of lIfe improvement with micronized Flavonoids. Angiology 2000; 51: 31–37.

26. Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations for the medical management of chronic venous disease: The role of Micronized Purified Flavanoid Fraction (MPFF). Phlebology 2017; 32 (1_suppl): 3–19.

27. Aziz Z, Huin WK, Badrul Hisham MD, Tang WL, Yaacob S. Efficacy and tolerability of micronized purified flavonoid fractions (MPFF) for haemorrhoids: A systematic review and meta‑analysis. Complement Ther Med 2018; 39: 49–55.

28. Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta‑analysis of randomized double‑blind placebo‑controlled trials. Int Angiol 2018; 37: 143–154.

29. Coleridge‑Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta‑analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005; 30: 198–208.

30. Allaert FA. Meta‑analysis of the impact of the principal venoactive drugs agents on malleolar venous edema. Int Angiol 2012; 31: 310–315.