Efficacy of a Low-Dose Diosmin Therapy on Improving Symptoms and Quality of Life in Patients with Chronic Venous Disease: Randomized, Double-Blind, Placebo-Controlled Trial

Raffaele Serra, Nicola Ielapi, Andrea Bitonti, Stefano Candido, Salvatore Fregola, Alessandro Gallo, Antonio Loria, Lucia Muraca, Luca Raimondo, Luminița Velcean, Simone Guadagna, Luca Gallelli, Raffaele Serra, Nicola Ielapi, Andrea Bitonti, Stefano Candido, Salvatore Fregola, Alessandro Gallo, Antonio Loria, Lucia Muraca, Luca Raimondo, Luminița Velcean, Simone Guadagna, Luca Gallelli

Abstract

Chronic Venous Disease (CVD) is a common medical condition affecting up to 80% of the general population. Clinical manifestations can range from mild to more severe signs and symptoms that contribute to the impairment of the quality of life (QoL) of affected patients. Among treatment options, venoactive drugs such as diosmin are widely used in the symptomatic treatment in all clinical stages. The aim of this study is to determine the effectiveness of a new formulated diosmin in relieving symptoms and improving QoL in patients suffering from CVD. In this randomized, double-blind, placebo-controlled, multicenter clinical study, CVD patients with a Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification system between C2 and C4 were randomized to receive a bioavailable diosmin (as μsmin® Plus) 450 mg tablet once daily or a placebo for 8 weeks. Clinical symptoms and QoL were monitored using the measurement of leg circumference, visual analogue scale (VAS) for pain, Global Index Score (GIS) and Venous Clinical Severity Score (VCSS). A total of 72 subjects completed the study. From week 4, leg edema was significantly decreased in the active group (p < 0.001). An improvement in the VAS score was observed in the active group compared to placebo at the end of treatment (p < 0.05). GIS and VCSS scores were significantly improved in the active group at week 8 (p < 0.001). No treatment related-side effects were recorded. The results of this study showed that the administration of low-dose μsmin® Plus was safe and effective in relieving symptoms and improving QoL in subjects with CVD.

Keywords: chronic venous disease; diosmin; quality of life; symptoms; μsmin® Plus.

Conflict of interest statement

Simone Guadagna works at Opera Contract Research Organization (Romania) which managed the study on behalf of Giellepi spa. None of the authors are involved in the commercial activity of Giellepi. The company did not contribute to the analysis of results, which was performed by a skilled statistician and academic authors. The presentation of the results and the preparation of the manuscript were performed by academic authors, but Simone Guadagna who works at the CRO that managed the study. Furthermore, the company did not take part in such activities nor in the revision of the manuscript.

Figures

Figure 1
Figure 1
Leg Circumference. (Black column: active; Grey column: placebo). *** p < 0.001 vs. baseline; # p < 0.05 active vs. placebo.
Figure 2
Figure 2
Global Index Score. (Black column: active; Grey column: placebo). *** p < 0.001 vs. baseline; ### p < 0.001 active vs. placebo.
Figure 3
Figure 3
Visual Analogue Scale (VAS) for pain. (Black column: active; Grey column: placebo). * p < 0.05 vs. baseline; ** p < 0.01 vs. baseline; *** p < 0.001 vs. baseline; # p < 0.05 active vs. baseline.
Figure 4
Figure 4
Venous Clinical Severity Score. (Black column: active; Grey column: placebo) *** p < 0.001 vs. baseline; ### p < 0.001 active vs. baseline.

References

    1. Serra R., Grande R., Butrico L., Fugetto F., de Franciscis S. Epidemiology, diagnosis and treatment of chronic venous disease: A systematic review. Chirurgia. 2016;24:34–45.
    1. Nicolaides N.A., Labropoulos N. Burden and Suffering in Chronic Venous Disease. Adv. Ther. 2019;36(Suppl. 1):1–4. doi: 10.1007/s12325-019-0882-6.
    1. Serra R., Ssempijja L., Provenzano M., Andreucci M. Genetic biomarkers in chronic venous disease. Biomark. Med. 2020;14:75–80. doi: 10.2217/bmm-2019-0408.
    1. Kostas T.I., Ioannou C.V., Drygiannakis I., Georgakarakos E., Kounos C., Tsetis D., Katsamouris A.N. Chronic venous disease progression and modification of predisposing factors. J. Vasc. Surg. 2010;51:900–907. doi: 10.1016/j.jvs.2009.10.119.
    1. Labropoulos N. How Does Chronic Venous Disease Progress from the First Symptoms to the Advanced Stages? A Review. Adv. Ther. 2019;36(Suppl. 1):13–19. doi: 10.1007/s12325-019-0885-3.
    1. Raffetto J.D., Mannello F. Pathophysiology of chronic venous disease. Int. Angiol. 2014;33:212–221.
    1. Partsch H. Varicose veins and chronic venous insufficiency. Vasa. 2009;38:293–301. doi: 10.1024/0301-1526.38.4.293.
    1. Serra R., Ielapi N., Bevacqua E., Rizzuto A., De Caridi G., Massara M., Casella F., Di Mizio G., de Franciscis S. Haemorrhage from varicose veins and varicose ulceration: A systematic review. Int. Wound J. 2018;15:829–833. doi: 10.1111/iwj.12934.
    1. Davies A.H. The Seriousness of Chronic Venous Disease: A Review of Real-World Evidence. Adv. Ther. 2019;36(Suppl. 1):5–12. doi: 10.1007/s12325-019-0881-7.
    1. Ruggiero M., Grande R., Naso A., Butrico L., Rubino P., Placida G.D., Cannistrà M., Serra R. Symptoms in patients with skin changes due to chronic venous insufficiency often lead to emergency care service: An Italian observational study. Int. Wound J. 2016;13:967–971. doi: 10.1111/iwj.12498.
    1. Nicolaides A., Kakkos S., Baekgaard N., Comerota A., de Maeseneer M., Eklof B., Giannoukas A.D., Lugli M., Maleti O., Myers K., et al. Management of chronic venous disorders of the lower limbs. Guidelines According to Scientific Evidence. Part I. Int. Angiol. 2018;37:181–254. doi: 10.23736/S0392-9590.20.04388-6.
    1. Mansilha A. Early Stages of Chronic Venous Disease: Medical Treatment Alone or in Addition to Endovenous Treatments. Adv. Ther. 2020;37(Suppl. 1):13–18. doi: 10.1007/s12325-019-01217-9.
    1. Ayala-García M.A., Reyes J.S., Muñoz Montes N., Guaní-Guerra E. Frequency of use of elastic compression stockings in patients with chronic venous disease of the lower extremities. Phlebology. 2019;34:481–485. doi: 10.1177/0268355518822356.
    1. Serra R., Grande R., Butrico L., Buffone G., Caliò F.G., Squillace A., Rizzo B.A., Massara M., Spinelli F., Ferrarese A.G., et al. Effects of a new nutraceutical substance on clinical and molecular parameters in patients with chronic venous ulceration. Int. Wound J. 2016;13:88–96. doi: 10.1111/iwj.12240.
    1. Mansilha A., Sousa J. Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy. Int. J. Mol. Sci. 2018;19:1669. doi: 10.3390/ijms19061669.
    1. Marinović Kulišić S., Lupi D. Pharmacological treatment in patients with chronic venous disease. Acta Dermatovenerol. Croat. 2012;20:197–200.
    1. Perrin M., Ramelet A.A. Pharmacological treatment of primary chronic venous disease: Rationale, results and unanswered questions. Eur. J. Vasc. Endovasc. Surg. 2011;41:117–125. doi: 10.1016/j.ejvs.2010.09.025.
    1. Andreozzi G.M. Sulodexide in the treatment of chronic venous disease. Am. J. Cardiovasc. Drugs. 2012;12:73–81. doi: 10.2165/11599360-000000000-00000.
    1. Kakkos S.K., Nicolaides A.N. 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.
    1. Russo R., Mancinelli A., Ciccone M., Terruzzi F., Pisano C., Severino L. Pharmacokinetic Profile of µSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats. Nat. Prod. Commun. 2015;10:1569–1572.
    1. Russo R., Chandradhara D., De Tommasi N. Comparative Bioavailability of Two Diosmin Formulations after Oral Administration to Healthy Volunteers. Molecules. 2018;23:2174. doi: 10.3390/molecules23092174.
    1. Eklöf B., Rutherford R.B., Bergan J.J., Carpentier P.H., Gloviczki P., Kistner R.L., Meissner M.H., Moneta G.L., Myers K., Padberg F.T., et al. Revision of the CEAP classification for chronic venous disorders: Consensus statement. J. Vasc. Surg. 2004;40:1248–1252. doi: 10.1016/j.jvs.2004.09.027.
    1. Biemans A.A., van der Velden S.K., Bruijninckx C.M., Buth J., Nijsten T. Validation of the chronic venous insufficiency quality of life questionnaire in Dutch patients treated for varicose veins. Eur. J. Vasc. Endovasc. Surg. 2011;42:246–253. doi: 10.1016/j.ejvs.2011.04.007.
    1. Boonstra A.M., Schiphorst Preuper H.R., Reneman M., Posthumus J.B., Stewart R.E. Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain. Int. J. Rehabil. Res. 2008;31:165–169. doi: 10.1097/MRR.0b013e3282fc0f93.
    1. Rutherford R.B., Padberg F.T., Jr., Comerota A.J., Kistner R.L., Meissner M.H., Moneta G.L. Venous severity scoring: An adjunct to venous outcome assessment. J. Vasc. Surg. 2000;31:1307–1312. doi: 10.1067/mva.2000.107094.
    1. Casili G., Lanza M., Campolo M., Messina S., Scuderi S., Ardizzone A., Filippone A., Paterniti I., Cuzzocrea S., Esposito E. Therapeutic potential of flavonoids in the treatment of chronic venous insufficiency. Vasc. Pharmacol. 2021;137:106825. doi: 10.1016/j.vph.2020.106825.
    1. Pfisterer L., König G., Hecker M., Korff T. Pathogenesis of varicose veins—Lessons from biomechanics. Vasa. 2014;43:88–99. doi: 10.1024/0301-1526/a000335.
    1. Castro-Ferreira R., Cardoso R., Leite-Moreira A., Mansilha A. The Role of Endothelial Dysfunction and Inflammation in Chronic Venous Disease. Ann. Vasc. Surg. 2018;46:380–393. doi: 10.1016/j.avsg.2017.06.131.
    1. Nicolaides A.N. Chronic venous disease and the leukocyte-endothelium interaction: From symptoms to ulceration. Angiology. 2005;56(Suppl. 1):S11–S19. doi: 10.1177/00033197050560i103.
    1. Bergan J. Molecular mechanisms in chronic venous insufficiency. Ann. Vasc. Surg. 2007;21:260–266. doi: 10.1016/j.avsg.2007.03.011.
    1. Bergan J.J., Pascarella L., Schmid-Schönbein G.W. Pathogenesis of primary chronic venous disease: Insights from animal models of venous hypertension. J. Vasc. Surg. 2008;47:183–192. doi: 10.1016/j.jvs.2007.09.028.
    1. Pocock E.S., Alsaigh T., Mazor R., Schmid-Schönbein G.W. Cellular and molecular basis of Venous insufficiency. Vasc. Cell. 2014;6:24. doi: 10.1186/s13221-014-0024-5.
    1. Feldo M., Wójciak-Kosior M., Sowa I., Kocki J., Bogucki J., Zubilewicz T., Kęsik J., Bogucka-Kocka A. Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules. 2019;24:3316. doi: 10.3390/molecules24183316.
    1. Najmanová I., Pourová J., Vopršalová M., Pilařová V., Semecký V., Nováková L., Mladěnka P. Flavonoid metabolite 3-(3-hydroxyphenyl)propionic acid formed by human microflora decreases arterial blood pressure in rats. Mol. Nutr. Food Res. 2016;60:981–991. doi: 10.1002/mnfr.201500761.
    1. Cova D., De Angelis L., Giavarini F., Palladini G., Perego R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int. J. Clin. Pharmacol. Ther. Toxicol. 1992;30:29–33.
    1. Applová L., Karlíčková J., Warncke P., Macáková K., Hrubša M., Macháček M., Tvrdý V., Fischer D., Mladěnka P. 4-Methylcatechol, a flavonoid metabolite with potent antiplatelet effects. Mol. Nutr. Food Res. 2019;63:e1900261. doi: 10.1002/mnfr.201900261.
    1. Kim D.H., Jung E.A., Sohng I.S., Han J.A., Kim T.H., Han M.J. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch. Pharm. Res. 1998;21:17–23. doi: 10.1007/BF03216747.
    1. Perego R., Beccaglia P., Angelini M., Villa P., Cova D. Pharmacokinetic studies of diosmin and diosmetin in perfused rat liver. Xenobiotica. 1993;23:1345–1352. doi: 10.3109/00498259309059444.
    1. Garner R.C., Garner J.V., 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;91:32–40. doi: 10.1002/jps.1168.
    1. Silvestro L., Tarcomnicu I., Dulea C., Attili N.R., Ciuca V., Peru D., Rizea Savu S. Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Anal. Bioanal. Chem. 2013;405:8295–8310. doi: 10.1007/s00216-013-7237-y.
    1. Shoab S.S., Porter J.B., Scurr J.H., Coleridge-Smith P.D. Effect of oral micronized purified flavonoid fraction treatment on leukocyte adhesion molecule expression in patients with chronic venous disease: A pilot study. J. Vasc. Surg. 2000;31:456–461. doi: 10.1067/mva.2000.102724.
    1. Ramelet A. Sclerotherapy. 6th ed. Elsevier; Amsterdam, The Netherlands: 2017. Venoactive Drugs; pp. 426–434.
    1. Sheikh P., Lohsiriwat V., Shelygin Y. Micronized purified flavonoid fraction in hemorrhoid disease: A systematic review and meta-analysis. Adv. Ther. 2020;37:2792–2812. doi: 10.1007/s12325-020-01353-7.
    1. Laliberté F., Bookhart B.K., Nelson W.W., Lefebvre P., Schein J.R., Rondeau-Leclaire J., Duh M.S. Impact of once-daily versus twice-daily dosing frequency on adherence to chronic medications among patients with venous thromboembolism. Patient. 2013;6:213–224. doi: 10.1007/s40271-013-0020-5.
    1. Lamping D.L., Schroter S., Kurz X., Kahn S.R., Abenhaim L. Evaluation of outcomes in chronic venous disorders of the leg: Development of a scientifically rigorous, patient-reported measure of symptoms and quality of life. J. Vasc. Surg. 2003;37:410–419. doi: 10.1067/mva.2003.152.
    1. Fokou M., Moifo B., Fongang E., Teyang A., Muna W. Characteristics of patients and patterns of chronic venous disease of the lower limbs in a referral hospital in Cameroon. J. Vasc. Surg. Venous Lymphat. Disord. 2018;6:90–95. doi: 10.1016/j.jvsv.2017.08.012.
    1. Catarinella F.S., Nieman F.H., Wittens C.H. An overview of the most commonly used venous quality of life and clinical outcome measurements. J. Vasc. Surg. Venous Lymphat. Disord. 2015;3:333–340. doi: 10.1016/j.jvsv.2014.09.003.
    1. Ulloa J.H. Micronized purified flavonoid fraction (MPFF) for patients suffering from chronic venous disease: A review of new evidence. Adv. Ther. 2019;36(Suppl. 1):20–25. doi: 10.1007/s12325-019-0884-4.
    1. Jantet G. Chronic venous insufficiency: Worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids. Angiology. 2002;53:245–256. doi: 10.1177/000331970205300301.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi