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Metformin:Currentknowledge

Metformin: Current knowledge

Hamid Nasri and Mahmoud Rafieian-Kopaei

Abstract
Diabetesmellitusisagroupofmetabolicdisordersinwhichthebloodglucoseishigherthannormallevels,duetoinsufficiencyof
insulinreleaseorimproperresponseofcellstoinsulin,resultinginhighbloodpressure.Theresultanthyperglycemiaproducessever
complications.Metformindrughasbeenshowntopreventdiabetesinpeoplewhoareathighriskanddecreasemostofthediabetic
complications.Recentreportsonmetformin,notonlyindicatesomeimplicationssuchasrenoprotectivepropertieshavebeen
suggestedformetformin,butsomereportsindicateitsadverseeffectsaswellthatarenegligiblewhenitsbenefitsarebroughtinto
account.Weaimedheretoreviewthenewimplicationsofmetforminanddiscussabouttheconcernsintheuseofmetformin,
referringtotherecentlypublishedpapers.
Keywords:Diabetes,diabetesmellitus,diabeticnephropathy,glucose,metformin,newapplications,polycysticovarysyndrome,

renoprotection

INTRODUCTION
Diabetesmellitusisagroupofmetabolicdisordersinwhichthebloodglucoseishigherthannormallevels,duetoinsufficiencyof
insulinreleaseorimproperresponseofcellstoinsulin,resultinginhighbloodpressure.Theresultanthyperglycemiaproducesthe
classicalsymptomsofpolyuria,polydipsiaandpolyphagia.Itmayalsocausenerveproblems,kidneyproblems,andblindness,lossof
limbs,andsexualdysfunction,increaseinheartattackorstroke.[1]Metformin(abiguanidederivative),bycontrollingbloodglucose
leveldecreasesthesecomplications.Metforminworksbyhelpingtorestorethebody'sresponsetoinsulin.Itdecreasestheamountof
bloodsugarthattheliverproducesandthattheintestinesorstomachabsorb.[2]Metformin,otherthanhypoglycemicactivity,has
beentakenwithdietandexercisechangestopreventdiabetesinpeoplewhoareathighriskforbecomingdiabetic.Itisalsousedin
womenwithpolycysticovariansyndrome.Metforminmaymakemenstrualcyclesmoreregularandincreasefertility.[3]Metformin
wasfirstsynthesizedandfoundtodecreasethebloodglucoselevelinthe1920showever,itwasnotusedforalongtime.Theuseof
metforminwasrekindledin1957,whentheresultsofaclinicaltrialwerepublishedconfirmingitseffectondiabetes.Metforminis
nowwidelyprescribedasanantidiabeticdrughowever,therehavebeenseriousconcernsaboutitsadverseeffects,especially
ketoacidosis.[4]Recently,notonlysomeimplicationshavebeendiscoveredformetformin,butalsotherearereportsindicatingthat
itsadverseeffectsarenegligiblewhenitsbenefitsarebroughtintoaccount.[3]Theoretically,itsusehasbeenprohibitedinalarge
groupofpatientswithtype2diabetesmellitusduetotheriskoflacticacidosis.However,ithasbeenshownthatseveraldiabetic
patientswhoareconsideredtobeatriskhavereceivedmetforminwithnoincreasedriskoflacticacidosis.[2,3,4,5]Furthermore,
recentlysomepapershavebeenpublishedindicatingrenoprotectivepropertiesformetformin.Weaimedheretoreviewthenew
implicationsofmetforminanddiscussabouttheconcernsintheuseofmetformin,referringtotherecentlypublishedpapers.

NEW AND OLD IMPLICATIONS AND THE MECHANISMS OF ACTION

Diabetes mellitus
Metforminisprimarilyusedforthetreatmentoftype2diabetesmellitus,particularlyinobese.patients.Metforminhasbeenshownto
reducediabetesmortalityandcomplicationsbythirtypercentcomparedtoinsulin,glibenclamideandchlorpropamide.[5]
Metforminreducesserumglucoselevelbyseveraldifferentmechanisms,notablythroughnonpancreaticmechanismswithout
increasinginsulinsecretion.Itincreasestheeffectsofinsulinhence,itistermedinsulinsensitizer.Metforminalsosuppressesthe
endogenousglucoseproductionbytheliver,whichismainlyduetoareductionintherateofgluconeogenesisandasmalleffecton
glycogenolysis.Moreover,metforminactivatestheenzymeadenosinemonophosphatekinase(AMPK)resultingintheinhibitionof
keyenzymesinvolvedingluconeogenesisandglycogensynthesisintheliverwhilestimulatinginsulinsignalingandglucosetransport
inmuscles.AMPKregulatesthecellularandorganmetabolismandanydecreaseinhepaticenergy,leadstotheactivationofAMPK.
Thisstudytoanextenthasputforthtoexplainthemechanismofmetforminactiononlivergluconeogenesis.[6,7]
Furthermore,metforminincreasestheperipheralglucosedisposalthatariseslargelythroughincreasednonoxidativeglucosedisposal

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intoskeletalmuscle.Itusuallydoesnotcausehypoglycemiaandthiscausetobeconsideredasauniqueantidiabeticdrug.[8]
Treatmentofdiabeteswithmetforminisassociatedwithlessweightgaincomparedwithinsulinandsulfonylureas.Weightgainhelps
inbetterglucosecontrol.Inastudyitwasshownthat,overa10yeartreatmentperiod,thepatientstreatedwithmetformingained
aboutonekg,thepatientstreatedwithglibenclamidegainedaboutthreekg,andthepatientstreatedwiththeinsulingainedsixkg
weight.[9]

Pre-diabetes
Thechanceofdevelopingtype2diabetesmellitusmaydecreaseinpeopleatriskforthisdiseasehowever,dietingandintensive
physicalexercisemayworksignificantlybetterforthispurpose.InalargestudyintheUnitedStates,participantsweregiven
placebo,lifestyleinterventionormetformin,andfollowedforthreeyears.Thelifestylemodificationsincludeda16lessontraining
onexerciseanddietingfollowedbymonthlysessionsforindividualswiththeaimofdecreasingthebodyweightby7%.These
patientsunderthisgroupwereengagedinaphysicalactivityforabout150minutes/week.Theincidenceofdiabetesmellitusinthis
groupwasby58%,andinmetformingroupby31%.Aftertenyears,theincidenceofthediseasewaslowerby34%inthepatientson
dietandexerciseand18%inthemetformingroup.[10]

Gestational diabetes
Severaltrialshavesuggestedthatmetforminisassafeandeffectiveasinsulinforthetreatmentofgestationaldiabetes,[11]andit
hasbeensuggestedthatthemotherswhohaveusedmetformininsteadofinsulinmightbehealthierintheneonatalperiod.[12]
However,evidenceisstilllackingonthelongtermsafetyofmetforminforbothchildrenandmothers.[13]

Polycystic ovary syndrome

Polycysticovarysyndrome(PCOS)isfrequentlyassociatedwithresistancetoinsulinandsince1994,metforminhasbeenproposedas
atreatmentforPCOS.[14]In2004,NationalInstituteforHealthandClinicalExcellencerecommendedtoprescribemetforminfor
womenwithPCOSandabodymassindexabove25foranovulationandinfertilitywhenothertherapieshavefailedtoproduce
acceptableresults.[15]However,severalsubsequentreviewsdidnotshowpromisingresultsanddidnotrecommenditfurtherorat
leastasafirstlinemedication,[16]exceptforwomenwithglucoseintolerance.[17]Theguidelinesusuallysuggestclomiphenetobe
thefirsttreatmentandrecommendlifestylemodificationindependentfromdrugtherapy.
Asystematicreviewusingcomparativetrialsofclomipheneandmetforminfoundequalresultsforinfertility[18]andABMJ
editorialsuggestedthatmetforminshouldbeusedasasecondchoice,ifclomiphenetreatmentfails.[19]Furthermore,alargereview
using27clinicaltrialsfoundthatmetforminwasnotassociatedwithanyincreaseinthenumberoflivebirthshowever,itimproved
ovulationrates,especiallywhenitwasusedincombinationwithclomiphene.[20]
Further,areviewrecommendedmetforminasafirstchoicebecauseofpositiveeffectsoninsulinresistance,hirsutism,anovulation
andobesity,whichareoftenassociatedwithpolycysticovarysyndrome.[21]
Thedifferenttrialdesignsmightbethereasonsforthecontradictoryresults.Forexample,consideringlivebirthrateinsteadof
pregnancyastheendpointmighthavebiasedafewtrialsagainstmetformin.[22]Anotherexplanationisthatmetforminmayhave
differentefficacyindifferentpopulations.

Cancer protection
Alargecasecontrolstudyhassuggestedthatmetforminmightprotectpatientsagainstpancreaticcancer.Inthisstudy,theriskof
pancreaticcancerinmetformingroupwas62%lowerthaninplacebogroupwhodidnotusemetformin.Theparticipantshaving
sulfonylureasorinsulinwerefoundtohavea2.5foldand5foldhigherriskofpancreaticcancer,respectively,incomparisonto
placebogroup.[23]Severalstudieshavesuggestedthatdiabeticpatientsusingmetforminmightlowertheriskofcancercomparedto
thoseusingotherantidiabeticdrugs.[24,25]However,theresultsneedconfirmationincontrolledtrials.[26]
Metforminhasshownastrongantiproliferativeeffectsoncolon,pancreatic,breast,ovarian,prostateandlungcancercells.
Preclinicalstudieshavealsoshownreliableantitumoraleffectsindifferentanimalmodels.Aclinicaltrialhasdemonstrated
beneficialeffectincolonandbreastcancers.[27]

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Themechanismofthisactionisnotclear.Otherantidiabeticdrugshavenotshownthesameanticanceractivitieshence,the
anticancereffectofmetforminshouldnotberelatedtoantidiabeticactivityofthisdrug.Metforminpossessesantioxidantactivity.
[28]Antioxidantshavebeenshowntohavevariousbeneficialeffectssuchasanticancer,[29,30,31,32]antidiabetes[33]and
antiatherosclerosis[34,35]properties.Therefore,somebeneficialeffectsofmetforminmightberelatedtoitsantioxidantactivity.

HIV-associated diabetes
TheuseofsomeofantiretroviraldrugsinHIVinfectionhasbeenassociatedwithglucosetolerance,insulinresistance,
hyperinsulinemiaandtype2diabetesmellitus.LowHDL,Hypertriglyceridemiaandhighriskofcardiovasculardiseaseshavebeen
reportedinthesepatients.Thesemetabolicalterationsarefrequentlyassociatedwithlossofsubcutaneousfatandincreasedvisceral
fat.[36,37]
Antiretroviraltherapieswithproteaseinhibitorsinhibitglucosetransporter(GLUT)4mediatedglucosetransport.[38]Theyare
likelytobe,inpart,responsiblefortheinsulinresistanceandbodycompositionchangesinHIVinfectedpatients.Metforminhas
beenshowntoreducevisceraladiposityandinsulinresistanceafter8weeksofdrugtherapyatdoseof850mg,3timesperday.[39]

Nephrotoxicity prevention
Recentstudieshavesuggestedthatmetforminmayhavetherapeuticorrenoprotectiveeffectsagainstnephrotoxicagents.[40,41]It
hasalsobeenshowntohaveagoodefficacyindiabeticnephropathy.[40,41,42,43,44]Furthermore,itsignificantlydecreases
albuminuriainpatientswithdiabetesmellitus.[41,42,43,44]However,theexactmechanismbeyondtheseeffectsisstillunknown.
Recentstudieshaveshownthattherapeuticeffectofmetforminismediatedthroughitsactiononadenosinemonophosphate(AMP)
activatedkinaseintissues.[43,44,45,46,47,48]Variousstudieshaveshownthatmetforminiscapableofdecreasingintracellular
reactiveoxygenspecies(ROS).[45,46,47,48,49]Itprotectstubularinjurythroughregulationofoxidativestressandrestoringthe
biochemicalalterationsonrenaltubules.Metforminmayalsoprotectthepodocytesindiabeticnephropathy.[47,48,49,50,51]
VariousstudieshaveshownthatAMPKactivationofmetforminissecondarytoitseffectonthemitochondriaastheprimarytarget.
[52]Recentstudieshavedemonstratedadirectormediatedmitochondrialeffectformetformin.[53]Whenmetforminisusedalone,
itsbeneficialeffectisduetothemildinhibitionofthemitochondrialrespiration.[54,55]
Theeffectofmitochondriainprogrammedcelldeathisusuallyassociatedwiththereleaseofapoptoticsignalingmolecules.[56]
Moreover,ROSproductionbymitochondriamayalsoleadtocelldegradation.[57]
MitochondriarepresentsasoneofthemajorcellularsourcesofROSgeneration,[50]andagreatnumberoftissuepathologies,which
induceoxidativestress.[58,59]Thesefindingsmayshowthecriticalroleofmitochondriaintheseconditions.[58,59]
ThenephrotoxicityofaminoglycosidesandmostofotherrenotoxicagentshasbeenattributedtoROS.[60]Incertainconditions,
intracellularROSmayreachatoxiclevel,resultinginoxidativedamageandmalfunctioningoftheorgan.[54]
WeconductedastudyonmaleWistarratstotestthepotentialpropertiesofmetformininprotectingthekidneyfromgentamicin
inducedacuterenalfailure,andtofindoutbypostponingthetreatmentwithmetformininacuterenalfailureexertssimilarbenefits
asongentamicinnephrotoxicityinrats.[61]Metforminnotonlyhadpreventiveeffectbutalsoexertedameliorativeactivityagainst
gentamicinnephrotoxicity.Hence,itmightbebeneficialinpatientsundertreatmentwiththisdrug.[49]
Metforminhasalsoshowntohavebeneficialeffectonrenalfunctionandstructureafterunilateralischemiareperfusioninrats.[62]
Theauthorsinthisstudyhaveconcludedthatmetforminhastissueprotectionwiththeactivationofendothelialnitricoxidesynthase
andAMPK.[61]
VariousstudieshaveshownthatROSoverproductionmightbethekeystartingevents,whichcausedevelopmentofcomplicationsof
diabetes.[63]However,theexactmechanismsthatcausehyperglycemiaanddiabeticnephropathyarenotelucidated.[64]Ithasbeen
shownthatnucleicacidscanbeaffectedbyoxidativestress,therebymodifyingthebasesinDNA.WhenDNAisdamagedthe
affectedcellsstartaresponsesuchascellcycledelay,DNArepairorapoptosisinduction.ROSgenerationbyoxidativestresscauses
celldeath.[65]Apoptosisisimplicatedinthepathogenesisofdiabeticnephropathy.ROSisaninducerofapoptosisinvariouscell
typesincludingpodocytes.[66]
Metforminisabletorestorethepodocytesindiabeticratsanddiabetesinducedpodocytelossindiabeticnephropathyhasbeen
attenuatedtoROS.[67]Podocyteapoptosisisassociatedwithincreasedalbuminuria.PhosphorylationofAMPKisreducedinthe
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kidneyofdiabeticrats.Therefore,metforminmayexertsomeofitseffectsbyimprovingtherenaloxidativestress.[67]These
findingsareinagreementwithotherstudiesshowingbeneficialantioxidantpropertiesofmetforminindiabeticrats.[68]
Thesefindingsmayencouragetheclinicaluseofmetforminalongwithnephrotoxicdrugsaswellasforpreventionofdiabetic
nephropathy.

Side effects
Metforminhasnotsignificantadverseeffectshowever,itmaycauseaseriousconditioncalledlacticacidosiswiththefollowing
symptoms:Dizziness,severedrowsiness,musclepain,tiredness,chills,blue/coldskin,fast/difficultbreathing,slow/irregular
heartbeat,stomachpainwithdiarrhea,nauseaorvomiting.[1,41,43,69]
Lacticacidosisusuallyoccursduetodrugoverdoseorinsomecontraindicatedconditions.Itismorelikelytooccurinpatientswith
certainmedicalconditions,includingaseriousinfection,liverorkidneydisease,recentsurgery,anyconditionsthatcausealowlevel
ofoxygeninthebloodorpoorcirculation(suchasrecentstroke,congestiveheartfailure,recentheartattack),heavyalcoholuse,
dehydration,Xrayorscanningproceduresthatrequireaninjectableiodinatedcontrastdrugandthoseolderthan80years.
[1,41,43,70]
Nausea,vomiting,stomachupset,diarrhea,weakness,orametallictasteinthemouthmayoccur.
Metforminusuallydoesnotcausehypoglycemiahowever,lowbloodsugarmayoccurifthisdrugisusedwithotherantidiabetic
drugs.Hypoglycemiaismorelikelytooccurwithheavyexercise,drinkinglargeamountsofalcohol,ornotconsumingenough
caloriesfromfood.
Symptomsofhyperglycemiaincludepolydipsia,polyuria,rapidbreathing,flushing,confusion,drowsiness,andfruitybreathodor.
[1,41,43,71,72]
Seriousallergicreactiontothisdrugisrarehowever,thisproductmaycontaininactiveingredients,whichcancauseallergic
reactionsorotherproblems.Highfever,diarrhea,vomiting,diureticsorexcesssweatingmaycausedehydrationandincreasetherisk
oflacticacidosis.Olderadultsmaybeatgreaterriskforsideeffectssuchaslowbloodsugarorlacticacidosis.[1,41,43,62,71]
Gastrointestinalintoleranceisoneofthemostfrequentlyoccurredandlacticacidosisisarare,butcausesseriousadverseeffects.
[73,74]Incidenceofmyocardialinfarction(MI)isalsoanimportanteventbutseenlessinmetformincomparedwithsulfonylurea
agents.[75]Metformininducedlacticacidosisisararebutimportantandfataladverseevent.
Apopulationbasedstudydemonstratedthataboutonefourthofpatientsprescribedmetforminhadcontraindicationstoitsuse.
However,contraindicationsrarelyresultedindiscontinuationofmetforminusage.[76]Thesedatahavebeenconfirmedbyseveral
otherstudiesindifferentcountries.[77,78]
Furthermore,inarecentreviewarticle,basedon347observationalcohortstudiesandprospectivecomparativetrials,noevidence
indicatingmetformintobeassociatedwithincreasedlevelsoflactateorincreasedriskoflacticacidosisincomparisontoother
antihyperglycaemicdrugshasbeenreported.
[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,
52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]Itshouldbenotedthatinthisreport,allclinical
trialsexcludedtheriskpatients.Therefore,thescenariomightberatherdifferent,inrealpopulation.
Inastudysampleof19,691type2diabetesmellitus(DM),patientswithestablishedatherothrombosisparticipatinginstudy,thetwo
yearmortalityratewassignificantlylessinpatientstreatedwithmetformincomparedwiththepatientsnottreatedwithmetformin.
[80,81]
Therefore,itmightbenecessarytoreconsiderthelistofcontraindicationsintheuseofmetformin.
However,consideringthehighprevalenceofstablerenalimpairment,congestiveheartfailureand/orcoronaryarterydiseasein
elderlypatients,thebenefitriskbalanceofmetformintreatmentareofparticularimportantandmorevaluabledataespecially
relevanttotheelderlypopulationarestillrequired.Inthisregard,benefitriskratiosareneededwithoutdeprivationofpatientsat
risk.

METFORMIN DURING PREGNANCY AND LACTATION

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Ithasbeenshownthatpregnancymayalterthefunctionofdrugmetabolizingenzymesanddrugtransportersinagestationalstage.
TheactivitiesofseveralhepaticcytochromeP450enzymessuchasCYP2D6andCYP3A4areincreased,whereastheactivityof
someothers,suchasCYP1A2,maybedecreased.Theactivitiesofsomerenaltransporters,includingorganiccationtransporterand
Pglycoproteinincreaseduringpregnancy.However,significantgapsstillexistinourunderstandingofthespectrumofdrug
metabolismandtransportgenesaffected,gestationalagedependentchangesintheactivityofencodeddrugmetabolizingand
transportingprocesses,andthemechanismsofpregnancyinducedalterations.[52,82]
Thepharmacokineticsofmetforminisalsoaffectedbypregnancy,whichisrelatedtothechangesinrenalfiltrationandnettubular
transport,whichcanbeestimatedroughlybytheuseofcreatinineclearance.Atthetimeofdelivery,thefetusisexposedtovariable
concentrationsofmetforminfromnegligibletoashighasmaternalconcentrations.However,infantexposuretometforminthrough
thebreastmilkislow.[83]
Metforminappearstobeeffectiveandsafeforthetreatmentofgestationaldiabetesmellitus,particularlyforoverweightorobese
women.Ithasbeensuggestedthatmetforminissafeduringpregnancy.However,asmetformincrossestheplacenta,itsuseduring
pregnancyraisesconcernsregardingpotentialadverseeffectsonthemotherandfetus.Furthermore,patientswithmultiplerisk
factorsforinsulinresistancemaynotmeettheirtreatmentgoalswithmetforminaloneandmayrequiresupplementarydrugssuchas
insulin.However,therearepotentialadvantagesfortheuseofmetforminoverinsuliningestationaldiabetesmellituswithrespectto
maternalweightgainandneonataloutcomes.Furthermore,theuseofmetforminthroughoutpregnancyinwomenwithpolycystic
ovarysyndromedecreasestheratesofearlypregnancylossandpretermlaborhenceprotectingagainstfetalgrowthrestriction.
Therehavebeennodemonstrableteratogeniceffects,intrauterinedeathsordevelopmentaldelayswiththeuseofmetformin.
Therefore,theevidencesupportstheefficacyandsafetyofmetforminduringpregnancywithrespecttoimmediatepregnancy
outcomes.However,becausetherearenoguidelinesforthecontinuoususeofmetformininpregnancy,thedurationoftreatmentis
basedonclinicaljudgmentandexperienceonacasebycasebasis.[84,85,86,87,88,89]Recently,theEndocrinSocietyhasnotonly
confirmedtheuseofmetforminduringpregnancybutalsohasrecommendeditasafirstlinetreatmentofcutaneousmanifestations,
forpreventionofpregnancycomplications,orforthetreatmentofobesity.[85,86]Itshouldbenotedthatnotallreferencesallowthe
useofmetformininthefirsttrimesterofpregnancy.[90]Therefore,itissuggestedthatmetformintherapybeusedforglycemic
controlonlyforthosewomenwithgestationaldiabeteswhodonothavesatisfactoryglycemiccontroldespitemedicalnutrition
therapyandwhorefuseorcannotuseinsulinorglyburideinthefirsttrimester.

CONCLUSION
Metforminisanoralantidiabeticdruginthebiguanideclassforthetreatmentoftype2diabetesmellitus,inparticular,in
overweightandobesepeopleandthosewithnormalkidneyfunction.
Metforminhasseveralbenefitsinpatientswithtype2diabetesmellitus,includingdecreasedhyperinsulinemia,weightreduction,
augmentedfibrinolysis,improvedlipidprofilesandenhancedendothelialfunction.
Althoughtheuseofmetforminindiabeteshasitssafetyconcerns,itsbenefitsandtherecentresultsindicatethatthenephroprotective
activityagainstnephrotoxicagentsonmetforminanditsrecentgoodsafetyrecordshaveledresearcherstoconsidertheuseofthis
drugmoreandmoreininsulinresistantstatesevenbeforethedevelopmentofhyperglycemia.

AUTHORS CONTRIBUTIONS
Allauthorshavecontributedindesigningthestudy.Bothofthemhaveassistedinpreparationofthefirstdraftofthemanuscriptor
revisingitcriticallyforimportantintellectualcontent.Theyhavereadandapprovedthecontentofthemanuscriptandconfirmedthe
accuracyorintegrityofanypartofthework.

Footnotes
Source of Support: Nil
Conflict of Interest: None declared.

Article information
J Res Med Sci. 2014 Jul; 19(7): 658664.
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PMCID: PMC4214027
Hamid Nasri and Mahmoud Rafieian-Kopaei1
Department of Nephrology, Division of Nephropathology, Isfahan University of Medical Sciences, Isfahan, Iran
1Medical

Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

Address for correspondence: Prof. Mahmoud Rafieian-Kopaei, Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord,
Iran. E-mail: rafieian@yahoo.com
Received 2013 Jul 24; Revised 2013 Dec 25; Accepted 2014 Jan 15.
Copyright : Journal of Research in Medical Sciences
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Articles from Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences are provided here courtesy of Medknow
Publications

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