Fixed-dose ruscus extract combination and its place in current clinical guidelines for the treatment of chronic venous diseases

Chronic venous diseases (CVD) is the most common lower extremity vascular pathology. Various vein-specific symptoms and syndromes associated with CVD negatively affect all components of the quality of life in the modern society. The appearance and development of vein-specific symptoms have been proven to be associated with C-nociceptor irritation evoked by the so-called algogens – biologically active substances occurred due to vascular inflammation and endothelial dysfunction along with local temperature elevation and intravenous pressure. Endothelial dysfunction in CVD is mainly due to phlebostasis with a decrease in shear stress, leading to hypoxia of endothelial cells. Further, a multi-stage mechanism of leukocyte-endothelial interaction is activated, which results in the development of venous microangiopathy at the microcirculatory level, as well as the valve apparatus injury and varicose transformation of the principal superficial veins at the macrocirculatory level. It is evident that suppression of the leukocyte-endothelial inflammatory reaction not only leads to a reduction or relief of vein-specific symptoms, but also prevents macro- and microcirculatory disorders. In this regard, the so-called phlebotropic, or venoactive, pharmacological drugs targeting different pathogenetic mechanisms of development and progression of CVD present great interest. In this case, despite the common to this group of drugs phleboprotective effect, the specific mechanisms for achieving it may have significant differences in various venoactive agents. In this review, we discuss the main indications and instructions for the use of phlebotropic drugs in patients with CVD, drawing on the most established international and Russian clinical guidelines.

1. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15(3):175–184. https://doi.org/10.1016/j.annepidem.2004.05.015.

2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol. 2012;31(2):105–115. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22466974.

3. Wrona M, Jöckel KH, Pannier F, Bock E, Hoffmann B, Rabe E. Association of Venous Disorders with Leg Symptoms: Results from the Bonn Vein Study 1. Eur J Vasc Endovasc Surg. 2015;50(3):360–367. https://doi.org/10.1016/j.ejvs.2015.05.013.

4. Lee AJ, Robertson LA, Boghossian SM, Allan PL, Ruckley CV, Fowkes FG, Evans CJ. Progression of varicose veins and chronic venous insufficiency in the general population in the Edinburgh Vein Study. J Vasc Surg Venous Lymphat Disord. 2015;3(1):18–26. https://doi.org/10.1016/j.jvsv.2014.09.008.

5. Salim S, Machin M, Patterson BO, Onida S, Davies AH. Global Epidemiology of Chronic Venous Disease: A Systematic Review With Pooled Prevalence Analysis. Ann Surg. 2021;274(6):971–976. https://doi.org/10.1097/SLA.0000000000004631.

6. Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120(11):3760–3772. https://doi.org/10.1172/JCI42843.

7. Vital A, Carles D, Serise JM, Boisseau MR. Evidence for unmyelinated C fibres and inflammatory cells in human varicose saphenous vein. Int J Angiol. 2010;19(2):e73–e77. https://doi.org/10.1055/s-0031-1278374.

8. Raffetto JD, Mannello F. Pathophysiology of chronic venous disease. Int Angiol. 2014;33(3):212–221. Available at: https://pubmed.ncbi.nlm.nih.gov/24755829.

9. Ortega MA, Fraile-Martínez O, García-Montero C, Álvarez-Mon MA, Chaowen C, Ruiz-Grande F et al. Understanding Chronic Venous Disease: A Critical Overview of Its Pathophysiology and Medical Management. J Clin Med. 2021;10(15):3239. https://doi.org/10.3390/jcm10153239.

10. Yun S. Comprehensive Review of Venous Pain. Ann Phlebology. 2021;19(3):35–38. https://doi.org/10.37923/phle.2021.19.3.35

11. Ramelet AA, Boisseau MR, Allegra C, Nicolaides A, Jaeger K, Carpentier P et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol Microcirc. 2005;33(4):309–319. Available at: https://pubmed.ncbi.nlm.nih.gov/16317240.

12. Agus GB. Medical treatment of chronic venous disease: evolution or involution? Minerva Cardioangiol. 2011;59(3):285–298. Available at: https://pubmed.ncbi.nlm.nih.gov/21516076.

13. Mazzaccaro D, Muzzarelli L, Modafferi A, Righini PC, Settembrini AM, Nano G. Use of venoactive drugs after surgery for varicose veins: a preliminary study. Int Angiol. 2018;37(1):79–84. https://doi.org/10.23736/S0392-9590.17.03875-5.

14. Mansilha A, Sousa J. Benefits of venoactive drug therapy in surgical or endovenous treatment for varicose veins: a systematic review. Int Angiol. 2019;38(4):291–298. https://doi.org/10.23736/S0392-9590.19.04216-0.

15. Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2020;11(11):CD003229. https://doi.org/10.1002/14651858.CD003229.pub4.

16. Boyle P, Diehm C, Robertson C. Meta-analysis of clinical trials of Cyclo 3 Fort in the treatment of chronic venous insufficiency. Int Angiol. 2003;22(3):250–262. Available at: https://pubmed.ncbi.nlm.nih.gov/14612852.

17. Masullo M, Pizza C, Piacente S. Ruscus Genus: A Rich Source of Bioactive Steroidal Saponins. Planta Med. 2016;82(18):1513–1524. https://doi.org/10.1055/s-0042-119728.

18. Rodrigues JPB, Fernandes Â, Dias MI, Pereira C, Pires TCSP, C Calhelha R et al. Phenolic Compounds and Bioactive Properties of Ruscus aculeatus L. (Asparagaceae): The Pharmacological Potential of an Underexploited Subshrub. Molecules. 2021;26(7):1882. https://doi.org/10.3390/molecules26071882.

19. Niu SL, Hao JH, Xu JY, Guan Q, Zhou ZC, Lv TM, Sun YT. Aculebiphenyl A-B, new biphenyl derivatives from Ruscus aculeatus. J Asian Nat Prod Res. 2023;25(11):1076–1084. https://doi.org/10.1080/10286020.2023.2254702.

20. Redman DA. Ruscus aculeatus (butcher’s broom) as a potential treatment for orthostatic hypotension, with a case report. J Altern Complement Med. 2000;6(6):539–549. https://doi.org/10.1089/acm.2000.6.539.

21. Dunouau C, Bellé R, Oulad-Ali A, Anton R, David B. Triterpenes and sterols from Ruscus aculeatus. Planta Med. 1996;62(2):189–190. https://doi.org/10.1055/s-2006-957858.

22. de Combarieu E, Falzoni M, Fuzzati N, et al. Identification of Ruscus steroidal saponins by HPLC-MS analysis. Fitoterapia. 2002;73(7-8):583–596. https://doi.org/10.1016/s0367-326x(02)00220-4.

23. Mimaki Y, Kuroda M, Kameyama A, Yokosuka A, Sashida Y. Aculeoside B, a new bisdesmosidic spirostanol saponin from the underground parts of Ruscus aculeatus. J Nat Prod. 1998;61(10):1279–1282. https://doi.org/10.1021/np9704563.

24. De Marino S, Festa C, Zollo F, Iorizzi M. Novel steroidal components from the underground parts of Ruscus aculeatus L. Molecules. 2012;17(12):14002–14014. https://doi.org/10.3390/molecules171214002.

25. Shaidakov EV, Rosukhovskiy DA. Efficacy of combination of needle extract, hesperidin and vitamin C in treatment of chronic venous diseases. Angiology and Vascular Surgery. 2021;27(2):82–91. (In Russ.) https://doi.org/10.33529/ANGIO2021208.

26. Jawien A, Bouskela E, Allaert FA, Nicolaïdes AN. The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of chronic venous disease. Int Angiol. 2017;36(1):31–41. https://doi.org/10.23736/S0392-9590.16.03788-3.

27. Bouskela E, Cyrino FZ, Marcelon G. Effects of Ruscus extract on the internal diameter of arterioles and venules of the hamster cheek pouch microcirculation. J Cardiovasc Pharmacol. 1993;22(2):221–224. https://doi.org/10.1097/00005344-199308000-00008.

28. Bouskela E, Cyrino FZ, Marcelon G. Possible mechanisms for the venular constriction elicited by Ruscus extract on hamster cheek pouch. J Cardiovasc Pharmacol. 1994;24(1):165–170. https://doi.org/10.1097/00005344-199407000-00025.

29. Rauly-Lestienne I, Heusler P, Cussac D, Lantoine-Adam F, de Almeida Cyrino FZG, Bouskela E. Contribution of muscarinic receptors to in vitro and in vivo effects of Ruscus extract. Microvasc Res. 2017;114:1–11. https://doi.org/10.1016/j.mvr.2017.05.005.

30. de Souza MDGC, Cyrino FZGA, Sicuro FL, Bouskela E. Effects of Ruscus extract on muscarinic receptors: Is there a role for endothelium derived relaxing factors on macromolecular permeability protection and microvascular diameter changes? Clin Hemorheol Microcirc. 2021;77(4):443–459. https://doi.org/10.3233/CH-201019.

31. Allaert FA. Combination of Ruscus aculeatus extract, hesperidin methyl chalcone and ascorbic acid: a comprehensive review of their pharmacological and clinical effects and of the pathophysiology of chronic venous disease. Int Angiol. 2016;35(2):111–116. Available at: https://pubmed.ncbi.nlm.nih.gov/26928296.

32. Wang Y, Liu B, Ma Y, Wang C, Ma H, Geng S. Oil/water interface behavior of hesperidin methylchalcone and its application in nanoemulsions. Food Chem. 2025;463(Pt 2):141235. https://doi.org/10.1016/j.foodchem.2024.141235.

33. Zhang J, Song N, Liu Y, Guo J. Platycodin D Inhibits β-Amyloid-Induced Inflammation and Oxidative Stress in BV-2 Cells Via Suppressing TLR4/NF-κB Signaling Pathway and Activating Nrf2/HO-1 Signaling Pathway. Neurochem Res. 2021;46(3):638–647. https://doi.org/10.1007/s11064-020-03198-6.

34. Jafni S, Sathya S, Arunkumar M, Kiruthiga C, Jeyakumar M, Murugesh E, Devi KP. Hesperidin Methyl Chalcone reduces extracellular Aβ(25-35) peptide aggregation and fibrillation and also protects Neuro 2a cells from Aβ(25-35) induced neuronal dysfunction. Bioorg Med Chem. 2023;96:117536. https://doi.org/10.1016/j.bmc.2023.117536.

35. Pinho-Ribeiro FA, Hohmann MS, Borghi SM, Zarpelon AC, Guazelli CF, Manchope MF et al. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB. Chem Biol Interact. 2015;228:88–99. https://doi.org/10.1016/j.cbi.2015.01.011.

36. Man MQ, Yang B, Elias PM. Benefits of Hesperidin for Cutaneous Functions. Evid Based Complement Alternat Med. 2019;2019:2676307. https://doi.org/10.1155/2019/2676307.

37. Kim HY, Park M, Kim K, Lee YM, Rhyu MR. Hesperetin Stimulates Cholecystokinin Secretion in Enteroendocrine STC-1 Cells. Biomol Ther. 2013;21(2):121–125. https://doi.org/10.4062/biomolther.2012.077.

38. Xiong H, Wang J, Ran Q, Lou G, Peng C, Gan Q et al. Hesperidin: A Therapeutic Agent For Obesity. Drug Des Devel Ther. 2019;13:3855–3866. https://doi.org/10.2147/DDDT.S227499.

39. Morshedzadeh N, Ramezani Ahmadi A, Behrouz V, Mir E. A narrative review on the role of hesperidin on metabolic parameters, liver enzymes, and inflammatory markers in nonalcoholic fatty liver disease. Food Sci Nutr. 2023;11(12):7523–7533. https://doi.org/10.1002/fsn3.3729.

40. Taheri A, Mobaser SE, Golpour P, Nourbakhsh M, Tavakoli-Yaraki M, Yarahmadi S, Nourbakhsh M. Hesperetin attenuates the expression of markers of adipose tissue fibrosis in pre-adipocytes. BMC Complement Med Ther. 2023;23(1):315. https://doi.org/10.1186/s12906-023-04152-z.

41. Lykkesfeldt J, Michels AJ, Frei B. Vitamin C. Adv Nutr. 2014;5(1):16–18. https://doi.org/10.3945/an.113.005157.

42. Hemilä H. Vitamin C supplementation and the common cold--was Linus Pauling right or wrong? Int J Vitam Nutr Res. 1997;67(5):329–335. Available at: https://pubmed.ncbi.nlm.nih.gov/9350474.

43. Carr AC, Lykkesfeldt J. Vitamin C: From Bench to Bedside. Nutrients. 2021;13(4):1102. https://doi.org/10.3390/nu13041102.

44. Padayatty SJ, Levine M. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 2016;22(6):463–493. https://doi.org/10.1111/odi.12446.

45. Gref R, Deloménie C, Maksimenko A, Gouadon E, Percoco G, Lati E et al. Vitamin C-squalene bioconjugate promotes epidermal thickening and collagen production in human skin. Sci Rep. 2020;10(1):16883. https://doi.org/10.1038/s41598-020-72704-1.

46. Sansilvestri-Morel P, Rupin A, Badier-Commander C, Fabiani JN, Verbeuren TJ. Chronic venous insufficiency: dysregulation of collagen synthesis. Angiology. 2003;54(Suppl. 1):S13–S18. https://doi.org/10.1177/0003319703054001S03.

47. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281(15):1415–1423. https://doi.org/10.1001/jama.281.15.1415.

48. Sauberlich HE. Pharmacology of vitamin C. Annu Rev Nutr. 1994;14:371–391. https://doi.org/10.1146/annurev.nu.14.070194.002103.

49. Tu Z, Yang J, Fan C. The role of different nutrients in the prevention and treatment of cardiovascular diseases. Front Immunol. 2024;15:1393378. https://doi.org/10.3389/fimmu.2024.1393378.

50. Kocot J, Luchowska-Kocot D, Kiełczykowska M, Musik I, Kurzepa J. Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders? Nutrients. 2017;9(7):659. https://doi.org/10.3390/nu9070659.

51. Mayrovitz HN, Aoki KC, Colon J. Chronic Venous Insufficiency With Emphasis on the Geriatric Population. Cureus. 2023;15(6):e40687. https://doi.org/10.7759/cureus.40687.

52. Kakkos SK, Allaert FA. Efficacy of Ruscus extract, HMC and vitamin C, constituents of Cyclo 3 fort®, on improving individual venous symptoms and edema: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol. 2017;36(2):93–106. https://doi.org/10.23736/S0392-9590.17.03815-9.

53. Kakkos SK, Bouskela E, Jawien A, Nicolaides AN. New data on chronic venous disease: a new place for Cyclo 3® Fort. Int Angiol. 2018;37(1):85–92. https://doi.org/10.23736/S0392-9590.17.03935-9

54. Urbanek T. The clinical efficacy of Ruscus Aesculatus extract: is there enough evidence to update the pharmacotherapy guidelines for chronic venous disease? Phlebological Review. 2017;25(1):75–80. https://doi.org/10.5114/pr.2017.70594.

55. Nicolaides A, Kakkos S, Baekgaard N, Comerota A, de Maeseneer M, Eklof B et al. Management of chronic venous disorders of the lower limbs. Guidelines According to Scientific Evidence. Part I. Int Angiol. 2018;37(3):181–254. https://doi.org/10.23736/S0392-9590.18.03999-8.

56. De Maeseneer MG, Kakkos SK, Aherne T, Baekgaard N, Black S, Blomgren et al. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. Eur J Vasc Endovasc Surg. 2022;63(2):184–267. https://doi.org/10.1016/j.ejvs.2021.12.024.

57. Gloviczki P, Lawrence PF, Wasan SM, Meissner MH, Almeida J, Brown KR et al. The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed by the Society of Interventional Radiology and the Society for Vascular Medicine. J Vasc Surg Venous Lymphat Disord. 2024;12(1):101670. https://doi.org/10.1016/j.jvsv.2023.08.011.

58. Allaert FA, Hugue C, Cazaubon M, Renaudin JM, Clavel T, Escourrou P. Correlation between improvement in functional signs and plethysmographic parameters during venoactive treatment (Cyclo 3 Fort). Int Angiol. 2011;30(3):272–277. Available at: https://pubmed.ncbi.nlm.nih.gov/21617611.

59. Guex JJ, Avril L, Enrici E, Enriquez E, Lis C, Taïeb C. Quality oflife improvement in Latin American patients suffering from chronic venous disorder using a combination of Ruscus aculeatus and hesperidin methyl-chalcone and ascorbic acid (quality study). Int Angiol. 2010;29(6):525–532. Available at: https://pubmed.ncbi.nlm.nih.gov/21173734.

60. de Almeida Cyrino FZG, Balthazar DS, Sicuro FL, Bouskela E. Effects of venotonic drugs on the microcirculation: Comparison between Ruscus extract and micronized diosmine1. Clin Hemorheol Microcirc. 2018;68(4):371–382. https://doi.org/10.3233/CH-170281.

61. Allaert FA. Meta-analysis of the impact of the principal venoactive drugs agents on malleolar venous edema. Int Angiol. 2012;31(4):310–315. Available at: https://pubmed.ncbi.nlm.nih.gov/22801396.

62. Апханова ТВ, Булатов ВЛ, Вахратьян ПЕ, Волков АМ, Волков АС, Гаврилов ЕК и др. Варикозное расширение вен нижних конечностей: клинические рекомендации. 2024. 178 p. Режим доступа: https://cr.minzdrav.gov.ru/preview-cr/680_2.