Rutin: therapeutic potential and recent advances in drug delivery

Introduction: Natural compounds such as bioflavonoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Rutin, a polyphenolic bioflavonoid has shown wide range of pharmacological applications due to its significant antioxidant properties. Conventionally, it is used as antimicrobial, antifungal, and antiallergic agent. However, current research has shown its multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, hypertension and hypercholesterolemia. Its use is advantageous over other flavonoids as it is a nontoxic and nonoxidizable molecule. Areas covered: This review focus on various studies done on rutin explaining its broad spectrum pharmacological activities. In addition, this review will also focus on the challenges associated with the drug and various approaches to improve the oral bioavailability of rutin. Expert opinion: Rutin is a highly potent molecule due to its strong antioxidant properties. In the near future, enhancing its bioavailability using novel drug delivery methods having minimum side effects will bring this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases.

[1]  Hyun Pyo Kim,et al.  Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from medicinal plants , 1999, Archives of pharmacal research.

[2]  Didem Deliorman Orhan,et al.  Antibacterial, antifungal, and antiviral activities of some flavonoids. , 2010, Microbiological research.

[3]  Palaash Kumar.  FORMULATION DESIGN AND EVALUTION OF RUTIN LOADED SELFEMULSIFYING DRUG DELIVARY SYSTEM (SEDDs) USING EDIBLE OIL , 2012 .

[4]  M. Pfaller,et al.  Candida albicans arthritis one year after successful treatment of fungemia in a healthy infant. , 1996, The Journal of pediatrics.

[5]  Wonhwa Lee,et al.  Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[6]  A. Zinsmeister,et al.  Autoimmune Disorders and Extraintestinal Manifestations in First-degree Familial and Sporadic Inflammatory Bowel Disease: A Case–Control Study , 2004, Inflammatory bowel diseases.

[7]  V. Villari,et al.  The rutin/beta-cyclodextrin interactions in fully aqueous solution: spectroscopic studies and biological assays. , 2005, Journal of pharmaceutical and biomedical analysis.

[8]  D Kromhout,et al.  Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands. , 1993, Nutrition and cancer.

[9]  Yongmoon Han.  Rutin has therapeutic effect on septic arthritis caused by Candida albicans. , 2009, International immunopharmacology.

[10]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[11]  D. Benvegnú,et al.  Hydrogels containing rutin intended for cutaneous administration: efficacy in wound healing in rats , 2012, Drug development and industrial pharmacy.

[12]  E. Middleton.  Effect of plant flavonoids on immune and inflammatory cell function. , 1998, Advances in experimental medicine and biology.

[13]  Guohua Gong,et al.  Rutin inhibits hydrogen peroxide-induced apoptosis through regulating reactive oxygen species mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells. , 2010, European journal of pharmacology.

[14]  S. Garcia-Vallvé,et al.  Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies , 2012, PloS one.

[15]  Kuang-Chi Lai,et al.  Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo , 2012, Environmental toxicology.

[16]  C. Rice-Evans,et al.  Flavonoids: antioxidants or signalling molecules? , 2004, Free radical biology & medicine.

[17]  Simoní Da Ros,et al.  Nanostructured Systems Containing Rutin: In Vitro Antioxidant Activity and Photostability Studies , 2010, Nanoscale research letters.

[18]  Anil Kumar,et al.  Conundrum and therapeutic potential of curcumin in drug delivery. , 2010, Critical reviews in therapeutic drug carrier systems.

[19]  L. Maggi,et al.  Fast- and Slow-Release Tablets for Oral Administration of Flavonoids: Rutin and Quercetin , 2002, Drug development and industrial pharmacy.

[20]  Xiangao Sun,et al.  Flavonoids exert diverse inhibitory effects on the activation of NF-κB , 2002 .

[21]  M. Bogo,et al.  Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish , 2011, Behavioural Brain Research.

[22]  P. Stanely Mainzen Prince,et al.  Preventive effect of rutin on lipids, lipoproteins, and ATPases in normal and isoproterenol‐induced myocardial infarction in rats , 2007, Journal of biochemical and molecular toxicology.

[23]  J. González‐Gallego,et al.  Anti-inflammatory properties of dietary flavonoids. , 2007, Nutricion hospitalaria.

[24]  Gary Williamson,et al.  Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. , 2005, The American journal of clinical nutrition.

[25]  A. Hay,et al.  Inhibition of HIV infection by flavanoids. , 1993, Antiviral research.

[26]  P. Kidd,et al.  A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). , 2005, Alternative medicine review : a journal of clinical therapeutic.

[27]  S. Johann,et al.  Antifungal activity of five species of Polygala , 2011, Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology].

[28]  X. Sun,et al.  Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB. , 2002, Transplantation proceedings.

[29]  A. Giraldi-Guimarães,et al.  Therapeutic potential of treatment with the flavonoid rutin after cortical focal ischemia in rats , 2013, Brain Research.

[30]  A. Annapurna,et al.  Preparation and Characterization of Quercetin and Rutin Cyclodextrin Inclusion Complexes , 2007, Drug development and industrial pharmacy.

[31]  M. Rashid,et al.  Antibacterial flavonoids from Desmos chinensis , 1996 .

[32]  S. Howell,et al.  Effects of flavonoids on insulin secretion and 45Ca2+ handling in rat islets of Langerhans. , 1985, The Journal of endocrinology.

[33]  K. Chopra,et al.  Protective effect of rutin, a polyphenolic flavonoid against haloperidol‐induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes , 2007, Fundamental & clinical pharmacology.

[34]  R. K. Bhattacharya,et al.  Protective effect of rutin, a flavonol glycoside, on the carcinogen-induced DNA damage and repair enzymes in rats. , 1996, Cancer letters.

[35]  R. Manavalan,et al.  LDL Lowering Properties Of Rutin In Diabetic Patients , 2010 .

[36]  Q. Xia,et al.  Rutin-induced Endothelium-dependent Vasorelaxation in Rat Aortic Rings and the Underlying Mechanism , 2005, 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference.

[37]  A. Aro,et al.  Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers , 2000, European Journal of Clinical Pharmacology.

[38]  J. González‐Gallego,et al.  The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. , 2007, European journal of pharmacology.

[39]  S. Rozental,et al.  Antimicrobial and antiviral activities of polyphenolics from Cocos nucifera Linn. (Palmae) husk fiber extract. , 2002, Research in microbiology.

[40]  V. Krutovskikh,et al.  Lack of tumor-promoting effects of flavonoids: studies on rat liver preneoplastic foci and on in vivo and in vitro gap junctional intercellular communication. , 1996, Nutrition and cancer.

[41]  A. Santos,et al.  Vasorelaxant and hypotensive effects of the extract and the isolated flavonoid rutin obtained from Polygala paniculata L. , 2011, The Journal of pharmacy and pharmacology.

[42]  S. Dixit.  Anticancer Effect of Rutin Isolated from the Methanolic Extract of Triticum aestivum Straw in Mice , 2014 .

[43]  A. Mahmoud,et al.  Antihyperglycemic, antihyperlipidemic and antioxidant effects and the probable mechanisms of action of Ruta graveolens infusion and rutin in nicotinamide-streptozotocin-induced diabetic rats. , 2010 .

[44]  T. Ishrat,et al.  Rutin protects the neural damage induced by transient focal ischemia in rats , 2009, Brain Research.

[45]  H. Javed,et al.  Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type , 2012, Neuroscience.

[46]  U. Mohammed,et al.  Naturally occurring polyphenolic antioxidants modulate IgE‐mediated mast cell activation , 2000, Immunology.

[47]  Myung-Sook Choi,et al.  Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. , 2006, The international journal of biochemistry & cell biology.

[48]  G. R. Castro,et al.  Antimicrobial activity of flavonoids from leaves of Tagetes minuta. , 1997, Journal of ethnopharmacology.

[49]  H. Ashida,et al.  Rutin-enhanced Antibacterial Activities of Flavonoids against Bacillus cereus and Salmonella enteritidis , 2002, Bioscience, biotechnology, and biochemistry.

[50]  Rainer H Müller,et al.  Development of an oral rutin nanocrystal formulation. , 2009, International journal of pharmaceutics.

[51]  A. Vajreswari,et al.  Effect of dietary fats on some membrane-bound enzyme activities, membrane lipid composition and fatty acid profiles of rat heart sarcolemma , 1992, Lipids.

[52]  P. Morazzoni,et al.  The flavonoids : new perspectives in biological activities and therapeutics , 1993 .

[53]  G. Jonas,et al.  Candida albicans arthritis in a healthy adult. , 1981, Southern medical journal.

[54]  E. van Nood,et al.  Flavonoids: a review of probable mechanisms of action and potential applications. , 2001, The American journal of clinical nutrition.

[55]  J. M. Romero,et al.  Candida arthritis in an immunocompetent patient without predisposing factors , 2005, Clinical Rheumatology.

[56]  Myung‐Sook Choi,et al.  Effect of rutin and tannic acid supplements on cholesterol metabolism in rats , 2002 .

[57]  W. Chang,et al.  Inhibitory effects of flavonoids on xanthine oxidase. , 1993, Anticancer research.

[58]  J. D. del Río,et al.  Uses and properties of Citrus flavonoids , 1997 .

[59]  Sanjay S. Jain,et al.  PHYSICOCHEMICAL CHARACTERIZATION AND DETERMINATION OF FREE RADICAL SCAVENGING ACTIVITY OF RUTIN-PHOSPHOLIPID COMPLEX , 2012 .

[60]  A. Lamprecht,et al.  Coated chitosan pellets containing rutin intended for the treatment of inflammatory bowel disease: in vitro characteristics and in vivo evaluation. , 2012, International journal of pharmaceutics.

[61]  E. Petkov,et al.  Inhibitory effect of some flavonoids and falvonoid mixtures on cyclic AMP phosphodiesterase activity of rat heart. , 1981, Planta medica.

[62]  F. Martel,et al.  Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. , 2011, Nutrition research.

[63]  V. Dobson,et al.  Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study , 2000, European Journal of Clinical Nutrition.

[64]  S. Ramos.  Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. , 2008, Molecular nutrition & food research.

[65]  K. Pandey,et al.  Plant polyphenols as dietary antioxidants in human health and disease , 2009, Oxidative medicine and cellular longevity.

[66]  Andrew J Lamb,et al.  Antimicrobial activity of flavonoids , 2005, International Journal of Antimicrobial Agents.

[67]  R. Pardini,et al.  Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids. A structure-activity study. , 1986, Biochemical pharmacology.

[68]  H. Bouriche,et al.  Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. , 2003, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[69]  N. Kamalakkannan,et al.  Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic wistar rats. , 2006, Basic & clinical pharmacology & toxicology.

[70]  P. Stanely Mainzen Prince,et al.  Protective Effects of Rutin on Mitochondrial Damage in Isoproterenol-Induced Cardiotoxic Rats: An In Vivo and In Vitro Study , 2010, Cardiovascular Toxicology.

[71]  Ajmal Ahmad,et al.  Rutin Protects Dopaminergic Neurons from Oxidative Stress in an Animal Model of Parkinson’s Disease , 2011, Neurotoxicity Research.

[72]  J. Trojanowski,et al.  Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration , 2008, The Journal of Neuroscience.

[73]  N. Kamalakkannan,et al.  Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues , 2006, Molecular and Cellular Biochemistry.

[74]  Chih-Min Huang,et al.  Lymphatic absorption of quercetin and rutin in rat and their pharmacokinetics in systemic plasma. , 2010, Journal of agricultural and food chemistry.

[75]  S. Sultana,et al.  Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFκB, TNF-α and caspase-3 expression in wistar rats. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[76]  L. Neckers,et al.  Metabolic and Pharmacological Properties of Rutin, a Dietary Quercetin Glycoside, for Treatment of Inflammatory Bowel Disease , 2005, Pharmaceutical Research.

[77]  M. Luczak,et al.  Influence of flavonoids on combined experimental infections with EMC virus and Staphylococcus aureus in mice. , 1989, Acta microbiologica Polonica.

[78]  S. Hendler,et al.  PDR for Nutritional Supplements , 2008 .

[79]  F. Hirayama,et al.  Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin , 2000, Pharmaceutical development and technology.

[80]  Ki Dong Park,et al.  In situ forming and rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing. , 2011, Biomacromolecules.

[81]  G. Wong,et al.  Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. , 1991, Carcinogenesis.

[82]  F. Jung,et al.  Leg oedema protection from a buckwheat herb tea in patients with chronic venous insufficiency: a single-centre, randomised, double-blind, placebo-controlled clinical trial , 1996, European Journal of Clinical Pharmacology.

[83]  Jiang‐Feng Yuan,et al.  In vitro antioxidant properties of rutin , 2008 .

[84]  R. Vishwakarma,et al.  Upregulation of Glut-4 and PPAR gamma by an isoflavone from Pterocarpus marsupium on L6 myotubes: a possible mechanism of action. , 2005, Journal of ethnopharmacology.

[85]  M. Semalty,et al.  Rutin-phospholipid complex: an innovative technique in novel drug delivery system- NDDS. , 2012, Current drug delivery.

[86]  Hyung-Ryong Kim,et al.  The protective effect of rutin against ischemia/reperfusion-associated hemodynamic alteration through antioxidant activity , 2012, Archives of Pharmacal Research.

[87]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[88]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. , 1996, Journal of pharmaceutical sciences.

[89]  D. Narayana,et al.  BIOFLAVONOIDS CLASSIFICATION, PHARMACOLOGICAL, BIOCHEMICAL EFFECTS AND THERAPEUTIC POTENTIAL , 2001 .

[90]  O. Aruoma,et al.  Chemopreventive actions of polyphenolic compounds in cancer , 2006, BioFactors.

[91]  M. Basha,et al.  Development of a novel vesicular system using a binary mixture of sorbitan monostearate and polyethylene glycol fatty acid esters for rectal delivery of rutin , 2013, Journal of liposome research.

[92]  T. Sakai,et al.  Effects of quercetin and/or restraint stress on formation of aberrant crypt foci induced by azoxymethane in rat colons. , 1997, Oncology.

[93]  J. Hook,et al.  An investigation into the supramolecular structure, solubility, stability and antioxidant activity of rutin/cyclodextrin inclusion complex. , 2013, Food chemistry.

[94]  Chan,et al.  2‐Hydroxypropyl‐β‐cyclodextrin increases aqueous solubility and photostability of all‐trans‐retinoic acid , 2000 .

[95]  C. Tagesson,et al.  Flavonoids as Phospholipase A2 Inhibitors: Importance of Their Structure for Selective Inhibition of Group II Phospholipase A2 , 1997, Inflammation.

[96]  L. Banjare.  Development of biocompatible nanoparticles for sustained topical delivery of Rutin , 2012 .

[97]  J. Papenbrock,et al.  Involvement of the Azotobacter vinelandii Rhodanese-Like Protein RhdA in the Glutathione Regeneration Pathway , 2012, PloS one.