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Toxicological evaluation of acute and sub-chronic ingestion of hydroalcoholic extract of Solanum cernuum Vell. in mice

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Toxicological evaluation of acute and sub-chronic ingestion of hydroalcoholic extract of Solanum cernuum Vell. in mice
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   JournalofEthnopharmacology 138 (2011) 508–512 ContentslistsavailableatSciVerseScienceDirect  Journal   of    Ethnopharmacology  journalhomepage:www.elsevier.com/locate/jethpharm Toxicological   evaluation   of    acute   and   sub-chronic   ingestion   of    hydroalcoholicextract   of    Solanum   cernuum   Vell.   in   mice Carlos   C.J.   Almanc¸a a ,   Samara   V.   Saldanha b ,   Dyeime   R.   Sousa a ,   Leonardo   O.   Trivilin a ,Louisiane   C.   Nunes a ,   Lenir   C.   Porfírio a ,   Bruno   G.   Marinho c , ∗ a DepartmentofVeterinaryMedicine,FederalUniversityofEspiritoSanto,Alegre,ES,Brazil b PharmacyDepartment,FacultyofPhilosophy,SciencesandLettersofAlegre,Alegre,ES,Brazil c LaboratoryofPharmacology,DepartmentofPhysiologicalSciences,FederalRuralUniversityofRiodeJaneiro,Seropédica,RJ,Brazil a   r   t   i   c   l   e   i   n   f   o  Articlehistory: Received30June2011Receivedinrevisedform26September2011Accepted26September2011 Available online 4 October 2011 Keywords: SolanaceaeToxicologySolamargineHepatotoxicity Solanumcernuum Vell a   b   s   t   r   a   c   t Ethnopharmacological   relevance:   Solanum   cernuum   Vellozo   isa   Brazilian   shrub   or   small   tree,   restrictedto   Southwest   states   of    the   country.   It   has   been   widely   used   for   the   treatment   of    many   ailments.   Thepharmacological   activity   of    the   extract   on   gastric   ulcer   hasbeen   the   major   therapeutic   target   proposedby   the   population   investigated. Materials   andmethods:   Inthe   acute   toxicity   test   was   used   increasing   doses   of    the   extract   (2,   4,   8,   12,16,   20   and   25   g   of    extract   per   kilogram   of    body   weight).   The   animal   behavior   was   observed   from   5   hafter   asingle   administration   of    the   extract   and   subsequently   monitored   daily   until   the   fourteenth   day,beyond   the   calculation   of    the   estimated   LD50   of    the   extract.   Inthe   test   sub-chronic   toxicity   wasused   twodosesof    the   extract   (0.1   and   1.4   g/kg)   and   the   parameters   analyzed   over   31   days   were:   body   weight,   foodintake,   behavior,   respiratory   rate,   movement   and   mortality   of    animals.   After   anesthesia,   blood   sampleswere   collected   for   hematological   and   biochemical   analysis.   The   animals   were   euthanized   followed   bymacroscopic   analysis   of    the   stomach   and   intestine.   Liver,   lungs   and   kidneys   were   removed,   weighed   andanalyzed   histopathologically. Results:   Inthe   acute   toxicity   test   was   observed   adose-dependent   mortality   and   the   value   of    estimatedLD50   was   14.50   g/kg.   In   the   hematological   and   biochemical   analyses   there   were   significant   increase   in   theactivities   of    AST   and   ALT   indicating   liver   toxicity,   but   the   extract   was   not   able   to   alter   food   intake,   bodyweight   and   organ   weights   after   31   days   of    treatment   and   it   did   not   produce   significant   histopathologicalchanges. Conclusion:   Therefore   we   can   consider   the   hydroalcoholic   extract   of    Solanum   cernuum   Vell   as   practicallynon-toxic   in   acute   administration   and   safe   in   the   sub-chronic   administration,   as   hepatotoxicity   wasobserved   only   with   the   highest   dose   used,   not   with   the   dose   routinely   used   bythe   native   population. © 2011 Elsevier Ireland Ltd. 1.Introduction Theuseofherbalmedicinesasalternativetreatmentshasbeenincreasingworldwideandgainingpopularityindevelopingcoun-tries(Rosidahetal.,2009).Althoughmedicinalplantsmay   havebiologicalactivitiesthatarebeneficialtohumans,thepotentialtox-icityofthesebioactivesubstanceshasnotbeenwellestablished(Rosidahetal.,2009).Thus,thesafetyandefficacyoftheseplants mustbestudiedthoroughlytomaximisetheirbenefitsformankind. ∗ Correspondingauthorat:DepartmentofPhysiologicalSciences,FederalRuralUniversityofRiodeJaneiro,LaboratoryofPharmacology,BR465,Km07,23890-000Seropédica,RJ,Brazil.Tel.:+552126823222;fax:+552126823222. E-mailaddresses: brunomarinho@ufrrj.br,bruno.marinho78@hotmail.com(B.G.Marinho). Theincreaseinnumberofusersasopposetothescarcityofscien-tificevidencesonthesafetyofthemedicinalplantshaveraisedconcernsregardingtoxicityanddetrimentaleffectsofthesereme-dies(Mohamedetal.,2011). Solanumcernuum Vellozo,alsoknowas Solanumpaleatum Schottand Solanumjubatum DunisaBrazilianshruborsmalltree,restrictedtoSouthweststatesofthecountry(Alvesetal.,2007).Itpresentserectshrub,perennial,littlebranched,withlonghairsontheyoungshoots.Alsopresentsleavessimple,entire,sub-coriaceous,long-petiolate,andpubescentontheunderside,with20–35cminlength.Itsleaveshaveanintensedarkgreencolorandbackofthebladehasacleargreencolor.Thefruitsareglobose,smallandyellowwhenripe(LorenziandMatos,2002). Solanumcernuum Vellozoisindicatedforthetreatmentofuri-narydisorders,actingasdesobstruentediuretic(Oliveiraetal.,2007).Itisalsousedtotreatgonorrhea,scabiesandvariousskin 0378-8741   © 2011 Elsevier Ireland Ltd. doi:10.1016/j.jep.2011.09.045 Open access under the Elsevier OA license.   Open access under the Elsevier OA license.    C.C.J.Almanc¸   aetal./JournalofEthnopharmacology 138 (2011) 508–512  509 diseasesbeingappliedinthehealingofskinulcers(Lorenzi,2002).Theliteratureshowspharmacologicalactivityofthehydroalco-holicextractongastriculcer(Araújoetal.,2002)andantineoplastic activityoftheconstituentspresentinthedichloromethaneextractof  Solanumcernuum (Grandoetal.,2008). Toxicityisdependentonfactorssuchascultivar,growingcon-ditions,light,plantpartingestedandtypeandconcentrationof glycoalkaloidpresent(Phillipsetal.,1996).Othermembersofthe Solanaceaefamilyofplants,whichincludetomatoes,potatoesandeggplants,aretoxictoman   andanimals( Jadhavetal.,1981).These plantsareknowntocontainseveraltypesofsteroidalglycoalka-loidsthataretoxic(Bakeretal.,1991).Solasonineandsolamargine aretwomajorglycoalkaloidsfoundinatleast100Solanumspecies(Blankemeyeretal.,1998).Consideringthesignificantuseofthis speciesforthetreatmentofacuteandchronicdisorders,presenceoftoxicconstituentsandthelownumberofscientificpapersaboutit,thepresentstudyaimstoassessthetoxiceffectsofacuteandsub-chronicadministrationofthehydroalcoholicextractof  Solanumcernuum Vell. 2.Materialsandmethods  2.1.Plantmaterial Thebotanicalmaterialusedintheexperimentwas   theleavesof  Solanumcernuum .ThematerialwascollectedinMarch2009inthecityofMunizFreire–EspiritoSanto,Brazil.Theplantwasclassi-fiedbyMSc   ÉrikaVonSohstendeSouzaMedeiros(Departmentof SystematicBotany,BotanicalGardenofRiodeJaneiro,Brazil)andavoucherspecimenwasdepositedintheHerbariumundernumberRB492873.  2.2.Preparationofplantextract  200goftheaerialpartsoftheplantwereground.A70%hydroal-coholicsolutionwasusedasextractionliquid.Theleavesweredriedinanovenat38 ◦ Cfor72handgroundinamill.Thentheyweremaceratedwith70%ethanolfor72h.Thenthemate-rialwasfilteredandsubjectedtoanewextractionforthesameperiod.ThefiltrateswereconcentratedinRotavaporundervac-uum,providingthecrudehydroalcoholicextract.Theyieldoftheextractwasabout18%(w/w).Thematerialwasplacedat − 20 ◦ Cuntilused.ChemicalsThefollowingsubstanceswereused:formalin(Merck,Darmstadt,Germany),70%ethanolanddimethylsulfoxide(Sigma–Aldrich,St.Louis,MO,   USA),KetamineandXylazine(Virbac,Carroscedex,France).  2.4.Animalsconditions Theprotocolforthisstudywasapprovedbytheethicscom-mitteeforAnimalResearchoftheFederalUniversityofEspiritoSantoundernumber002/2009.PathogenfreeSwissfemalemice,weighing17–24gwereusedinappropriateconditionsfortheimplementationofresearch.Theanimalswerekeptinaroomwithtemperaturemaintainedat22 ◦ C,relativehumidityof55 ± 10%and12-hcycleofdayandnightlightconditions.Tapwaterandfoodwerereadilyaccessibletothemicethroughoutthestudy,buttheanimalswerefastedforaperiodof8hpriortooraladministrationofthe Solanumcernuum hydroalcoholicextract.  2.5.Treatments 2.5.1.Acuteoraltoxicitystudy AcutetoxicitytestwasperformedaccordingtotheWorldHealthOrganization(WHO)guideline(WHO,2000)andtheOrganization ofEconomicCo-operationandDevelopment(OECD)guidelinefortestingofchemicals(OECD,2001).Theanimalsweredividedinto 9groupsof6animals.Thisdivisionwasbasedontheweightof theanimals.The9groupsweredividedtoreceivedosesof2,4,8,12,16,20and25gofextractperkilogramofbodyweight,beyondthevehicleandcontrolgroups.Phosphatebuffersalineassociatedwithdimethylsulfoxidewasusedasavehicle,ataconcentrationof5%,forthepreparationofdifferentdosesoftheextract.Theintroductionofdimethylsulfoxidewasnecessaryforthesolubiliza-tionoftheextract.Thecontrolgroupwas   composedofmicethatreceivedphosphatebuffersalineonly.Theanimalbehaviorwasobservedfrom5hafterasingleadministrationoftheextractandsubsequentlymonitoreddailyuntilthefourteenthday.Thetoxic-ityevaluationwasperformedafterexposuretoasingledose.Acutetoxicitywasexpressedbytherequireddoseing/kgbodyweighttocausedeathin50%ofanimalstested(LD 50 ).  2.5.2.Sub-chronicoraltoxicitystudy Themethodwas   performedfollowingtheprotocoldescribedbytheWHO   guideline(WHO,2000)andtheOECDguidelinefor testingofchemicals(OECD,1981).Pathogenfreeandnulliparous Swissfemalemice(between17gand24g)werehousedingroupsofmatchedweightsunderthesameconditionsasdescribedpre-viously.Intotal24micewereusedinthisstudy(4groupsof6animals).Thechoiceofdosesforthisstudywas   doneasfollows:thelowestdoseusedwas0.1g/kg,asthisistheapproximatedoseusedbythenativepopulation,accordingtoinformationcollected,andthelargestdosewas1.4g/kg,sincethiscorrespondsto10%of thecalculatedestimatedLD50(14.50g/kg).The Solanumcernuum hydroalcoholicextractwasadministeredsuspendedinphosphatebuffersalineassociatedwithdimethylsulfoxideasavehicle.Theextractwasadministereddailybyoralgavagetothemiceusingaplasticcannulaintubatedontheneedlefittedontoasyringe.Thedeviationsinnormalbehavior,respiratoryrate,movementandmortality,aswellasthebodyweightchangesandfoodintakeofmiceweremonitoreddailyover31days.Onday31,allanimalswereanesthetizedintraperitoneallywithacombinationofketamine(60mg/kg) ± xylazine(8mg/kg).Afteranesthesia,bloodsampleswerecollectedbycardiacpunctureandtransferredtotubescontainingEDTAforhematologicalandbio-chemicalanalysis.Theanimalswereeuthanizedbyanestheticoverdose,stomachswereremovedandanincisionalongthegreatercurvaturewasmadeandanincisionwas   madealongthegut.Thenumberofulcers(singleormultipleerosion,ulcerorperfora-tion)andhyperemiawasmeasured.Liver,lungsandkidneyswereremovedandweighedindividually.Lerfoneticamente.  2.6.Bloodanalyses HematologicalandbiochemicalanalyseswereperformedattheClinicalPathologylaboratorylocatedintheVeterinaryHos-pitaloftheFederalUniversityofEspiritoSanto.Theredbloodcell(RBC),hematocrit,hemoglobin,totalleukocytes,lymphocytes,monocytes,eosinophilsandtotalplasmaproteinweredeterminedbymanualtechniquesestablishedinthelaboratory.BiochemicalanalyseswereprocessedaccordingtoprotocolsofthelaboratoryusingcommercialkitsproducedbyLabtestdiagnósticaSA(MinasGerais,Brazil)for:urea(Ref.:27),creatinine(Ref.:35–100),albu-min   (Ref.:19),ALT(alaninetransaminase)(Ref.:53–200)andAST(aspartatetransaminase)(Ref.:52–200).  2.7.Histopathologicalanalysis Aftereuthanasia,allanimalswereautopsiedandeachanimalwas   collectedfragmentsoflung,liverandkidney.Thefragmentswerefixedin10%formalinandhistologicallyprocessed.Sectionsof5  mthicknesswereobtainedonarotarymicrotomeandthen  510  C.C.J.Almanc¸   aetal./JournalofEthnopharmacology 138 (2011) 508–512 thematerialwas   stainedbyhematoxylin-eosin(HE)(Luna,1968).Microscopicanalysiswasbasedonobservationofmorphologicalchanges.  2.8.Statisticalanalysis Allexperimentalgroupswerecomposedof6animals.Theresultsarepresentedasthemean ± SD.Statisticalsignificancebetweengroupswasperformedbytheapplicationofoneway   anal-ysesofvariance(ANOVA)followedbyBonferroni’stest. P  <0.05wasconsideredasstatisticallysignificant.TheestimatedLD50wasobtainedbyfittingthedatapointsrepresentingthepercentageof deathswithincreasingdosesoftheextractcalculatedbynonlinearregressionmethodusingtheGraphPadPrismsoftwareversion3.0.(SanDiego,CA,USA). 3.Results  3.1.Acuteoraltoxicity Theeffectsof  Solanumcernuum hydroalcoholicextractareshowninTable1.Therewasadose-dependentincreaseinmortal- ity.Oneanimaldiedatadoseof8g/kg,2animalsdiedatadoseof 12g/kg,4animalsdiedatadoseof16g/kgandallanimalsdiedatadoseof20and25g/kg.Atotalof42animalstreatedwiththeextract,19animalsdied,resultinginamortalityrateof45%.Intermsof latencyofmortality,atadoseof8g/kgtheanimalsdiedbefore24h,whereasathigherdosestheanimalsdiedwithlessthan12h.Thesymptomsassociatedwithingestionoftheextractinclude:dis-orientation,hyperactivity,piloerectionandhyperventilation.Atalldosesoftheextractsideeffectswereobserved.Themaximumtol-erateddosewas   4g/kgandthecalculatedLD50=14.50g/kgbodyweight(95%confidenceintervals:10.78–19.50g/kg).  3.2.Sub-chronicoraltoxicity 3.2.1.Generalbehavioroftheanimals Nosignificantchangeinbodyweightwasobservedoverthe31daysofstudy,sincetherewasnotsignificantdifferencebetweentheresultsrepresentingthecontrolgroup,vehiclegroup,thelow-estdose(0.1g/kg)andhigherdose(1.4g/kg)andnochangeindailyfoodintakewasobservedduringthestudy(datanotshown).Duringthe31daysofstudy,theanimalsthatreceivedthelowestdoseshowedsalivation,whilethosewhoreceivedthehighestdoseshowedsalivation,hyperactivityanddiarrhea.Vehicleandcontrolgroupsdidnotshowsymptomsoftoxicity.Nodeathwasobservedinthetestsub-chronictoxicity.  3.2.2.Effectonthehematologicalandbiochemicalblood parametersofthemice Thehematologicalandbiochemicalparametersobtainedwiththelowest(0.1g/kg),highestdose(1.4g/kg)andvehiclegroupdidnotshowsignificantchangeinrelationtothecontrolgroup( P  >0.05),buttherewassignificantincreaseintheactivitiesofASTandALTinbloodchemistry(Table2).Thesestatisticaldifferences appearedtobebiologicallyrelevantandshowntoberelatedtosub-chronictreatmentwiththeextract.  3.2.3.Effectonthewetweightsofmiceorgansafter31-daytreatmentperiod Thewetweightsofmiceorgansofbothtreated(0.1and1.4g/kg),vehicleandcontrolgroupsarepresentedinTable3.Thesub-chronic oralingestionof  Solanumcernuum hydroalcoholicextractover31daysdidnotcausesignificantchangesintheweightsoftheorgans(i.e.,kidneys,lungsandliver)inthegroupsreceivingtheextractandvehiclewhencomparedwiththecontrolgroup.  3.2.4.Histopathologicalstudy Thelungs,kidneysandliverweretheorgansexamined.Theanalysisoftheorganswasmadeinthethirty-firstdayoftreat-ment.Nolesionorpathologicalchangesattributabletotreatmentwerefoundintheorgansofanimalsinthetreatedgroupsorvehi-cleandcontrolgroups(datanotshown).Areasofhyperemiaandmacroscopiclesionsinthegastrointestinalmucosawerenotfound(datanotshown). 4.Discussion Solanumcernuum vellisaplantthathasbioactivesubstancescapableofproducingbothdesirableandundesirableeffects.Ithasbeenwidelyusedforthetreatmentofmanyailments.Manystudieshavedemonstratedtheirutility,includingtheirbiologicalactivi-ties.Thepharmacologicalactivityoftheextractongastriculcerhasbeenthemajortherapeutictargetproposedbythepopulationinvestigated(Oliveiraetal.,2007).Thetoxicologicalevaluationof  thehydroalcoholicextractof  Solanumcernuum Vell.wasperformedtoevaluatetherisksofacuteandsubchronicadministration,sinceitiswidelyusedfortherapeuticpurposes.Asingleadministrationoftheextractwithincreasingdosesproducedadose-dependentincreaseinmortalityandareduc-tioninthelatencyofmortality.AccordingtoLoomisandHayesclassification(1996),   chemicalsubstancewithaLD50withintherangeof5000–15000mg/kgisconsideredaspracticallynon-toxic.Thecalculated Solanumcernuum estimatedLD50beingfoundinthisrange,suggeststhattheplantshouldberegardedasprac-ticallynon-toxicinacuteingestion,butbeingabletoproduceundesirablebehavioralsymptoms(i.e.,hyperactivity,disorienta-tion,pilo-erectionandhyperventilation).Sub-chronicingestionofhydroalcoholicextractof  Solanumcer-nuum producedbehavioralchangesoflowintensity,butwas   notabletoaffectfoodintakeandweightgainofanimalsduringthe31daysoftreatment.Since,changesinbodyweightandfoodintakehavebeenusedasindicatorsofadverseeffectsofdrugsandchemicals(MukindaandEagles,2010),suggestingthatoraldoses administereddidnotalterthenormalgrowthofanimals.Thehaematopoieticsystemisoneofthemostsensitivetargetsfortoxiccompoundsandanimportantindexofphysiologicalandpathologicalstatusinman   andanimal(MukindaandSyce,2007). Inhematologicalanalysistherewerenotdifferencesbetweenthetreated,vehicleandcontrolgroups.Thisindicatesthatthesub-chronicadministrationoftheextractisnotabletoproducetoxiceffectsonthehematopoieticsystem.Asoneofthebiochemicalparametersanalyzed,ASTisnormallyfoundinthecytoplasmandmitochondriaofmanycells,primarilyincardiacmuscle,liverandskeletalmuscle.Itsconcentrationismuchlower,however,inthekidney,pancreasanderythrocytes(CostaSilvaetal.,2008).Thesechangesoccurinthebloodwhenthehep- aticcellularpermeabilityischangedorwhennecrosisandcellularinjuryoccurs.Theseenzymesareusedasmarkersofliverfunctionandthusserveasindicatorsoflivertoxicity(Upuretal.,2009). Analysisofbiochemicalparametersshowedasignificantincreaseinthelevelsoftransaminaseenzymes(ASTandALT)inthegroupreceivingtheextractatadoseof1.4g/kgcomparedtothecon-trolgroup.Thus,theadministrationoftheextractwasresponsibleforliverdamageinmicedemonstratedbysignificantelevationof serumtransaminases.AccordingtoTeoetal.(2002),   aftersomeexposuretopotentiallytoxicsubstances,therewillbeaslightreductioninbodyweightgainandinternalorganweights.Nosignificant  C.C.J.Almanc¸   aetal./JournalofEthnopharmacology 138 (2011) 508–512  511  Table1 Effectsof  Solanuncernuum Vellhydroalcoholicextractinmiceafteracuteoraladministration.Treatmentdose(g/kg)AnimalsEffectsD/TRelationbetweendeadandtotaltreatedmice(%)Mortalitylatency(h)SymptomsoftoxicityControl0/60–NoneVehicle 0/6 0 – None2   0/60–Hyperactivityanddisorientation4 0/6   0–Hyperactivityanddisorientation8   1/617<24Hyperactivityanddisorientation12   2/633<12Hyperactivityanddisorientation,pilo-erectionandhyperventilation16   4/667<12Hyperactivityanddisorientation,pilo-erectionandhyperventilation20 6/6 100 <12 Hyperactivityanddisorientation,pilo-erectionandhyperventilation25 6/6 100 <12 Hyperactivityanddisorientation,pilo-erectionandhyperventilationD:dead,andT:totaltreatedmice.  Table2 Effectsof  Solanuncernuum Vellhydroalcoholicextractonthehematologicalandbiochemicalbloodparametersofbloodofmiceafter31-dayperiodoforaladministration.Parameter(units)ControlVehicleLowdose(0.1g/kg)Highdose(1.4g/kg)RBC( × 10 12 /L) 7.1  ± 0.26.4  ± 0.36.9  ± 0.27.3  ± 0.1Hemoglobin(g/dL)10.9 ± 0.911.1 ± 1.19.2 ± 1.310.8 ± 0.8Haematocrit(%) 30.5 ± 2.631.9 ± 3.630.2 ± 3.931.0 ± 2.4Leukocytes(10 3 /mm 3 )7.1 ± 1.26.5 ± 1.58.5 ± 3.16.5 ± 0.9Total   protein(g/dL)6.1 ± 0.56.1 ± 0.35.9 ± 0.45.7 ± 0.3Lymphocytes(%)64.0 ± 4.067.0 ± 3.962.0 ± 3.269.8 ± 3.7Monocytes(%)11.2 ± 3.29.1 ± 3.711.5 ± 4.912.9 ± 3.3Eosinophils(%) 5.5  ± 2.16.0 ± 2.67.1 ± 3.64.2 ± 1.7Urea   (mg/dL)68.0 ± 3.367.9 ± 4.872.7 ± 5.569.0 ± 3.9Creatinine(mg/dL) 0.4 ± 0.20.4 ± 0.10.4 ± 0.10.5 ± 0.1Albumin(g/dL)2.5 ± 0.12.4 ± 0.22.4 ± 0.22.6 ± 0.2ALT   (U/L)60.2 ± 5.358.4 ± 7.461.9 ± 5.789.8 ± 9.7 * AST(U/L) 72.3  ± 5.475.2  ± 6.382.2  ± 11.0148.1  ± 12.2 ** P  <0.05againstcontrolgroup.  Table3 Wet   weightsofkidney,lungandliverofmicesub-chronicallytreatedwith Solanuncernuum Vellhydroalcoholicextract.DosegroupWet   weight(g;mean ± S.D.; n =6)LungKidneyLiverControl0.16 ± 0.370.41 ± 0.071.12 ± 0.03Vehicle0.17 ± 0.050.42 ± 0.041.13 ± 0.04Low   dose(0.1g/kg)0.16 ± 0.050.37 ± 0.051.16 ± 0.05Highdose(1.4g/kg) 0.16  ± 0.030.38 ± 0.021.10 ± 0.03* P  <0.05againstcontrolgroup. differencewasobservedbetweentheweightsoftheorgansexam-ined,indicatingthatthesub-chronicadministrationoftheextractdidnotaffectthewetweight,organ-to-bodyweightratio,inaddi-tiontotheirmacroscopiccharacteristics(i.e.,appearance,color,size).Histopathologicalevaluationandmicroscopicexaminationwerecarriedoutontheisolatedorgansofboththetreatedandcontrolgroups.Theselectedorgansobtainedfrombothtreatedandcontrolsanimalsshowednormalarchitecture(datanotshown)suggestingthattherewerenotdetrimentalchangesormorpho-logicaldisturbancescausedbydailyoraladministrationofthe Solanumcernuum Vellextract.Themacroscopicexaminationof thestomachandintestinedidnotshowchangesonthegas-trointestinalmucosa,demonstratingthatthecauseofdiarrheainducedbysub-chronicadministrationoftheextractisnotduetoitsirritantaction.SeveralspeciesofthegenusSolanumhaveshownstimulatingactionsonvisceralsmoothmusclesbyinhibit-ingacetylcholinesteraseormuscarinicreceptoractivation(Mansetal.,2004),andthesemay   bethetargetsofmoleculespresentinthehydroalcoholicextractof  Solanumcernuum Vell,howevermorestudiesareneededtoelucidatethiseffect.Theseobserva-tionsdemonstratethatprolongedadministrationoftheextractwasnotabletoinduceadetectableliverdamageinhistopathologicalexaminations,althoughtheinjuryisalreadydetectableinliverfunctiontests.Adirectcomparisonbetweenthetoxiceffectsproducedinhumansandlaboratoryanimalsisinadequate,becausetheypresentpharmacokineticdifferences,asinitsbiotransformation,absorptionandexcretion,leadingtoconsequentdifferencesinpharmacokineticparameters(half-life,clearance,bioavailability),besidestheproductionofdifferentmetabolites(Abassetal.,2009). Thus,theconsequencesproducedbyoraladministrationoftheextractcanbemanifesteddifferentlyinvariousspecies.Insummary,thehydroalcoholicextractof  Solanumcernuum Vellwas   foundtobepracticallynon-toxicwhenoralacuteandsub-chronictoxicitiesinmicewereperformed.However,nodirectevidencehasbeenreportedtoconfirmthisideainhumans.There-foremorestudiesareneededtoclarifyitstoxicityinanimalsandhumans. 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