Research Article HESPERIDIN AND DIOSMIN - A NOVEL
E-ISSN 2250-0944ISSN 2250-1150doi: 10.31838/ijprt/10.02.04Research ArticleHESPERIDIN AND DIOSMIN - A NOVEL DRUGSJAYDEEP ROY1, MOHAMMAD AZAMTHULLA1*, DHRUBOJYOTHI MUKKERJEE21Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences,MSR Nagar, Bangalore, India -5600542Department of Pharmaceutics, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences,MSR Nagar, Bangalore, India -560054*Author for CorrespondenceDr. Mohammad AzamthullaDepartment of Pharmacology, Faculty of Pharmacy, M.S. Ramaiah University of Applied Science, MSRNagar, MSRIT Post, Bangalore-560054, INDIAPhone: 91-080-23608942E-mail: mohammadazamthulla@gmail.comReceived: 01.09.19, Revised: 08.10.19, Accepted: 14.11.19ABSTRACT:Hesperidin, famously known as Vitamin P and Diosmin are the popular, abundant and inexpensive productsobtained from citrus agronomy. With no signs of toxicity, these flavonoids are largely consumed as a dietarysupplement and have a long history of medication. In various studies, conducted on Hesperidin & Diosmin havereported a number of protective potentials such as neuroprotective, cardio protective, hepato protective, antiinflammatory, antioxidant, lipid lowering, and insulin-sensitizing properties. Despite their enormous remedialpotential, the poor aqueous solubility and minimal bioavailability are some major curbs that restrict theutilization of Hesperidin and Diosmin in medical perception. Though, future of medicine belongs to synthesisand usage of nano-dimensioned materials by means of nanotechnology which has been revolutionising thedelivery of different constituents with much more precision oriented delivery to the target.This review highlights the in vivo and clinical studies to elucidate the therapeutic and pharmacologicalproperties of Hesperidin & Diosmin that have been reported since 2015, also displays the gaps in ourknowledge about both the compounds and the growing influence of nanotechnology to overcome thecharacteristic limitations which deserves more exploration.KEYWORDS: Flavonoids, Diosmin, Hesperidin, Nano formulationINTRODUCTIONSince ancient times, mankind have beenexploiting the natural resources for numerousmedicinal purposes. With the track of time, theinquisitiveness nature of men to explore themedicinal benefits of natural resources is beingincreased and now becoming a prime focus ofscientific research (1). Flavonoids are amongstthe class of naturally occurring phytoconstituents which are found in most of thecitrus plants, berries, green tea, black tea, redwine, cocoa, etc. Diosmin and Hesperidin arethe two citric fruit derived flavonoids marketedas dietary supplements also as a combinationfamously known as micronized purifiedflavonoid fraction (Daflon) which act on venoustone, lymphatic vessels, micro-circulation andtreats hemorrhoids. Numerous studies onDiosmin and Hesperidin have reported variouspharmacological activities. New findings haverevealed that Dios has anti-parkinsonismproperty and hesperidin has shown antiatherogenic and anti-inflammatory activity.Despite of continuous research transformationsand efforts aiming to vanquish the challengesof Hesperidin and Diosmin, the application ofnanoparticle formulations may act as a“panacea” which logically incorporated anexemplary model for treating a varied range ofchronic disorders with the application of Nanohesperidin/Diosmin through effective drugdelivery process. Numerous in vivo studies haveaddressed about the development of specificsite delivery of Hesperidin & Diosmin withbetter permeability, and increased biodistribution with significant efficient responses.Information’s were collected via electronicsearch by using Science Direct, PubMed,Nature and other internet sources.Hesperidin and DiosminDiosmin and Hesperidin are flavanoneglycosides majorly found in citrus fruits side,Hesperitin-7-rutinoside),C28H34O15 is a yellow to brown powder with amolecular weight of 610.56. It is insoluble inwater, shows solubility in pyridine, DMC,NaOH. Have a melting point from 250-255 Cshow a characteristic absorption spectrum at285nm (Fig.1). Diosmin is a bioflavonoid,25 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL flavone-7-rutinoside), C28H32O15 isyellow-brown to brown powder with amolecular weight of 608.54. Insolubility inwater, solubility in DMSO, NaOH like organicsolvents, melting point 274 C shows maximumabsorption at 268nm.Diosmin can be found in the plants Teucriumgnaphalodes, citrus, vetches, hyssop (2). It isbeen reported for numerous activities but ispopularly known to have neuroprotectiveactivity (3). Hesperidin is a flavanone glycoside,obtained in a large amount from the Rutaceaefamily, citrus plants like grapefruit, lemon,orange, tangerine, etc. even from various otherplant species such peppermint and welsh onion(4,5). Hesperidin has been reported fornumerous activities such as antioxidant, antiinflammatory, anti-viral, anti-carcinogenic andhas been reported to protect against DNAdamage, lipid peroxidation. In combinationwith other bioflavonoids like Diosmin, it ismarketed as Daflon-500mg (Servier) tabletswhichcontainmicronizedflavonoidshesperidin (50mg) and Diosmin (450mg) totreat lymphedema and are majorly used totreat blood vessel disorders such as varicoseveins, venous stasis, and hemorrhoids. In astudy using animal models, the combinationwas evaluated by for safety and toxicity studiesshowing good GIT acceptability of themicronized formulation with no genotoxicity, nodrug incompatibility or interaction (6).However, Maher and Sabir has investigated theeffect of the Diosmin and Hesperidincombination on hypercholesterolemia andhyperglycemia in patients with type 2 diabetesmellitus. Reporting reduction in glucose levelsand cholesterol levels with no adverse events,therefore, reducing the cardiovascular riskfactor in diabetic patients (7).Dietary intake of flavonoids; HES, DIOSBeing the secondary plant metabolites,flavonoids are not synthesized in the humanbody. Therefore they are consumed through thedietary sources including fruits (citrus fruits,grapes, pomegranates, berries, and apples),vegetables (broccoli, celery, onions, and leafygreens), soy products, legumes and beverages(red wine, tea) (8). The intake of the flavonoidsvaries greatly depending on the availability ofquality food and dietary habits of the consumerwith different preferences. On globalcomparison the intake of flavonoids in Asians ismorethanwesterns;EuropeansandAmericans. Diosmin and Hesperidin, are notbeen widely reported for any interactions withdrug or food substances. Dietary supplementsof both the compounds are present in themarket for treatment and prevention ofvascularsystem-relateddisordersandimprovement of cardiovascular health. Fewstudies have shown anti-microbial, antiinflammatory like activities but the mechanismof action for these activities are not beenrevealed. Some studies (Table 1 & 2) have alsoreported the compounds may have aneuroprotective & cardioprotective activitywhich can help to prevent neuro-degeneration& cardiac-related problems if these flavonoidsare included into daily supplementaryconsumption from childhood to the old ones(3).Table 1: Products of Diosmin and Hesperidin, available respectively alone in the marketSNo1LabellerBrand NameDosageActivity/ PurposeDulac FarmaceuticiDiosmin Expert-OmnivenlegsGel creamHeavy legs; varicoseveins2Dulac FarmaceuticiGel creamTreatment of piles34Dr MaxSwansonCapsulesCapsulesVascular systemCardiovascular health5Thorne ResearchDiosmin Exper- proctocomplexDiosminaHesperidin dietarysupplementHMC hesperidin 250mgCapsulesVascular system6Piping RockHesperidin 500mgCapsulesVascular systemTable 2: Products of Diosmin and Hesperidin combination available in the marketS No1LabellerServierBrand NameDaflon/ VenixxaDosageTabletsActivity/PurposeVaricose veins,HemorrhoidsMicrocirculation ofhemorrhoid plexus2Dulac FarmaceuticiDiosmin rdiovascular health4Purity productsHesperidin and DiosmincomplexCapsulesVascular system26 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGSLITERATURE STUDYFlavonoids have gained popularity due to theirbroad range of benefits, now different workshad been done on these two compoundsspecifically to evaluate their activity alone andwith nanoparticles. A list of tables below hadbeen put to summarize the important worksdone (Table 3 and 4).Table 3: Various biological activities reported for DiosminS. No.1.Reported byAhmedet al.,2016Research focusResults concluded by the authorsActivities concludedEvaluation ofdiosmin in causingdownregulation ofoxidative markersin alloxan-induceddiabeticnephropathy alongwith controlling theNF- kB signaltransductionpathwayHepatoprotectiveactivity diosminand sildenafilagainst cholestaticliver cirrhosis androle of Keap1/Nrf-2 and P38MAPK/NFκB/iNOS signalingpathwayneuroprotectiveand cognitiveimproving actionin traumatic braininjury (TBI) ratmodelOral administration of diosminshows normalization of the levelof NF- kB, showing role inmaintaining renal function, andelevation of malondialdehyde witha declination of glutathione, nitricoxideand,catalaseandsuperoxide dismutase. Concludinganti-hyperglycemia-mediatedoxidative stressAnti-oxidant,antiinflammatory,antidiabetic activity diosmin alone and with sildenafiland found combination therapy ismoreeffective.Combinationalleviates liver cirrhosis withupregulation of Nrf-2, GSH,SOD, eNOS, and cytoglobin anddownregulation of Keap-1, NFκB, P38-MAPK, MDA, and iNOS.Pretreatment with Diosmin hasrevealed protective effects againstmemory impairment due to (TBI).The protective action may be dueto a decrease in the TNF-αconcentration in the ydecreasingmyeloperoxidase, NF-κB, andTNF-αlevels.Alongwithaugmentation of IL-10 levels.Including suppression of oxidativestress and apoptosis by antioxidant and cytoprotective actionThe study provided evidence thatdiosmin produce anti-hyperalgesiceffects by acting centrally onopioid and D2 dopaminergicreceptors, and reduction incytokines levels shows peripheralactionAnti-oxidant property of diosmininhibiting cardiac mitochondrialoxidativestress/damageinmyocardial infarcted ratsHepatoprotective activity(10).The study showed a significantAnti-Alzheimer’s (15).2.Ali etal.,20183.Ali,FanaeiandKeikhaei,20174.Arab etal.,2015Anti-ulcer activityagainst ethanolinduced gastricinjury5.CarballoVillalobos etal.,2018Hyperalgesic effectcentrally andperipherally inneuropathic pain6.Queenthy,Mainzen lineinduced heartmitochondrialoxidative stressReduction of7.Neuroprotective(11).activityAnti-Ulcer activity (12).Anti-hyperalgesic (13).Cardioprotective activity(14).27 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGSer etal.,20168.Shalkami,HassanandBakr,20179.Christine et al.,201810. Shabani, 2018cerebral Aβ levels,tauhyperphosphorylation,neuroinflammation, and cognitiveimpairment inAlzheimerdiseased miceDiosmin againstacetic acidinduced ulcerativecolitisEvaluation of antiinflammatory andantiradical effects2% diosmin creamon human skinculture as a modelNeuroprotectiveactivity inscopolamineinduced cognitivedegradation/impairmentreduction of Alzheimer pathologyand cognitive impairment inAlzheimer induced and inhibitedAβ generation and microglialactivation along also inhibited APPγ-secretase and GSK-3βThe study revealed the significantelevationinmarkersofinflammation (TNF-α, COX-II &MPO)andoxidativestressrepresents the increase in coloncaspase-3expression.Aftertreatment with Diosmin, decreasedcolon damage index whencompared with acetic acid causeddamage index, and declination ininflammatory and oxidative stressmarkers were observed thereforereducingtheexpressionofcaspase-3Under the UV-B irradiation pyrimidineformationandhydrogen peroxide productionshowing the anti-radical effect anddecreased IL-8 release shows antiinflammatory effect.Scopolamine-inducedcognitiveimpairment and disruption ofsynaptic plasticity prevention bydiosmin. The decline in TNF-αconcentrationasaproinflammatory cytokine in thehippocampusAST - Alanine aminotransferase, ALT Aspartateaminotransferase,GSHGlutathione, CAT - Catalase, GPx Glutathione peroxidase, SOD - Superoxidedismutase, MDA - Malondialdehyde, TAC Total antioxidant capacity, IL6- Interleukin 6,Anti-inflammatory, antiapoptotic,anti-oxidant(16).Anti-inflammatory, antiradical (17).Neuroprotective(18).activityTNF-α - Tumor necrosis factor α, MPO Myeloperoxidase, NF-κB - Nuclear factorkappa light chain enhancer of activated B cells,MAPK – Mitogen Activated Protein Kinases andiNOS - Inducible nitric oxide synthaseTable 4: Various biological activities reported for HesperidinS No.1.2.Reported byAnsaret al.,2018Bhargava etal.,2019Research focusResults concluded by the authorsActivities concludedThestudyevaluatedantieffectbyhesperidin againstoxidativestressinduced by nanozinc oxide particlesStudy the agonisticaction peroxisomeproliferatoractivated receptorHesperidinmitigatedthebiomarker levels such as AST, ALT,and MDA, 88GSH, GPx, CAT,SOD which are opposite in nanozinc oxide induced hepatotoxicity.Hepatoprotective (19).Compared to the enalaprilHesperidincombination,Hesperidin and enalapril alonetreatment exhibited similar effects,Cardioprotective activity(20).28 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGSgamma (PPAR- rophysignaling pathwaysExaminedthehesperidinsupplement effecton inflammatorymarkers and bloodpressure in type 2diabetes patientsin a double-blindcontrolled clinicaltrialNeuroprotectiveeffect of hesperidinin learning andmemorydeficitmice3.Homayouni etal.,20184.HongandAn,20185.KosariNasabet al.,20186.Li etal.,20187.Li iquimodinduced psoriasisin mice model andhumankeratinocytes cells8.Liu gdepression-relatedsymptoms in micewith mild traumaticbrain injuryThe wound healingabilityofhesperidin g pathological changes,suppressing oxidative stress alongwithincreasingPPAR-γexpressionPatients were observed with asignificant difference in diastolic,mean arterial blood pressure,along with a decrease in TACserum and andantiinflammatory actionAnti-hypertensive, antiinflammatory (21).Hesperidin significantly reversedthe decreased phosphorylation ofGSK-3β, Akt, lessened Nrf2 andincreased expression of HO-1,phosphorylation of IκBα alongwith caused inhibition of RAGEexpression and NF κB/p65Depressive-like behaviors causeincreases inflammatory cytokinesand oxidative markers and reduceBNDF levels in the hippocampusregion. Hesperidin reversed sant(23).activitySignificant upregulation of mRNAexpressions in wound tissues suchas VEGF-c, Ang-1, Tie-2, TGF-βand Smad 2/3, also increasedSOD, GSH levels by hesperidin,which are downregulated bystreptozotocinImprovement in skin lesions ofimiquimod-induced mice edhumankeratinocytescellproliferation. In addition, it alsodecreased and normalized insulinand glucose levels, further foundto modulate the levels of leptin,adiponectin,andresistin.Inhibiting the initiation of the IRS1/ERK1/2 signaling pathwayHesperidin effectively inhibitedROS production due to highglucoseandalsoshowedscavenging activity by normalizingvarious biomarkers along withopposite effect on high glucoseinduced cell apoptosis pathwayvia caspase-9/3 upregulation,cytochrome c release into cytosols.Wound healing activity(24).Anti-dermatitis eticretinopathycausingvisual impairment (26).29 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGS9.Menget al.,201810. Poetiniet al.,2018Investigatedhesperidin's abilitytomodulateinflammatoryresponses, ttenuating actionagainstIroninduced anogaster asParkinson's diseasemodelSignificantly decreased levels ofTNF-α, IL-1β, CAT, SOD alongwith suppressed expression of Bcl2/Bax and elevated PPAR- γ inmice modelCardioprotective activity(27).It significantly decreased the ironlevels in the brain responsible forParkinson disease, along withscavenging of reactive species,improving motor function, andcholinergic activity in the fliesAnti-parkinsonis (28)AST - Alanine aminotransferase, ALT- Aspartateaminotransferase, GSH - Glutathione, CAT Catalase, GPx - Glutathione peroxidase, SOD Superoxidedismutase,MDAMalondialdehyde, TAC - Total antioxidantcapacity, IL6 - Interleukin 6, TNF-α - Tumornecrosis factor α, VEGF-c - Vascular EndothelialGrowth Factor C, Ang-1 - Angiopoietin 1, TGFβ - Transforming growth factor beta, GSK-3β -Glycogen synthase kinase 3 beta, Akt - alsoknown as Protein kinase B, Nrf2 - Nuclearfactor erythroid 2, IκBα - Inhibitor of kappa Bprotein alphaOther than animal studies, clinical studies arealso been done to evaluate their effects. Intable 5 and 6 Hesperidin and Diasmin clinicalstudies are reported (Table 5 and 6).Table 5: Status of recent and on-going clinical trials reported for Hesperidin for various diseasesS No1.2.3.StudyEffect of hesperidin on insulinsensitivityEffect of hesperidin on Bonemetabolism and Bonemineral density ofpostmenopausal womenvascular effect of hesperidinon metabolic syndromeSponsorUniversity ofMarylandNestléUniversity ofRome TorVergataStatusWithdrawnPhase2ConditionsInsulin entaccessorysaphenous veinsTable 6: Status of recent and on-going clinical trials reported for Diosmin for various diseasesS. No.1.2.3.4.StudyEffect of Detralex (Daflon)for anti-inflammatoryactivityEffect of Diosmin forinfertilites preventionEffect of Diosmin 600mgand Diosmin Hesperidinfor chronic venousinsufficiencyThe efficiency of Diosmin600mg for chronic venousdisease of lower pletedPhase4Completed2, 3FundaçãoEducacionalSerra cVenous diseaseof Lower Limb30 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGSNano-approach for Hesperidin & Diosminto enhance bioavailability for variousactivities:As both the compounds endow various kinds ofproperties such as anti-microbial, anti-viral,anti-inflammatory, anti-oxidant and antitumour effects as summarized in above tables.Hesperidin and Diosmin face GIT absorptionproblem due to low solubility in water, they areonly soluble in few organic solvents and thisresults in low bioavailability of the compoundsin the body. Numerous research groups arefocusing on how to improve the bioavailabilityand provide efficient targeted delivery withtransport stimulation.New approaches toproviding direct delivery into the cells includenano formulation like entrapment in diamondlike nanoparticles, phospholipid complex,cyclodextrin complex, etc. Various biologicalactivities reported for Diosmin and Hesperidinand application of nanoparticles and showedin table 7.Table 7: Various biological activities reported for Diosmin and Hesperidin and application ofnanoparticlesS. No.Reported byResearch focusResults concluded by the Activitiesauthorsconcluded1.Corciova etEvaluationof agar diffusion method was Antioxidant, antial., 2015antibacterialand usedtoculture bacterial (29).antioxidant activity of StaphylococcusHesperidin:βaureus ATCCcyclodextrin25923, EscherichiacomplexescoliATCC25922and Candida albicans ATCC 10231, the complexshowed antibacterial activity.Inhibition of lipoxygenaseactivity,DPPHradicalscavenging activity showedantioxidant activity2.Sahu et al.,SynthesizingAg using human promyelocytic Antibacterial,2016nanoparticlesfor leukemia(HL-60)cells cytotoxicity (30)flavonoids:investigated cytotoxicity andhesperidin, diosmin, bacterial effect concludingandnaringinto Agnanoparticlesfromevaluate antibacterial flavonoids showed goodand cytotoxicity effect stability, better antibacterial,and cytotoxic activity3.(Thomas et Mechanismof The complex formation of Anti-canceral., 2019)interactionof Diosmin-AuNps with ctDNA, activity (31)Diosmin and gold through MTT assay, revealednanoparticleswith toxicity and anti-proliferativecalf thymus DNAeffect on normal human celllines and MCF-7(Mary et al., 2017) formulated a chitosanbased nanoformulation for hesperidin toovercome its water insolubility, aimed topassively target cancer cells (32). Chitosanbased hesperidin nano-formulation enhanceshesperidin induced apoptosis of HCT15 cellsexposing it be a likely candidate to treatcolorectal cancer. Another β-Cyclodextrinbased nanocomplexes of hesperidin wasformulated by (Corciova et al., 2015),demonstrated the enhancement in thesolubility, anti-bacterial and antioxidantactivities of hesperidin (29).Conclusion and future perspectiveDiosmin and Hesperidin are among the classof flavonoids gaining popularity globallybecause of their potential health benefits inminimizing neurodegenerative signs, bloodvessels inflammation, microbial, improvingcardiovascular health and effective antioxidant,and influencing immunomodulation activities.Either alone or in combination, they are able tomodulate the activities of various targets whichplay a pivotal role to produce a biological andtherapeutic action, where they are alsodepended on their physiochemical andstructural properties.31 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGS1.2.3.4.5.Both the compounds show poor solubility,absorption, and distribution which are themajor setbacks to produce any therapeuticactivity and Nanotechnology plays a vital rolehere. The reasons for these could be theirmolecular weight, solubility, structure, pHsensitivity etc. at present scenario themicronization of their combination (Daflon500mg) have helped in improving its solubilityand GIT absorption. Interestingly, recent studieshaveproposedtheapplicationofnanotechnology can improve the solubility,bioavailability, pharmacokinetics, targetedtreatment, and their therapeutic action.Nanotechnology has already achieved manymilestones in the bio and medical field andhelping to explore more new and better ways totreat and prevent modern day diseases.Nanotechnology application is modifying theway of delivering active compounds in lessamount but more efficiently, prolongingcirculation & bioavailability, drug exposure tothe specific target, and minimizing multidrugresistance. The nano formulations of thesecompoundscanbeadministeredintraperitoneally, intranasal, or intravenoustherefore, improving the way of treatment andpreventionofCVD,neurodegenerativedisorders, bacterial, viral and several otherdiseases. Therefore, this review suggests morestudies on both the compounds with nanoapproach to explore its new findings.6.ACKNOWLEDGEMENTSAuthors thanks Dean Dr. V. Madhavan, ofPharmacy,Ramaiah University of Applied Science,Bangalore, and Karnataka, India.13.REFERENCESPetrovska, B., 2012. Historical review of medicinalplants usage. Phcog Rev, 6(11), pp.15-17.Marin, F., Ortuño, A., Benavente-Garcia, O., DelRio, J.A., 1998. Distribution of Flavone GlycosideDiosmin in Hyssopus fficinalis Plants: ChangesDuring Growth. Planta Med, 64(2), pp.181-182.Nabo, W.E.E., Oluwadamilola, O.A., Oyetunde,T.O., 2018. Cardioprotective Effects of CurcuminNisin Based Poly Lactic Acid Nanoparticle onMyocardial Infarction in Guinea Pigs. Sci Rep, 8,pp.16649.Areias, F.M., Valento, P., Andrade, P.B., Ferreres,F., Seabra, R.M., 2001. Phenolic fingerprint ofpeppermint leaves. Food Chemistry, 73(3),pp.307–311.Ren, H., Endo, H., Hayashi, T., 2001. Antioxidativeand antimutagenic activities and polyphenolcontent of pesticide-free and organically cultivatedgreen vegetables using water-soluble chitosan as asoil modifier and leaf surface spray. J Sci FoodAgric, 81(15), , O.C., 1997. Angiology Safety and Securityof Daflon 500 mg in Venous Insufficiency and inHemorrhoidal Disease. Angiology, 45(6), pp.579 584.Maher, S., Sabri, N.A., 2009. Evaluation of clinicalactivity and safety of Daflon 500 mg in type 2diabetic female patients. Saudi Pharm J, 17(3),pp.199–207.Manach, C., Scalbert, A., Morand, C., Remesy, C.,Jimenez LRemesy, C., 2018. Polyphenols: foodsources and bioavailability. Am J Clin Nutr, 79(5),pp. 727–747.Ahmed, S., Mundhe, N., Borgohain, M.,Chowdhury, L., Kwatra, M., Bolshette, N., Lahkar,M., 2016. Diosmin Modulates the NF-kB SignalTransduction Pathways and Downregulation ofVarious Oxidative Stress Markers in AlloxanInduced Diabetic Nephropathy. Mediat Inflamm,39(5), pp. 1783–1797.Ali, F.E.M., Azouz, A.A., Bakr, A.G., ective effects of diosmin and/orsildenafil against cholestatic liver cirrhosis: Therole of Keap-1/Nrf-2 and P 38 -MAPK/NFκB/iNOS signaling pathway. Food Chem Toxicol,120, pp. 294–304.Mirshekar, M.A., Fanaei, H., Keikhaei, F., Javan, F.S.,2017. Diosmin improved cognitive deficit andamplified brain electrical activity in the rat modelof traumatic brain injuryBiomed Pharmacother, 93,pp. 1220–1229.Arab, H.H., Salama, S.A., Omar, H.A., Arafa, E.S.A.,Maghrabi, I.A., 2015. Diosmin Protects againstEthanol-Induced Gastric Injury in Rats: Novel AntiUlcer Actions. Plos One, 10(3), pp. 1–21.Carballo-Villalobos, AI., González-Trujano, M.E.,Pellicer, F., Alvarado-Vásquez, N., López-Muñoz,F.J., 2018. Central and peripheral anti-hyperalgesiceffects of diosmin in a neuropathic pain model inrats. Biomed Pharmacother, 97, pp. 310–320.Sharmila Queenthy, S., Stanely Mainzen Prince, P.,John, B., 2017. Diosmin Prevents IsoproterenolInduced Heart Mitochondrial Oxidative Stress inRats. Cardiovascular Toxicology, 18(2), pp. 120–130.Sawmiller, D., Habib, A., Li, S., Darlington, D., Hou,H., Tian, J., Tan, J., 2016. Diosmin reduces lammation, and cognitive impairment inthe 3xTg-AD mice. J Neuroimmunol, 299, pp. 98–106.Shalkami, A.S., Hassan, M.I.A., Bakr, A.G., 2017.Anti-apoptotic activity of diosmin in acetic acidinduced ulcerative colitis. Hum Exp Toxicol, 37(1),pp. 78–86.Christine M Boisnic S., Branchet, M.C., GouhierKodas, C., Verriere, F., Jabbour, V., 2018. Antiinflammatory and antiradical effects of a 2%diosmin cream in a human skin organ culture asmodel. J Cosmet Dermatol, 10, pp. 1–7Shaban, H.A., Barth, R., Bystricky, K., 2018.Formation of correlated chromatin domains atnanoscale dynamic resolution during transcription.Nucleic Acids Res, 46(13), pp. 71–77.32 International Journal of Pharmacy Research & Technology July - Dec 2020 Vol 10 Issue 2
Jaydeep Roy et al / HESPERIDIN AND DIOSMIN - A NOVEL DRUGS19. Ansar, S., Abudawood, M., Alaraj, A.S.A., Hamed,S.S., 2018. Hesperidin alleviates zinc oxidenanoparticle induced hepatotoxicity and oxidativestress. BMC Pharmacol Toxicol, 9(1), pp. 1-6.20. Bhargava, P., Verma,V.K., Malik, S., Khan, S.I.,Bhatia, J., Arya, D.S., 2018. Hesperidin regressescardiac hypertrophy by virtue of PPAR-γ agonistic,anti-inflammatory, antiapoptotic, and antioxidantproperties. J Biochem Mol Toxicol, 12, pp. 1-9.21. Homayouni, F., Haidari, F., Hedayati, M., Zakerkish,M., Ahmadi, K., 2018. Blood pressure lowering andanti-inflammatory effects of hesperidin in type 2diabetes; a randomized double-blind controlledclinical trial. Phytother Res, 32(6), pp. 1073–1079.22. Hong, Y., An Z Hong, Y., An, Z., 2018. Hesperidinattenuates learning and memory deficits inAPP/PS1 mice through activation of Akt/Nrf2signaling and inhibition of RAGE/NF-κB signaling.Arch. Pharm. Res, 41(6), pp. 655–663.23. Kosari-Nasab, M., Shokouhi, G., Ghorbanihaghjo,A., Abbasi, M.M., Salari, A.A., 2018. Hesperidinattenuates depression-related symptoms in micewith mild traumatic brain injury. Life Sci, 213, pp.198–205.24. Li, W., Kandhare, A.D., Mukherjee, A.A.,Bodhankar, S.L.,2018. Hesperidin, a Plant FlavonoidAccelerated the Cutaneous Wound Healing inStreptozotocin-Induced Diabetic Rats: Role of TgfB/Smads and Ang-1/Tie2 Signaling Pathways. ExcliJournal, 17, pp. 399 - 419.25. Li, X., Xie, X., Zhang, L., Meng, Y., Li,N., Wang, M.,Li, P., 2019. Hesperidin inhibits keratinocyteproliferation and imiquimod-induced psoriasis-likedermatitis via the IRS-1/ERK1/2 pathway. Life Sci,5(219), pp. 311-321.26. Liu, W.Y., Liou, S.S., Hong, T.Y., Liu, I.M., 2018.Hesperidin Prevents High Glucose-InducedDamage of Retinal Pigment Epithelial Cells, PlantaMed, 84(14), pp. 1030–1037.27. Meng, C., Guo, Z., Li, D., Li, H., He, J., Wen, D.,Luo, B., 2018. Preventive effect of hesperidinmodulates inflammatory responses and antioxidantstatus following acute myocardial infarctionthrough the expression of PPAR‑γ and Bcl‑2 inmodel mice. Mol Med Rep, 17(1), pp. 1261–1268.28. Poetini, M.R., Araujo,
veins, venous stasis, and hemorrhoids. In a study using animal models, the combination was evaluated by for safety and toxicity studies showing good GIT acceptability of the micronized formulation with no genotoxicity, no drug incompatibility or inter
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