Rutin Chronic venous insufficiency (CVI), and related signs and symptoms of venous and diabetic microangiopathy, can be effectively treated with O-(β-hydroxyethyl)-rutosides.22 A study evaluating the clinical efficacy of O-(beta-hydroxyethyl)-rutosides in subjects with severe CVI demonstrated the long-term efficacy of HR in CVI patients. HR also prevents the most severe complications of CVI along with controlling signs/symptoms and edema in CVI.23

A Cochrane review study involving 53 trials and 6013 participants; mean age 50 years showed that rutosides, diosmine, Horse Chestnut Fruit Powder extract 200mg + Sweet Orange Extract 200mg + hidrosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed Menaquinone 1.5mg + Ascorbic Acid 30mg + D Alpha Tocopheryl 60mcg + extract and aminaftone in patients with CVI at any stage of the disease have beneficial effects on oedema and on some signs and Niacin 10mg + Run 50mg + Cholecalciferol 400mcg Horse Chestnut Fruit Powder extract 200mg + Sweet Orange Extract 200mg + symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo Menaquinone 1.5mg + Ascorbic Acid 30mg + D Alpha Tocopheryl 60mcg + but also can produce more adverse effects.24 Niacin 10mg + Run 50mg + Cholecalciferol 400mcg

α-D-Tocopherol, Rutin in CVI A comparative clinical study showed that oral administration of alpha-tocopherol, rutin, Melilotus officinalis and Centella asiatica in 30 patients with chronic venous insufficiency had a significant improvement of the clinical symptomatology suggesting the use Chronic Venous insufficiency: of these compounds in chronic venous insufficiency.25 A Natural remedy for Spotlight on the combination of Horse Chestnut extract, Cholecalciferol Sweet Orange Extract, Menaquinone, Ascorbic Acid, Number of Varicose veins... Studies suggest that there is an increased prevalence of influential studies Alpha Tocopherol, Niacin, Rutin and Cholecalciferol Vitamin D deficiency in patients with chronic venous leg ulcers.26 Compound Recommendation RCTs Meta-analyses Calcium dobesilate Grade A 3 2 Guideline recommendations MPFF Grade A 4 1 Grade B recommendation was assigned for HSCE and Hydroxyethylrutosides Grade A 5 1 Calcium dobesilate, Micronized Purified Flavonoid HCSE (escin) Grade B 1 2 Fraction (MPFF), and hydroxyethylrutoside (ie, Ruscus extracts Grade B 2 1 References oxerutins) were assigned a Grade A recommendation, the 1.Veraart JC. Ned Tijdschr Geneeskd. 2002;146(5):199-203. 2.Brunner F et al. Br J Clin Pharmacol. 2001;51(3):219-24. 3.Grudzińska E et al. Cent Eur J Immunol. highest level of recommendation by the International Diosmin (synthetic) Grade C 1 2014;39(4):525-31. 4.Dudek-Makuch M et al. Revista Brasileira de Farmacognosia.2015; 25:533-541. 5.Patel SK and Surowiec SM. Venous Insufficiency. Accessed Consensus Statement (Siena, 2005) and the Consensus Troxerutin Grade C 2 from website https://www.ncbi.nlm.nih.gov/books/NBK430975/ as on 14.12.2018. 6.Rusak A et al. Adv Clin Exp Med. 2018;27(5):695-701. 7.Spiridon M et al. Maedica (Buchar). 2017;12(1):59-61. 8.Hyder ON et al. R I Med J (2013). 2017;100(5):37-39. 9.Aesculus hippocastanum (Horse chestnut). Alternative Medicine Statement led by Nicolaides in 2008, with regard to Chronic Ginkgo biloba Grade C 2 Review. 2009;14(3):278-283. 10.Pittler MH et al. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230. 11.Underland V et al. Global Adv Health Med. Venous Disease-related symptoms. The use of MPFF and Proanthocyanidines Grade C 2 2012;1(1):122-123. 12.Dickson S et al. J Herb Pharmacother. 2004;4(2):19-32. 13.Lv X et al. Chem Cent J. 2015;9:68. 14.Carballo-Villalobos AI et al. Biomed Res Int. 2016;2016:8263463. 15.Krief I. Lille Med. 1980;25(8):470-472. 16.Ramelet AA. Angiology. 2001;52 Suppl 1:S49-56. 17.Jawien A et al. Int Angiol. pentoxifylline in combination with compression in Troxerutin + coumarin Grade C 1 2017;36(1):31-41. 18.Glowinski J et al. Eur J Vasc Endovasc Surg. 2002;23(6):550-555. 19.Beulens JW et al. Br J Nutr. 2013;110(8):1357-1368. 20.Cario- longstanding or large venous ulcers was recommended and Centella asiatica Grade C 1 T o u m a n i a n t z C e t a l . J V a s c R e s . 2 0 0 7 ; 4 4 ( 6 ) : 4 4 4 - 4 5 9 . 2 1 . S c h u r g e r s L J . A c c e s s e d f r o m w e b s i t e assigned Grade 1B in the latest edition of the Handbook of https://pdfs.semanticscholar.org/f844/9e649856f09bd017d4b4432f4fb1a7e02404.pdf as on 15.12.2018. 22.Stuard S et al. Int J Angiol. 2008;17(3):143-148. Naftazone Grade C 1 Venous Disorders (2009).27 23.Cesarone MR et al. Panminerva Med. 2010;52(2 Suppl 1):43-8. 24.Martinez-Zapata MJ et al. Cochrane Database Syst Rev. 2016 Apr 6;4:CD003229. 25.Cataldi A et al. Minerva Cardioangiol. 2001;49(2):159-163. 26.Burkievcz CJ et al. Rev Col Bras Cir. 2012;39(1):60-63. 27.Gillet JL. Medicographia. 2011;33:285-291. Abbreviations: HCSE, horse chestnut seed extract; MPFF, Table 1. Grades of recommendation of the International Consensus micronized purified flavonoid fraction; RCT, randomized Statement clinical trial. Indications: Used as a supplement to treat · Varicose veins · Pigmentation Summary · Oedema and Inflammation · Achy, Tired or swollen legs • Chronic venous insufficiency (CVI) is a complex of symptoms occurring on the lower leg, which includes varicose veins, oedema, pigmentation and venous leg ulceration. Dosage • Varicose veins of the lower limb affect a sizable fraction of the adult population and result in considerable suffering. · One capsule 1-2 times daily as advised by the Physician • The limited possibilities of non-invasive treatment and prevention calls for the analysis of new potential targets of pharmacotherapy. • Medicines from plant origin play a significant role in the pharmacological treatment of CVI. • Clinical review data suggests that Horse chestnut extract is an efficacious and safe short-term treatment for CVI. • Micronized purified flavonoid fraction containing diosmin and hesperidin is a potent venotropic drug used in the treatment of venous insufficiency. • Supplementation of Ascorbic Acid, α-D-Tocopherol, Menaquinone, Rutosides and Cholecalciferol may have beneficial outcome in treatment of varicose veins. • International Consensus Statement recommends the use of Horse chestnut extract, Micronized Purified Flavonoid Fraction. Disomin and hydroxyethylrutoside for Chronic Venous Disease-related symptoms. Thus a combination of Horse Chestnut extract, Sweet Orange Extract, Menaquinone, Ascorbic Acid, D Alpha 61/C, 6th Main Road, 4th Phase, 7th Block, B.S.K 3rd Stage, Bangalore - 560085.

Tocopheryl, Niacin, Rutin and Cholecalciferol may be a useful combination in treating Chronic Venous Disease-related 2018 symptoms. A Natural remedy for Varicose veins... Chronic Venous insufficiency: Spotlight on the combination of Horse Chestnut extract, Sweet Orange be "good" or "fairly good." Only 2 patients rated 70 Extract, Menaquinone, Ascorbic Acid, Alpha Tocopherol, Niacin, Rutin and Cholecalciferol tolerability as poor at visit 3 (Figure 2). 65 Hypoxia of endothelium ↓ ATP Counteracting In total, 91 adverse events were reported, of which the reduction of ATP only 4 were rated as probably related to the study drug. 60 Introduction The majority of patients rated efficacy to be "very Release of PLA 51 Visit 2 Chronic venous insufficiency (CVI) is a complex of symptoms occurring on the lower leg, which includes varicose veins, 2 ↑ Prostaglandins Ihibition of PLA2 good" or "good," with only 10 patients reporting no Release of PAF oedema, pigmentation and venous leg ulceration.1 Varicose veins of the lower limb affect a sizable fraction of the adult effect by the end of the study. The results of this study 50 Visit 3 population and result in considerable suffering. Visible varicose veins are found in 20-25% of females and 10-15% of male adults, HCSE / indicated that horse chestnut tablets were a safe, well- 2 with a high familial incidence. Dilated veins and incompetent valves are the common manifestation of the disease. tolerated and efficacious treatment for Widmer stage I 40 Inflammation 12 CVI is caused by a decompensation of the venous system together with reflux in the superficial, deep and/or perforating veins of AESCIN and II CVI. the lower leg in supine position. The exact pathogenesis of the skin symptoms is still largely unclear. Treatment of varicose veins involves several methods: compression therapy, if need be combined with sclerotherapy or surgery, or with supportive 30

Sweet Orange Extract – Source of No.of Patients medication.1 The limited possibilities of non-invasive treatment and prevention calls for the analysis of new potential targets of Neutrophil adhesion and Edema Neutrophil activation 3 aggregation inhibition neutrophil adhesion Hesperidin and Diosmin pharmacotherapy. AESCIN 19 20 Inhibition of Citrus fruits are good sources of nutrition with an Medicines from plant origin play a significant role in the pharmacological treatment of CVI. The most popular ones include the Ion channel Release of elastase and other enzymes 4 ↓ Blood flow elastase and other ample amount of Vitamin C. Plenty of active natural horsechestnut seed extract and flavonoids: diosmin, hesperidin, rutin, and its derivative – troxerutin. HCSE / sensitization; enhanced Release of fibroblast growth factor venous tension/capillary enzymes metabolites including flavonoids, alkaloids, coumarins, 10 6 7 This article outlines the role of Horse chestnut extract, Flavonoids and Vitamins in the treatment of Chronic Venous sealing Release of PGF limonoids, carotenoids, phenolic acids and essential insufficiency. Damage to venous walls 2α 3 Hypoxia Vein enlargment oils, have been found in Citrus fruits. 1 1 Owing to these metabolites, Citrus fruits exhibit 0 Good Fairly Good Quite Good Poor Chronic Venous insufficiency-Plausible pathology and Management options Figure 1. Mechanisms of Horse chestnut seed extract /aescin activity in chronic venous insufficiency plentiful bioactivities including anti-oxidant, anti- Chronic venous insufficiency (CVI) typically refers to lower extremity edema, skin trophic changes, and discomfort secondary to inflammatory, anti-cancer, anti-microbial and anti- Tolerability allergy activities, as well as cardiovascular effect, venous hypertension. Chronic venous insufficiency is a prevalent disease process. Epidemiology studies suggest that in the Six trials (n = 502) suggested a WMD of 32.1 ml (95% CI 13.49 to 50.72) in favour of HCSE compared with placebo. One trial general population between 1% to 17% of men and 1% to 40% of women may experience chronic venous insufficiency. Despite neuroprotective effect, hepatoprotective effect, Figure 2. Patients' perception of tolerability over the treatment period for the indicated that HCSE may be as effective as treatment with compression stockings (Table 1). Adverse events were usually mild and 13 10,11 obesity control, etc. safety population this wide range, non-western countries appear to have a lower overall prevalence. Among all chronic venous insufficiency infrequent. The review data suggested that HCSE is an efficacious and safe short-term treatment for CVI. patients, approximately 1% to 2.7% will develop a venous stasis ulcer.5 Micronized purified flavonoid fraction (MPFF) Venous disease with concomitant varicose veins is presently a very common clinical phenomenon consisting of the destruction significantly reduces venous reflux in an animal model of venous hypertension, protecting the valves from narrowing and latient or population: Patients with chronic venous decreasing the number of lymphocytes T on the valves. Flavonoids administered for 60 days seem to decrease the plasma of vein valves, backward blood flow (venous reflux) and dilated veins. This in turn, may lead to serious complications, such as insufficiency Intervention: Horse chestnut seed extract 3 thrombosis, skin changes and leg ulcers. The development of varicose veins is due to genetic, hormonal and environmental Comparison: Placebo concentrations of some endothelium activation markers (ICAM-and VCAM). factors. The exact mechanism of their formation has not been identified. The main destructive factor is venous hypertension, Illustrative Comparative Risks (95% Confidence Interval) Flavonoids in citrus fruits like hesperidin and diosmin alone or combined have been reported to possess significant anti- which may lead to the remodeling of vein walls and vein valves. It is thought that long-term high pressure in veins may activate Assumed risk Corresponding risk No. of quality of the inflammatory activity. A combination of diosmin (450mg) and hesperidin (50mg) has been used clinically in the treatment of matrix metalloproteinases (MMPs), initiate coagulation and complement cascades, and activate platelets, leukocytes and larticipants tvidence venous insufficiency as a purified micronized flavonoid fraction that contains 90% diosmin and 10% hesperidin.14,15 Outcomes llacebo Horse chestnut seed extract (rtudies) (GRAat) macrophages as well.6 CVI is a potentially severe pathology that has been under diagnosed and undertreated for a long time and Micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin-Daflon 500 mg) is a potent venotropic 7 requires patience from the patient as well as care from the physician. Mean reduction of The mean reduction of lower leg The mean reduction of lower leg 502 (6) ⊕⊕⊕ drug used in the treatment of venous insufficiency. Pharmacological and clinical studies have demonstrated the comprehensive lower leg volume volume in the control groups was – volume in the intervention groups was Moderatea Compression therapy between 20-50 mmHg remains the cornerstone of any treatment plan for chronic venous insufficiency. In (mL) 45.65 32.10 higher (13.49-50.72 higher) mode of action of Daflon 500 mg: it increases venous tone, it improves lymph drainage, and it protects the microcirculation. addition to compression therapy, calf muscle exercises should be performed as part of any treatment plan.8 Clinical international, prospective, multicenter, randomized, controlled studies versus placebo studies documenting the effects ⊕⊕ 16 A combination therapy of compression stockings and medication to relieve swelling is currently the most typically used therapy Mean reduction of The mean reduction of The mean reduction of circumference at 80 (3) of Daflon 500 mg in CVI at advanced stages with edema, skin changes, and venous leg ulcer are reviewed. circumference at ankle circumference at ankle in the control ankle in the intervention groups was 4.71 Lowb,c in the United States. In Europe,where it has been studied extensively, Horse chestnut seed extract (HCSE) is a more popular (mm) groups was –1.3 higher 9 choice and has been shown in numerous clinical trials to be a highly effective therapy, equal to that of compression stockings. (1.13-8.28 higher) Ascorbic Acid and α-D-Tocopherol Studies have also shown that coumarins, flavonoids, saponosides and other plant extracts have demonstrated mild improvement Mean reduction of The mean reduction of circumference at The mean reduction of circumference at 80 (3) ⊕⊕ 8 Vitamin C is considered important for vessel protection because apart from its antioxidative function it also takes part in collagen in edema-related symptoms. circumference at calf calf in the control groups was –1.23 calf in the intervention groups was 3.51 Lowb,c synthesis.3 Clinical research indicates that combination of Ruscus extract, hesperidin methyl chalcone, and vitamin C is (mm) higher (0.58-6.45 higher) helpful to relieve the symptoms of venous disease.17 Varicose veins, and especially those complicated with superficial Horse Chestnut extract Improvement in leg pain 44 per 100 63 per 100 (52-76 per 100) 418 (1) ⊕ thrombophlebitis have revealed increased free radical generation. Proved contribution of free radicals to the pathogenesis of d,e,f Horse chestnut (Aesculus hippocastanum) is a large deciduous, rapidly-growing tree, the seed extract of which was used as a Very low varicose veins implies that administration of safe antioxidants (vitamin C and E, flavonoids) may have a beneficial outcome.  The levels of superoxide anion and lipid peroxides can be decreased by administration of the small molecule antioxidant treatment for many ailments, including rheumatism, rectal complaints, 3 bladder and gastrointestinal disorders, fever (first Reduction of leg The mean reduction of leg pain in The mean reduction of leg pain in the 30 (1) ⊕ 18 written account in 1720), hemorrhoids (as early as 1886) and leg cramps.9 Horse chestnut seeds are rich in saponins (3-5%), over pain (VAS 0-100) the control groups was 0.2 inter-vention groups was 42.40 higher Very lowb,g vitamin C and E. thirty of which have been isolated and identified. The main compound is aescin – a mixture of acylated triterpene glycosides.4 (34.9-49.9 higher)

Aescin has been shown to have anti-edematous, anti-inflammatory and venotonic properties that may be attributable to Improvement of edema 41 per 100 66 per 100 (53-81) 346 (1) ⊕ Menaquinone – Role in CVI decreased vascular permeability (Figure 1).4,9 Very lowd,e,f Vitamin K has new role to play in vascular biology. Recent reports have attributed the potential health benefits of vitamin K Abbreviations: GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; VAS, visual analog scale. beyond its function to activate hepatic coagulation factors. Several studies have suggested that Menaquinones, also known as Clinical efficacy of Horse chestnut extract in CVI vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, also known as vitamin K .19 Research suggests that high expression of matrix Gla protein (MGP) in varicose veins may contribute to venous wall A Cochrane database review study of 17 trials evaluated the efficacy and safety of oral horse chestnut seed extract (HCSE) versus 1 An open, monocentric study was carried out to assess primarily, the safety and tolerability of Aesculus hippocastanum in the remodeling by affecting proliferation and mineralization processes probably through impaired carboxylation of MGP.20 placebo, or reference therapy, for the treatment of CVI. treatment of CVI. The review results showed that there appeared to be an improvement in CVI related signs and symptoms with HCSE compared As vitamin K is an essential cofactor for MGP carboxylation, it might be expected that the local vascular vitamin K status is The study included 87 patients and they underwent 8 consecutive weeks of treatment and were asked to take one 50 mg Aesculus insufficient in varicose vein to mediate full carboxylation of all newly formed MGP. with placebo. Six trials reported a significant reduction of leg pain in the HCSE groups compared with the placebo groups, while hippocastanum tablet, twice daily. another reported a statistically significant improvement compared with baseline. One trial suggested a weighted mean difference Published data shows that in varicose smooth muscle cell cultures vitamin K supplementation inhibited the mineralization process, Patients judged the tolerability of the study medication in the majority of the cases at visits 2 and 3 (90 and 95%, respectively) to suggesting that in vitro, carboxylation of MGP could be partly induced and that the inhibitory effect of MGP could be restored. (WMD) of 42.4 mm (95% confidence interval (CI) 34.9 to 49.9) measured on a 100 mm visual analogue scale. Leg volume was 20,21 assessed in seven placebo-controlled trials. Active MGP could inhibit both proliferation and mineralization of veins, thereby helping inhibit the development of varicose veins.