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Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application

Authors:
Sania Ashrafi at University of Dhaka
Sania Ashrafi
Safaet Alam at Bangladesh Council of Scientific and Industrial Research
Safaet Alam
Arifa Sultana at University of Dhaka
Arifa Sultana
Asef Raj at BRAC University
Asef Raj
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Abstract and Figures

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotec-tive, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.
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Molecules2023,28,3149.https://doi.org/10.3390/molecules28073149www.mdpi.com/journal/molecules
Review
Papaverine:AMiraculousAlkaloidfromOpiumandIts
MultimedicinalApplication
SaniaAshrafi
1
,SafaetAlam
1,2,
*,ArifaSultana
1
,AsefRaj
1
,NazimUddinEmon
3,4
,FahmidaTasnimRichi
1
,
TasnuvaSharmin
1
,MyunghanMoon
5
,MoonNyeoPark
5
andBongleeKim
5,
*
1
DepartmentofPharmaceuticalChemistry,UniversityofDhaka,Dhaka1000,Bangladesh
2
DrugsandToxinsResearchDivision,BCSIRLaboratoriesRajshahi,BangladeshCouncilofScientificand
IndustrialResearch,Rajshahi6206,Bangladesh
3
DepartmentofPharmacy,FacultyofScienceandEngineering,InternationalIslamicUniversityChiagong,
Chiagong4318,Bangladesh
4
DepartmentofChemistryandBiochemistry,CellandMolecularBiologyProgram,UniversityofArkansas,
Fayeeville,AR72701,USA
5
DepartmentofPathology,CollegeofKoreanMedicine,KyungHeeUniversity,
Seoul02447,RepublicofKorea
*Correspondence:safaet.du@gmail.com(S.A.);bongleekim@khu.ac.kr(B.K.)
Abstract:Thepharmacologicalactionsofbenzylisoquinolinealkaloidsarequitesubstantial,and
haverecentlyaractedmuchaention.Oneoftheprinciplebenzylisoquinolinealkaloidshasbeen
foundintheunripeseedcapsulesofPapaversomniferumL.Althoughitlacksanalgesiceffectsandis
unrelatedtothecompoundsinthemorphineclass,itisaperipheralvasodilatorandhasadirect
effectonvessels.Itisreportedtoinhibitthecyclicadenosinemonophosphate(cAMP)andcyclic
guanosinemonophosphate(cGMP)phosphodiesteraseinsmoothmuscles,andithasbeenobserved
toincreaseintracellularlevelsofcAMPandcGMP.Itinducescoronary,cerebral,andpulmonary
arterydilatationandhelpstolowercerebralvascularresistanceandenhancecerebralbloodflow.
Currentpharmacologicalresearchhasrevealedthatpapaverinedemonstratesavarietyofbiological
activities,includingactivityagainsterectiledysfunction,postoperativevasospasms,andpulmonary
vasoconstriction,aswellasantiviral,cardioprotective,anti-inflammatory,anticancer,neuroprotec-
tive,andgestationalactions.Itwasrecentlydemonstratedthatpapaverinehasthepotentialtocon-
trolSARS-CoV-2bypreventingitscytopathiceffect.Theseexperimentswerecarriedoutbothin
vitroandinvivoandrequireanextensiveunderstandingofthemechanismsofaction.Withits
multiplemechanisms,papaverinecanbeconsideredasanaturalcompoundthatisusedtodevelop
therapeuticdrugs.Tovalidateitsapplications,additionalresearchisrequiredintoitsprecisether-
apeuticmechanismsaswellasitsacuteandchronictoxicities.Therefore,thegoalofthisreviewis
todiscussthemajorstudiesandreportedclinicalstudieslookingintothepharmacologicaleffects
ofpapaverineandthemechanismsofactionunderneaththeseeffects.Additionally,itisrecom-
mendedtoconductfurtherresearchviasignificantpharmacodynamicandpharmacokineticstudies.
Keywords:Papaversomniferum;opium;benzylisoquinoline;papaverine;alkaloid;antiviral;anti-
cancer;SARS-CoV-2;
1.Introduction
Sinceancienttimes,medicinalplantshaveplayedakeyroleintraditionalmedicine
systems.Phytochemicalsarebeingminedmorefrequentlytofindnovelleadsinthedrug
discoveryprocessortofindbeeralternativestoexistingones[1–5].Around75%ofthe
globalpopulation,mostlyfromdevelopingcountries,dependprimarilyontraditional
herbalmedicinesduetotheiraffordabilityandenvironmentallybeneficialqualities[6].
Citation:Ashrafi,S.;Alam,S.;
Sultana,A.;Raj,A.;Emon,N.U.;
Richi,F.T.;Sharmin,T.;Moon,M.;
Park,M.N.;Kim,B.Papaverine:A
MiraculousAlkaloidfromOpium
andItsMultimedicinalApplication.
M
olecules2023,28,3149.hps://
doi.org/10.3390/molecules28073149
AcademicEditors:GiovanniLentini,
MariaMaddalenaCavalluzziand
SolomonHabtemariam
Received:13March2023
Revised:28March2023
Accepted:29March2023
Published:31March2023
Copyright:©2023bytheauthors.Li-
censeeMDPI,Basel,Swierland.
Thisarticleisanopenaccessarticle
distributedunderthetermsandcon-
ditionsoftheCreativeCommonsAt-
tribution(CCBY)license(hps://cre-
ativecommons.org/licenses/by/4.0/).
Molecules2023,28,31496of22
Accordingtoestimates,20%ofplantspeciesproduce12,000alkaloidscombined,
manyofwhichhavebeenusedinbothtraditionalandmodern-daymedicineforcenturies.
Amongthese,about2500ofthesubstancesaremembersofastructurallydiverseclassof
metabolitesknownasbenzylisoquinolinealkaloids(BIAs),whichalsoincludestheopiate
drugsmorphineandcodeine.Additionally,thebenzylisoquinolinealkaloidfamilyisa
prominentclassofplant-derivedchemicalsthathasshownawiderangeofpharmacolog-
icalactivity,includingantibacterial,antitussive,antispasmodic,andanticancerproperties
[7,8].
Aprominentbenzylisoquinolinealkaloidispapaverine,whichcanbeobtainedfrom
PapaverinesomniferumL.(opiumpoppy).Theopiumalkaloidsincludepapaverine,mor-
phine,codeine,thebaine,noscapine,andnarceine,aswellasasmallpercentageofsome
othercompounds.Variouspiecesoftraditionalresearchevidencehavedemonstrated
opiumalkaloidsinChineseandIndianherbalmedicinetobeeffectiveattreatingavariety
ofailments,includingchroniccough,rectumprolapse,diarrhea,dysentery,andgastroin-
testinalissues.Inaddition,papaverinehasalsobeenincorporatedintherapeuticseings
totreaterectiledysfunction,smoothmusclespasms,andspasmsassociatedwithgastro-
intestinalproblems.Scientistshavealsofoundpapaverineasanonselectivephos-
phodiesterase(PDE)inhibitorinmammals,boostingtheamountofcAMPandcGMP
availableforcellsignaling[9].Hence,thissecondarymetabolitedemandsfurtherexplo-
rationandrequirespharmacologicalresearchinvestigations.Therefore,thecurrentstudy
focusesonthemolecularmechanismsofpapaverine’spharmacologicalpotentialasthey
havebeeninvestigatedindiverseexperimentalmodels.
2.NaturalSourceofPapaverine
Duetotheirphytochemicalcomposition,membersofthegenusPapaver(family:Pa-
paveraceae)arerecognizedfortheirtherapeuticbenefits.ThemostsignificantPapaverspe-
ciesthatcontributesphytochemicalsfordrugdevelopmentisPapaversomniferumL.
(opiumpoppy),whichishighlyproducedincountriessuchasAfghanistan,Myanmar,
Mexico,Laos,Turkey,Czechia,andSpain.OthercommonlycultivatedPapaverspeciesin-
cludeP.bracteatumLindl.(Persianpoppy),P.rhoeasL.(commonpoppyorcornpoppy),
P.dubiumL.,P.pseudo‐orientaleMedw.,andP.orientaleL.,whicharegrownathighalti-
tudesinnorthandnorthwestIran,Russia,theCaucasiaregion,Europe,andAmerica[10].
P.somniferumL.producespapaverinenaturallyinitsunripeseedcapsules.Atotalof40
alkaloidshavebeenfoundintheplant;however,morphine(10–15%),noscapine(4–5%),
codeine(1–3%),papaverine(1–3%),andthebaine(1–3%)arethefiveprimaryalkaloids.
TheprevalenceofpapaverineinIndianspeciesrangesfrom0.5%to3%[11].
3.ChemistryofPapaverine
Benzylisoquinolinealkaloidsholdaprominentplaceinalkaloidchemistryasthey
serveasinvivoprecursorstomanyothernaturallyoccurringisoquinolines.Theyareei-
ther1,2,3,4-tetrahydro,asincoclaurineandN-nororientaline,orfullyaromatic,asinpa-
paverine,palaudine,andescholamine.RingAinthebenzylisoquinolinealkaloidsmay
possesstwoorthreeoxygenatedsubstituents,whileringChasonlyoneortwosubstitu-
ents[12].
Papaverine,alsoknownbyitsIUPACnomenclature1-[(3,4-dimethoxyphenyl)me-
thyl]-6,7-dimethoxyisoquinoline,isoneoftheprincipalbenzylisoquinolinealkaloids
foundinP.somniferum[13,14].Naturally,itisproducedasabyproductofmorphine,co-
deine,andnarcotinesynthesis.Itsm/zratiowasdeterminedtobe340.15417[15].Itisa
neutralsolidthatonlyslightlydissolvesinwater[16].Therearefourmethoxygroupsin
papaverine.EvenifthemoleculelacksaTV-methylgroup,itstillfunctionsasatertiary
base.Itisconsideredapyridinederivativebecauseitmaybereducedtoasecondary
aminebyaddingfourhydrogenatoms,withtheheterocyclicringfusedtoabenzenering
[12](Figure1).
Molecules2023,28,31497of22
Figure1.Structureofpapaverine.
GuidoGoldschmiedtfirstillustratedthestructureofthepapaverinebetweenthe
yearsof1885and1898.Byformingmethiodideanddemonstratingthepresenceoffour
methoxygroupspermole,heestablishedtheexistenceofatertiarynitrogenatom.Under
differentconditions,thebasewasoxidizedwithpotassiumpermanganatetoproducevar-
iousrelatedcompounds(Figure2).
Figure2.Similarcompoundsofpapaverinehelpedtoelucidatethestructureofpapaverine.
Thecurrentstructurewasrecognizedaspapaverinebasedontheevidencemen-
tionedaboveandotherrelevantdata.Followingthesuccessfulsynthesisofpapaverinein
1909,PictetandGamsvalidatedthemolecularstructure[14].
4.BiosynthesisofPapaverine
Twounitsoftyrosinecontributeastheprecursorsforthebiosynthesisofpapaverine,
andtheintermediateproductsinclude(S)-norcoclaurine,laudanine,norlaudanine,retic-
uline,norreticuline,tetrahydropapaverine,anddihydropapaverine.Recentinvestigations
revealedthattheprimarypathwayofpapaverinebiosynthesisintheopiumpoppyhas
beenidentifiedbysystematicsilencingofbenzylisoquinolinealkaloidbiosyntheticgenes.
Therearetwosuggestedmetabolicpathwaysfor(S)-norcoclaurine.Oneinvolves
onlyN-demethylatedintermediates(theNHpathway),whereastheotherinvolves(S)-
reticulineandinvolvesanumberofN-methylatedintermediates(theNCH
3
pathway)
[13,17,18].TheNHrouteadvancesvia(S)-norreticuline[13,19,20](Figure3),whereasthe
NCH
3
routeinvolves(S)-reticuline[13,15,20,21](Figure4).
Molecules2023,28,31497of22
Figure3.TheNHpathwayofpapaverinesynthesis.TYDC=tyrosinedecarboxylase,TyrAT=L-tyrosineaminotransferase,4HPPDC=4-hydroxyphenylpyruvate
decarboxylase,3OHase=tyramine3-hydroxylase,NCS=norcoclaurinesynthase,6OMT=norcoclaurine-6-O-methyltransferase,3’OHase=3’hydroxylase,3’OMT
=3′-O-methyltransferase,4’OMT=3′-hydroxy-N-methylcoclaurine4′-O-methyltransferase,7OMT=norreticuline7-O-methyltransferase,DBOX=dihydrobenzo-
phenanthridineoxidase.
Molecules2023,28,31498of22
Figure4.TheNCH
3
pathwayofpapaverinesynthesis.6OMT=norcoclaurine-6-O-methyltransferase,CNMT=coclaurine-N-methyltransferase,NMCH=(S)-N-
methylcoclaurine3′-hydroxylase,4’OMT=4′-O-methyltransferase,7OMT=reticuline7-O-methyltransferase,3’OMT=3′-O-methyltransferase,LNdeMT=lauda-
nosineN-demethylase,DBOX=dihydrobenzophenanthridineoxidase.
Molecules2023,28,31499of22
ThefirststepinpapaverinebiosynthesisisthecondensationoftwoL-tyrosinederiv-
atives,4-hydroxyphenylacetaldehyde(4HPAA)anddopamine,whichisaccomplished
throughdecarboxylation,meta-hydroxylation,andtransaminationtoproducetheprecur-
sortoallotherbenzylisoquinolinealkaloids,(S)-norcoclaurine.Tyrosinedecarboxylase
(TYDC)andtyramine3-hydroxylase(3OHase)transformL-tyrosineintotyramineand
dopamine,respectively.L-tyrosinecanbetransaminatedbyL-tyrosineaminotransferase
(TyrAT)intheproductionof4HPAA,andthendecarboxylatedbyanenzymeidentified
as4-hydroxyphenylpyruvatedecarboxylase(4HPPDC).Norcoclaurinesynthase(NCS)is
theenzymethatcatalyzesthecondensationof(S)-norcoclaurinefrom4HPAAanddopa-
mine.
Norcoclaurine-6-O-methyltransferase(6OMT)firsttransforms(S)-norcoclaurineinto
(S)-coclaurine.IntheNHpathway,(S)-coclaurinefirstundergoes3′hydroxylationby3′
hydroxylase(3′OHase)andthenisconvertedto(S)-norreticulineby3′-O-methyltransfer-
ase(3′OMT).Ontheotherhand,intheNCH3pathway,(S)-coclaurineistakenupbycoc-
laurineN-methyltransferase(CNMT)toyield(S)-N-methylcoclaurine.(S)-N-methylcoc-
laurineishydroxylatedto3′-hydroxy-N-methylcoclaurineby(S)-N-methylcoclaurine3′-
hydroxylase(NMCH),whichisthentransformedinto(S)-reticulineby3′-hydroxy-N-
Methylcoclaurine4′-O-methyltransferase(4′OMT).Itisinterestingtonotethatonly
NMCHhasbeenreportedtoexhibitstrictstereoisomerandsubstratespecificity,accepting
only(S)-N-methylcoclaurineandrejectingeitherthecorresponding(R)-N-methylcoclau-
rineorN-desmethylcompounds.Asadistinction,theO-andN-methyltransferasesoften
acceptawiderangeof(R)-and(S)-tetrahydroisoquinolines[19].Theenzymereticuline7-
O-methyltransferase(7OMT)canfurthermethylatereticulinetoproducelaudanine,
whichcanthenbefullyO-methylatedtolaudanosineby3′-O-methyltransferase.
ThefinalstepsinpapaverinebiosynthesiscomprisetheoxidationofthefullyO-
methylatedandN-desmethylmoleculetetrahydropapaverinebydihydrobenzophenan-
thridineoxidase(DBOX).
Advancedquantumchemicaldensityfunctionaltheory(DFT)calculations,aswellas
diffusereflectance(Ds),experimentalelectronicabsorption(EAs),matrix-associatedlaser
desorptionionization(MALDI)coupledwithOrbitrapimagingmassspectrometry(MS),
fluorescencespectroscopy(Fs),andcirculardichroic(CD)havebeenusedfortheoretical
andexperimentalelucidationofthepapaverinebiosyntheticpathwayvia(S)-reticuline
(theNCH3pathway)[19,20,22].
5.MechanismofActionofPapaverine
Papaverineisrecognizedasthemosteffectivesmoothmusclerelaxant,asitactsdi-
rectlyonsmoothmusclebyexertingastrongvasodilatingeffect.Ithasbeenobservedto
boostintracellularlevelsofcAMPandcGMPbyblockingthecAMPandcGMPphos-
phodiesteraseinsmoothmuscles(Figure5)[23–27].Inhibitingthereleaseofcalciumfrom
theintracellularspaceandobstructingcalciumionchannelsinthecellmembranearetwo
otherwaysthatpapaverinemaywork[28].
Molecules2023,28,314910of22
Figure5.Mechanismofactionofpapaverineinsmoothmusclerelaxation.Smoothmusclecontrac-
tionrequiresfivesteps:AftertheincreaseinintracellularCa
2+
concentrationfromtheextracellular
fluid,theseionsbindtoaproteincalledcalmodulin(CaM).Thiscomplexactivatesaproteincalled
myosinlight-chainkinase(MLCK)(papaverineinhibitsthisstep),whichsubsequentlyphosphory-
lateslightchainsofmyosinheads,increasingthemyosinATPaseactivity.Finally,activemyosin
cross-bridgesslidealongactinandcreatemuscletensiontocontractthecell.
6.PharmacologicalPropertiesofPapaverine
PapaverinehasbeendemonstratedtobeaparticularPDE
10
Aphosphodiesterasein-
hibitor,whichismostlyfoundinthestriatumofthebrain.Thechronicinjectionofitinto
miceresultedinmotorandcognitivedeficitsaswellaselevatedanxiety.Otherstudies
havesuggestedthatitmayalsohaveanantipsychoticeffect.However,notallresearch
hassupportedthistheory[29,30].Nevertheless,papaverinehasbeenapprovedforthe
treatmentofGIT,bileduct,andureterspasmolyticdisorders[31].
6.1.ActivityagainstErectileDysfunction(ED)
PDE
5
inhibitorsareusedasthefirst-linetherapyforED[32].Asapopularvasodila-
tor,theirusagehasbeenobservedtoimprovepenileimpotence[33].ItsabilitytotreatED
andimpotencehasbeenknownforalongtime.Byfar,thelargestnumberofstudieshave
beenpublisheddemonstratingtheeffectivenessofpapaverineintreatingerectiledysfunc-
tion(ED)andimpotence[34].Threesimultaneousandsynergisticprocessesworkto-
gethertomaintainnormalerectilefunction:(1)relaxationofthecavernosalsmoothmus-
cle,(2)anincreaseinpenilearterialinflowcausedbyneurologicalactivity,and(3)are-
strictionofvenousoutflowfromthepenis.Theseprocessesoccurduetothefollowing:(1)
theactivationofcGMP-dependentproteinkinaseG(PKG);(2)theactivationofcGMP-
dependentionchannelsthatreduceintracellularCa
2+
byCa
2+
sequestrationand/orextru-
sion;(3)theopeningofK
+
channels,causingthehyperpolarizationofcorpuscavernosum
smoothmusclecells;and(4)theactivationofmyosinlight-chainphosphatases.Theobjec-
tiveofEDpharmacotherapyistodevelopnovelpharmacologicaltargetsthatinhibitthe
contractilesystems(α-adrenoceptorantagonists)andactivate(e.g.,prostaglandinE
1
(PGE
1
),NO-donors,andforskolin)oraugment(e.g.,PDEinhibitorsandgenetherapy)the
vasodilatorysystemstoproducegreatertrabecularsmoothmusclerelaxationofthecor-
poracavernosa[35–37](Figure6).
Molecules2023,28,314911of22
Figure6.Mechanismofactionofpapaverineinrelaxationofcavernosalsmoothmuscle.Papaverine
blockscAMPandcGMPphosphodiesterasetoraisetheconcentrationofcAMPandcGMP,which
furtherreleasesMLCPthatdephosphorylatesmyosin,resultinginsmoothmusclerelaxationand
increasedcGMPthatactivatesPKGandleadstosmoothmusclerelaxation(1).ActivatedPKGlow-
ersCa
2+
influx.Ca
2+
activatesMLCK,whichcontractssmoothmuscleviamyosinphosphorylation
(2).PapaverineinduceseffluxofK+withsubsequenthyperpolarizationandrelaxationofcorpora
cavernosasmoothmusclecells.
Intracavernouspapaverinewasfoundtoplayavitalroleinthemanagementofmale
erectilefailureinastudyon48patientswithpsychogenicimpotence.Intracavernouspa-
paverineinduceserectionbyseveralmechanisms.Itrelaxesthesmoothmusclesofsinus-
oidsandincreasesthearterialflowtothecorpora.Theuseofpapaverinehasalsobeen
linkedtoincreasedvenousoutflowresistance[34,38].Researchconductedon17menwith
organicimpotencerevealedpapaverinegeltocauseanoticeablylargercavernousartery
diameter[39].Althoughitsuseasamonotherapytotreatimpotencewasinitiallyques-
tionedduetopriapismbeingasignificantsideeffect(whichoccursin15–18%ofpatients),
physicianssoondiscoveredthatthissideeffectwasdose-dependentandonlyoccursin
patientswithneurogenicimpotence[40,41].Tolessentoxicityandpriapism,papaverine
wascombinedwithphentolamineandPGE
1
[35].Byraisingtheamountofintracellular
cyclicadenosinemonophosphate,relaxingthesmoothmuscleofthecavernousbodyand
helicinearteries,andinhibitingtheenzymephosphodiesterase,papaverineandphentola-
minewereabletosignificantlyincreaseerectionsinvariousexperiments[42,43].Ithas
beenobservedthatpapaverine’seffectivenessisequaltothatoforalsildenafilinadiffer-
enttrialthatinvolved31malepatientswhohadEDinjuriesandwereintheearlystages
ofparaplegia[44].Recently,itwasdiscoveredthatanewtopicalformulationusinglyo-
tropicliquidcrystal(LLC)systemsandpapaverine-HClwasasuitableandefficientsub-
stitutefortheinjectableformulationinthetreatmentofED[34].Accordingtoastudy
conductedinvitro,thesubstanceincreasesthemotilityofpost-thawsperm[34].
6.2.ActivityagainstPulmonaryVas o c o n s t r i c tion
Theprotectiveeffectsofpapaverineonthelungshavebeendemonstratedthrough
variousmechanisms.Inamodelofpulmonaryembolismcausedbyautologousblood
clotsinrabbitlungsthatwereisolatedandperfused,papaverinewasdiscoveredtolessen
pulmonaryvasoconstrictionandedema.Inthepulmonaryvascularbed,papaverinecan
diminishthevasoconstrictorresponsetoET-1,TxA
2
,andserotoninwithoutalteringtheir
Molecules2023,28,314912of22
release.ItisgenerallyknownthatPDEinhibitorsalsohaveantiplateleteffectsduetotheir
abilitytoraisecAMPlevels.Papaverine,inparticular,hasbeendemonstratedtoreduce
plateletaggregationbroughtonbyADPaswell.Suchanoutcomemighthavecontributed
tothebeerresultsobservedinthepapaverine-treatedgroupin[45].Itwasdiscovered
thatitinhibitsvoltage-gatedCa2+channelsinaconcentration-dependentmanner,result-
ingintherelaxationoftrachealsmoothmuscle[46].Papaverinewithnifedipineeffectively
decreasedthepulmonaryarteryvasoconstrictionbroughtonbyECS(Euro-Collinssolu-
tion).TheelevationincAMPcausedbypapaverinemayimprovelungpreservation.Ad-
ditionally,ithasbeennotedtoreduceCa2+influxviacellmembranes[34].
6.3.PostoperativeVas o s p a s m
Tosignificantlyminimizepostoperativevasospasmsandmaintainregularvascular
morphologythroughoutantispasmodictherapy,papaverine-loadedelectrospunfibrous
membranesweredeveloped[47].Inarabbitmodel,itwasdiscoveredthattheintra-arte-
rialrouteismoreeffectiveforloweringautologousblood-inducedcerebralvasospasms
[48].Foraverylongtime,papaverinehasbeenusedtopreventvasospasmsinducedby
subarachnoidhemorrhage[49].Innumerousinvestigations,includinginpatientswho
hadaneurysmalsubarachnoidhemorrhages,theeffectivenessofpapaverineinavoiding
vasospasmswasvalidated.Papaverinecanbegiveneitheronitsownorinconjunction
withtransluminalballoonangioplasty.Inthesecircumstances,papaverinehasbeenfound
toimprovecerebraloxygenation,increasetheangiographicvesseldiameter,decreasethe
extendedcerebralcirculationtime,andboostcerebralbloodflowinanefforttoprevent
cerebralinfarction.Here,asignificantbarrieristheshort-livednatureofpapaverine[50–
53].Asustained-releaseformulationthatcanbeimplantedintracraniallymightminimize
this,anditwouldalsolowerthelikelihoodofhypotensionduringsurgery[54].Neverthe-
less,adifferenttrialinvolving31patientswithasubarachnoidhemorrhage-relatedvaso-
spasmfoundnoadditionalbenefitsfrompapaverinewhencomparedtothemedicaltreat-
mentofvasospasmsalone.Theauthorscametotheconclusionthatchangingthetimeor
indicationsfortherapeuticinterventioncouldbeadvantageous[49].Anotherretrospec-
tivestudyonnineconsecutivepatientswithacutelarge-arteryocclusiontreatedwitha
stentretrieverandintra-arterialpapaverinedemonstratedanincreaseinthecaliberand
flowoftheinfusedarteries,suggestingasafeandeffectivemethodoftreatingcerebral
vasospasmsfollowingmechanicalthrombectomyinacuteischemicstroke[55].Another
investigationof27patientswithasubarachnoidhemorrhage-relatedsymptomaticvaso-
spasmdiscoveredthatintra-arterialpapaverineconsistentlyreducescerebralcirculation
time[56].Followingintra-arterialinfusionofpapaverine,individualswithsymptomatic
vasospasmsshowedanimprovementincerebraloxygenationaswellasareductionin
cerebrallacticacidosis[57].
6.4.AntiviralProperties
Papaverineisalsorecognizedforitsantiviralactivitiesagainstdifferenthumanvi-
rusesandthemurineretrovirus,MSV-Harvey.Ithasbeenhypothesizedthat,atleastfor
themeaslesvirus,interferencewithcellularDNAsynthesisdirectly,competitiveandre-
versiblebindingtotheDNAmolecule,oranincreaseinendogenouscAMPwillimpede
viralRNAsynthesisandthephosphorylationofviralproteins[58].Inastudy,papaverine
suppressedtheviralgrowthofmeaslesinneuroblastomacellsbyinhibitingthesynthesis
ofviralRNAsinadose-dependentandreversiblemanner[59].Itwasreportedtoshow
effectiveantiviralactivitybyinhibitingthereplicationoftheCMVvirus.Themechanism
ofactionunderlyingtherelaxingeffectofthesedrugsonsmoothmusclemaypreventat
leasttheinitialcellrounding,anditispossiblethatacriticalphysiologicevent(s)(e.g.,the
riseinintracellularfreeCa2+)maybeimportanttobothearlycellularresponsesandCMV
replication[60].PapaverineinhibitedthereplicationofHIVinH9celllinesbyblocking
theRTactivityandp24expression.Italsoshowedinhibitingactivityintheperipheral
bloodmononuclearcell(PBMC)culturebyinfluencingtheviralmarkersRTandp24
Molecules2023,28,314913of22
[58,61].Itinhibitedthereplicationofthemeaslesvirusinneuralcells[62].Papaverine
showedadose-dependentinhibitionofmultiplestrainsofinfluenzaviruswhen
A/WSN/33(H1N1),A/Udorn/72(H3N2),andB/Lee/40wereusedinastudy[63].Inavery
recentstudy,papaverinerevealeditsabilitytoinhibittheSARS-CoV-2cytopathicityin
thehumanepithelialcolorectaladenocarcinomacellline,Caco-2[64](Table1).
Tab l e 1.Antiviralpropertiesofpapaverine.
MoleculeActivity
Against
Experimental
ApproachesKeyResultMechanism
ofActionReference
Papaverine
hydrochlo‐
ride
HIV
Determinationofviral
replicationbyliquid
competitionradioim-
munoassayinH9cell
lineandinperipheral
bloodmononuclearcell
(PBMC)culture.
-Thedrugatacon-
centrationof10
µg/mLresultedin
noreversetran-
scriptaseactivityor
p24expression-spe-
cificviralmarkersin
thesupernatantand
novirusantigende-
tectionatthecellu-
larlevel.
-Thedrugaffected
thesynthesisofthe
envprecursorpro-
teingpl60.
-Amarkeddecrease
intheexpressionof
theviralproteins
wasalsoobserved
aftertreatmentwith
papaverine.
-InterferewithDNAsyn-
thesisthroughcompeti-
tiveandreversiblebind-
ingtotheDNAmolecule.
-Fromthedata,theau-
thorsconcludedthatpa-
paverineseemstoaffect
thelatestepsofHIVrep-
lication.Infact,theselec-
tiveeffectsondifferent
proteinssuggestthatpa-
paverineactsafterre-
versetranscription.
[58]
Determinationofviral
replicationinMT4cell
lineandinperipheral
bloodmononuclearcell
(PBMC)culture.Exami-
nationofT-celllym-
phocytes.
Papaverinesignifi-
cantlyinhibitedHIV
replicationbymore
than99%atdosesof
30µMwithanCD50
andED50of32µM
and5.8µM,respec-
tively.
Thedrugmightaffectcel-
lularDNAsynthesisand
reversetranscription,in-
directlyinhibitingHIV
replication.
[61]
PapaverineMeaslesvirus
Determinationofviral
replicationinneural
andnon-neuralcells.
Analysisofmechanism
fortheinhibitionofvi-
ralreplication.
Suppressionofvi-
rusgrowthwas
mostprominentin
neuroblastomacells,
followedbythatin
epidermoidcarci-
nomaandglioblas-
tomacells.
-SynthesisofviralRNAs,
includinggenomicRNA
andmRNA,wasinhib-
ited.
-Phosphorylationofthe
viralproteinswasinhib-
ited.
[59]
PapaverineCMV
Assaysforinhibitionof
infectiousCMVyields
onhumanembryo
skin-muscle(SM)cells.
Assaysfortherateof
Inhibitionofthe
multiplicationof
CMV.Papaverine
wasthemostpotent
ofthethreedrugs
-Relaxingeffectofpapa-
verineonsmoothmuscle
mayatleastpreventthe
initialcellrounding.
[60]
Molecules2023,28,314914of22
cellDNAsynthesisby
measuringtheincorpo-
rationof[methyl3H]
thymidineintocell
DNA.
(papaverine,vera-
pamilandsodium
nitroprusside);ata
concentrationof30
µg/m(80µM)the
CMVyieldwasin-
hibitedby5.21log10
at120hrpostinfec-
tion(PI).
-Thegreaterpotencyof
papaverinerelativetoni-
troprussidemayhavere-
sultedfromincreasedlev-
elsofbothcyclicAMP
(cAMP)andcyclicGMP
(cGMP)ratherthanfrom
cGMPalone.
-Itispossiblethatacriti-
calphysiologicevent(s)
(e.g.,theriseinintracellu-
larfreeCa2+)maybeim-
portanttobothearlycel-
lularresponsesandCMV
replication.
Papaverine
Variousstrainsofin-
fluenzavirusaswell
astheparamyxovi-
rusesparainfluenza
virus5(PIV5),human
parainfluenzavirus3
(HPIV3),andrespira-
torysyncytialvirus
(RSV)
Determinationofanti-
viralactivitybyplaque
reductionneutraliza-
tiontest(PRNT).
Dose-dependentin-
hibitionofinfluenza
virusstrains.
-Kineticstudiesdemon-
stratedthatpapaverine
inhibitedinfluenzavirus
infectionatalatestagein
theviruslifecycle
throughthesuppression
ofnuclearexportof
vRNP,andalsointerfered
withthehostcellular
cAMPandMEK/ERKcas-
cadepathways.
[63]
PapaverineSARS-CoV-2Cytopathicityassays.
InhibitSARS-CoV-2
cytopathicityinthe
humanepithelial
colorectaladenocar-
cinomacellline,
Caco-2,withIC50
valueof1.1±0.39.
Additionalstudiesre-
quired.[64]
6.5.CardiovascularActivity
Papaverineexhibitedpotentcardioprotectiveeffectsbydiversemechanisms.Itdi-
rectlystimulatedthesinusrateandatrialcontractilitybydemonstratingpositivechrono-
tropicandinotropiceffectsonanisolatedatrialpreparationfromadog,whichagain
pointstotheinhibitionofPDEandaccumulatedcAMP.Additionally,papaverinemay
partiallytriggerthereleaseofcatecholaminesfromadrenergicnervefibersandmayin-
terferewiththeprocessofadenosineuptake.Itishypothesizedthatpapaverinemaydi-
rectlystimulateatrialcontractilityandSAnodalpacemakeractivity[65].Similareffects
werefoundinanotherstudywherepapaverinedisplayedpositiveinotropiceffectson
atrialpreparation,whereasinventricularpreparation,itdidnotaffecttheforceofcon-
tractionsignificantly[66].PapaverineinhibitsbothhKv1.5andnativehKv1.5channelsin
aconcentration,voltage,state,andtime-dependentmanner.Thisinteractionshowsthat
papaverinemaychangecardiacexcitabilityinvivo[67].
Molecules2023,28,314915of22
6.6.Anti‐InflammatoryActivity
ThroughthecAMP/PKAandMEK/Erkpathways,papaverinereducedtheexpres-
sionofproinflammatoryfactorsandinhibitedtheactivationofprimaryretinalmicroglia
causedbyLPS,andtheMEK/ErkpathwaymaybepartiallyregulatedbycAMP/PKA,
whichcanprovidetheoreticalandexperimentalsupportforitsprotectionofthecentral
nervoussystem[68].Yoshikawaetal.firstnoticedthatpapaverinecouldpreventthere-
leaseofTNF-αandIL-1βinLPS-inducedBV2cells[69].Similaractivitieswerereported
inanotherstudywherepapaverinepreventedtheproductionofnitricoxideandproin-
flammatorycytokinesinLPS-stimulatedmicroglia[31].Furthermore,itappearedtohave
anti-inflammatoryeffectsinmousemodelsbyinhibitinghighmobilitygroupbox1-me-
diatedinflammatoryresponses[70].SimilareffectsweredemonstratedinLPS-stimulated
macrophagesandmicrogliawherepapaverinesuppressedTNF-α[68,71],IL1β,andthe
NF-κBsignalingpathway[72],thusprovingitspotentialtotreatneurodegenerativedis-
eases.
6.7.AnticancerActivity
Itwasfoundthatpapaverineeffectivelyinducedamorphologicalchangeandinhib-
itedproliferationandtheinvasivepotentialofhumanprostatecelllinesPC-3,DU145,and
LNCaPprimarilythroughitsPDE-inhibitingcapability,whichresultedinraisedcAMP
levels[73].SimilareffectswerereportedontheLNCaPcelllineduetoasynergisticeffect
inducedbyacombinationofpapaverineandprostaglandinE2(PGE2)[74]andonPC-3by
inducingapoptosisandcellcyclearrestalongwiththedownregulationofNFkBandthe
PI3K/Aktsignalingpathway[75].Thephytochemicalhasbeenreportedtoexhibitcyto-
toxiceffectsoncancerousHT29,T47D,andHT1080celllineswithoutaffectingthenon-
cancerousmouseNIH3T3celllineascomparedtodoxorubicin,awidelyusedanticancer
drug.ThemechanismbehinditwasselectiveDNAdamageandtheinductionofapoptosis
oncancerouscelllines[76].Itexpressedacytotoxiceffectagainstcancerstemcells,espe-
ciallyhumanbreastcancercelllineMCF-7,byarrestingthecellcycleintheG1phaseand
inducingapoptosis[77].Antiproliferativeactivityofthecompoundwasreportedonhepa-
tocarcinomacelllineHepG-2asitaffectedthetelomeraseactivity[78].Ithasbeenproven
tobeaneffectiveradiosensitizingagentthatreducestherateofoxygenconsumption
throughtheinhibitionofmitochondrialcomplexI.Thus,thecompoundwasfoundtoim-
provetheresponsetoradiationtherapyandisapotentialcandidatefortumorhypoxia
treatment[9].Papaverineisfoundtopreventcellmigrationanddelayzebrafishdevelop-
mentbysuppressingthekit-signalingpathway[79].Thecompoundsignificantlyinhib-
itedtheproliferationofhumanglioblastomacelllinesU87MGandT98Gandthetumor
volumeintheU87MGxenograftmousemodel[80,81].Thepapaverine–Au(III)complex
wasreportedtohavebeercytotoxicactivitiesagainsthumanbreastcancerMCF-7cells
andhepatocellularcarcinomaHepG-2cellsthanpapaverineitself,andtheinhibitingabil-
itywashigherthanthatofcisplatinagainstMCF-7[16].Caroverine,whichisonederiva-
tiveofpapaverine,preventedtheexpressionofVEGF,whichisawell-knowntumor-pro-
motingfactor[82].Inanotherstudy,apapaverineoxidationproductthatisa6a,12a-di-
azadibenzo-[a,g]fluorenyliumderivativeinhibitedtheMCF-7celllinebyblockingthe
G0/G1phaseofthecellcycleandtelomeraseactivity[83].AninvestigationinvolvingS.
cerevisiaeanddockingandmoleculardynamicsimulationstudiesshowedevidencethat
papaverineinducesROS-mediatedapoptosisandinhibitsBcr-Abldownstreamsignaling
[84](Table2).
Molecules2023,28,314916of22
Tab l e 2.Anticancerpropertiesofpapaverine.
MoleculeCellLineCellTypeSignificantBenefit
AchievedReference
PapaverinePC-3,DU145,and
LNCaPProstatecancer
Inducedmorphologic
changeandalsoraised
intracellularcyclic
AMPlevelsinLNCaP
cells.
[73]
Papaverinecombined
withprostaglandinE2
(PGE2)
LNCaPProstatecancer
Decreasedproliferation
andmalignancyof
LNCaPcellsand
causedthesuppression
oftheexpressionofon-
cogenessuchasc-myc
andBcl-2indifferenti-
atedLNCaPcells.
[74]
PapaverinePC-3Prostatecancer
Showedcytotoxicef-
fectsbyinducingearly
andlateapoptosis
alongwithinducing
sub-G1cellcyclearrest,
andcausedthedown-
regulationofBlc-2,
Bax,andNF-kBpro-
teinsandPI3Kand
phospho-Aktexpres-
sion.
[75]
PapaverineHT29,T47D,and
HT1080
Colorectalcancer,
breastcancer,andfi-
brosarcomacells
Showedcytotoxicef-
fectsbyselectiveDNA
damageandinduction
ofapoptosis.
[76]
PapaverineMCF-7andMDA-MB-
231Breastcancer
Showedcytotoxicef-
fectsbyarrestingcell
cycleinG0/G1phase
andinducingapopto-
sis.
[77]
PapaverineHepG-2Hepatocarcinoma
Inducedantiprolifera-
tiveactivitybyinhibit-
ingtelomerasethrough
downregulationof
hTERTgene.
[78]
Papaverinecombined
withtemozolomideU87MGandT98GGlioblastoma
Significantlyinhibited
theclonogenicityofthe
celllines,delayedtu-
morgrowth,andin-
creasedtheradiosensi-
tivityofT98Gcells.
[80,81]
Papaverine–Au(III)
complexMCF-7andHepG-2
Breastcancerand
hepatocellularcarci-
noma
Showedsignificantcy-
totoxicactivityagainst
theexaminedcelllines.
[16]
Molecules2023,28,314917of22
Additionally,theAu
complexshowedanti-
canceractivityagainst
thebreastcancerMCF-
7cellsbetterthanthat
ofcisplatin.
Papaverine
HCT15(colon),A549
(lung),HeLa(cervical),
K562(Bcr-Ablpositive
CML),andRAW264.7
Colon,lung,cervical,
andlymphoblastcan-
cers
InducedROS-mediated
apoptosisandinhibited
Bcr-Abldownstream
signaling.
[84]
Caroverine,derivative
ofpapaverineLT97andSW480ColorectalcancerInhibitionofexpres-
sionofVEGF.[82]
6a,12a‐diazadibenzo‐
[a,g]fluorenylium,de‐
rivativeofpapaverine
MCF-7Breastcancer
InhibitionofMCF-7
celllinebyblocking
G0/G1phaseofthecell
cycleandtelomerase
activity.
[83]
6.8.NeuroprotectiveEffect
Papaverinemayalsoexertneuroprotectiveeffectstotreatneuropsychiatricdiseases
suchasschizophreniaanddepression[85,86].Inaclinicaltrialinvolvingthreefemalepa-
tientswithtardivedyskinesia,itwasrevealedthatdaily300to600mgdosesofpapaverine
improvedthedyskinesiaconditionwithoutshowinganysideeffects.Theauthorscon-
cludedthattheeffectswereduetotheinhibitionofthedopaminepathway,whichmight
bethereasonfordyskineticmovements[87].Thestudywasagainconductedwithalarger
numberofpatientsviatheoraladministrationofsustained-release150mgpapaverine
capsules.Twooutofninepatientsshowedclinicalimprovements[88].Oro-facialdyski-
nesiawasimprovedinanotherclinicaltrialconductedon150patients[89].Papaverine
wasalsofoundtopotentiatenervegrowthfactor(NGF)-inducedneuriteoutgrowthin
PC12cellsinaconcentration-dependentmanner[90].Bysignificantlyraisingthelevelsof
BDNF,synapsin-IIa,DCX,pCREB,IL-10,andGSHinvariousbrainregionswhilesignifi-
cantlyloweringthelevelsofTNF-α,IL-6,andTBARS,thedrugwasfoundtorestorethe
basicbehavioralphenotypeinautismspectrumdisorder[9].Anotherstudyrevealedthat
thesubstancemaybeusefulinreducingtheischemicinfarctvolume,suggestingthatit
maybeusedtotreatcerebralischemiainclinicalpractice[91].BymodifyingtheNF-Band
CREBsignalingpathways,itpreventstheactivationoftheNLRP3inflammasome,which
reducesmicroglialactivationandneuronalcelldeath.Asaresult,itcouldbeapromising
treatmentforParkinson’sdisease,whichisexacerbatedbysystemicinflammation[92].In
thesubacuteMPTP/PanimalmodelofParkinson’sdisease,thedatarevealedthatpapa-
verinereducesneuroinflammationandMMP-3production,whichpreventsdopaminergic
neuronalcelldeathandα-synucleinaggregation.Inlightofthis,itmightbeaviablemed-
icationforthemanagementofParkinson’sdisease[93].Papaverineenhancedcognitive
functioninamousemodelwithHuntington’sdiseasebyinhibitingPDE10,resultingin
cAMP-responsiveelement-bindingprotein(CREB)phosphorylationandGluA1[94].It
alsoprovidedefficientprotectiontothespinalcordduringdescendingthoracicandthora-
coabdominalaorticaneurysmrepairsurgerybyperfusingthespinalcord[1].Inanother
study,papaverinerevealeditsdirecteffectonsynapticvesicles,whichwasexhibitedvia
theincreaseinnorepinephrineanddopamine-β-hydroxylasefromisolatedperfusedcat
spleen[95].Furthermore,papaverinetemporarilyincreasedsublingualmicrocirculatory
bloodflowinsepticshockpatientswhoneededvasoconstrictorstomaintainbloodpres-
sureduringfluidresuscitationwithoutaffectingsystemichemodynamics[96].

Molecules2023,28,314918of22
6.9.GestationalActivity
Inthe1990s,researchonpapaverineanditsderivativesrevealedthattheycould
shortenthetimeneededforthefirststageoflabor.AspecificinhibitorofPDE4,drotaver-
inehydrochloride,isahomologofpapaverine.Becauseofitsabilitytorelaxsmoothmus-
cles,itwasfoundtobebeneficialinacceleratingcervicaldilation[97].Madhuetal.found
thatwomenwhoweretreatedwithdrotaverinethroughthelatentphaseoflaborhada
significantlyshortertimebetweentheadministrationofthemedicationandthedelivery
ofthefetuscomparedtowomenwhoweretreatedwithaplacebo.Thestudyinvolved146
womenwhogavebirthvaginally(182mincomparedto245minwithaplacebo)[98].An-
otherretrospectivecomparativeinvestigationof498pregnantwomenindicatedthat
short-termprenatalexposuretopapaverineadjustedforindicationwasnotlinkedtopre-
termbirths,cesareanbirth,reducedbirthweight,smallgestationalage,orperinataldeath
[99].Additionally,itwasclaimedthatthemedicationworkedwelltolowerpre-eclamptic
patients’bloodpressure[100].
6.10.OtherActivities
Papaverinehydrochlorideisequallyaseffectiveassodiumdiclofenacfortheshort-
termreliefofacuterenalcolicpain,anditmaybeadvantageousinpatientswithcontra-
indicationsaccordingtoaprospective,single-blindclinicalstudythatinvolved86patients
withacuterenalcolicwhoweregiven120mgintravenouspapaverinehydrochloride
[101].Anotherstudyfoundthattheinjectionofalprostadilandpapaverineintothesper-
maticcordprotectedagainstischemia/reperfusioninjuryfollowingright-sidetestestor-
sionandreducedhistologicalalterationsfollowingtesticularischemia-reperfusioninjury
[102].
7.LimitationsoftheStudy
Executinganidealdrugdiscoveryanddevelopmentprocessisoneoftheprimary
challengesforthepharmaceuticalresearchcommunity.ADMEisacriticalstepinthedrug
designprocessthatinvestigatesthefateofadrugmoleculeafteringestion.Notably,drug
metabolismstudiesarecriticalprocessesforoptimizingtheleadcompoundswithoptimal
PK/PDfeatures,identifyingnewchemicalentitiesbasedonthediscoveryofactivemetab-
olites,minimizingpotentialsafetyliabilitiesduetothedevelopmentofreactiveortoxic
metabolites,comparingpreclinicalmetabolisminanimalswithhumanstoguaranteethat
animalsusedinexperimentshavethepotentialtoadequatelycoverhumanmetabolites
andsupporthumandosepredictions,andsoon[103].However,ADMEandthePK/PD
parametersofpapaverinewerenotevidentinthisreview.Whenitcomestodrugarition
duringtheclinicalstageofdevelopment,compoundfailureratesbecauseofthetoxicity
priortohumantestingarerelativelyhigh,andtheymayaccountforupto30%oftheloss.
Inordertoestablishananticipatedsafedoserangeandtogatherknowledgeondrugdis-
tribution,organ-specifictoxicity,andmetabolism,toxicologystudiesinatleasttwonon-
humanspeciesaretypicallyutilized[104].Thetoxicologicalparametersofpapaverine
werenotdefinedinthisreview.Propertranslationanddeterminationofthemaximum
recommendedstartingdoseinhumansisacriticaltaskinnewdrugdevelopmentand
research[105].Nospecificdoseofpapaverinewasstudiedinthisreview.Moreover,study
dataarenotavailableforuseinlactatingmothersandpediatricandgeriatricpatients.The
three-dimensionalityofmoleculesisintimatelyrelatedtotheclinicalsuccessofdrugcan-
didates[106],whichwasnotelaboratedoninthisreview.Theefficacyoftraditionalmed-
icinesisfrequentlytheconsequenceofasynergisticinteractionbetweennumerouscom-
ponents,targets,andpathways[107].Thisreviewdidnotincludethepositiveornegative
synergisticeffectsofpossibleanalogsofpapaverinefoundinopium.Possiblesideeffects
ofpapaverineincludepriapism,penilefibrosis,andarrythmia[108].Nostudieshavebeen
Molecules2023,28,314919of22
conductedonwhetherthesesideeffectscanbeutilizedasasecondaryusageviarepur-
posing;e.g.,metforministhefirst-linetherapyoftypeIIdiabetes,anditcanberepurposed
asanantiobesitydrugforbothdiabeticandnondiabeticpatients[109,110].
8.DiscussionandFutureRecommendations
Papaverinehasbeenproventobeahigh-valueopioidalkaloidinthefieldofthera-
peuticseitherinsolitudeorincombinationwithothermetabolites/molecules[9].Itwas
approvedbytheFoodandDrugAdministration(FDA)oftheUnitedStatesasavasodila-
tortobepredominantlyusedinthetreatmentofcerebralvasospasmsandcoronarycircu-
lation[108].Severalpreclinicalandclinicalstudiesalsodemonstrateditspotentialefficacy
againstpulmonaryvasoconstriction,erectiledysfunction,postoperativevasospasms,
someparticularviralinfections,inflammation,cardiacexcitability,carcinoma,neurologi-
caldisturbances,gestationaldifficulties,pre-eclampsia,acuterenalcolicpain,andische-
mia-reperfusioninjury,aswellasothermusclespasm-orientedcomplications
[87,88,91,101].Someofthenotablemechanismsunderlyingthedifferentpharmacological
actionsincludevasodilation,theactivationofcGMPandcAMP-dependentbiomolecules,
theinhibitionofvasoconstrictorresponsestobiomolecules,interferencewithcertainviral
nucleicacids,theinhibitionofcytokinerelease(suchasTNF-α,IL-1β,andNF-κB),the
apoptosisofdiseasedcells,thepotentiationofneuriteoutgrowth,thealterationofdiffer-
entbiomolecularsignalingpathways,etc.,whicharediscussedthroughoutthisreview.
Asaconsequence,themultiplebioactivecapabilitiesofpapaverinesuggestthatitmay
alsobeaneffectivenaturalphytoconstituentindiseasemanagement.Moreover,synthetic
drugsconsistofseveraldrawbacks,suchasalackofbioavailability,cost-effectiveissues,
drugresistanceissues,unexpectedadverseeffects,etc.[111].Tocombatthesedrawbacks,
thereisaneedtosearchforleadcompoundsamongthenaturalsubstances[112].Plants
areapresentfromtheEarththathavebeenprovidingusvitalphytochemicalsforthou-
sandsofyears[113,114].Bioactivephytochemicalsfromnaturalsourcesplaypivotalroles
indrugdiscoveryanddevelopment.Almost80%ofallcurrentlyavailabledrugsareeither
directlyderivedfromplantorareamodifiedversion[115,116].Alkaloidsareaveryim-
portantclassofbioactivephytochemicalsthatplayasignificantroleindrugdiscovery
[117].Thus,papaverineisapotentialnaturaldrugcandidatethatmaybeutilizedinthe
nearfuture.Researchersshouldcarryoutseveralstudiesonthepapaverinealkaloid,in-
cludingbystudyingthedeterminationandrevisionofitsPK/PDparameters,thethera-
peuticindex,safetyandtoxicologicalprofiles,dosage,drug–druginteractions,drug-food
interactions,andotherimportantparameters.Consideringallthesefactors,papaverine
shouldbesubjectedtoextensiveresearchtoestablishitasanoveldrugand/orleadcom-
pound.Thisreviewwillprovidefutureresearcherswithimportantinsightsforfurther
studiesonthisconspicuousalkaloid.
9.Conclusions
Themajorityofthealkaloidsisolatedfromtheopiumpoppyseed,suchasmorphine
andcodeine,haveanalgesicproperties;nevertheless,papaverinevariesfromtheopium
groupofalkaloidsbothchemicallyandtherapeutically.Whilethemajorityoftheprimary
alkaloidchemicalsderivedfromtheopiumpoppyarenarcoticandhaveananalgesicef-
fect,themajorityofpapaverine’spharmacologicalusageisasanon-narcotic,non-analge-
sicsmoothmusclerelaxantandvasodilator.Papaverineisarecognizedinhibitorofphos-
phodiesterases.PapaverineisFDA-approvedandisalreadyinclinicaluseasavasodila-
tor.Itisgainingmoreandmoreaentionforuseinotherbiologicalactivities.Withinthe
scopeofthiswork,wedescribedmultiplebioactivepropertiesofpapaverineinaddition
tothemolecularmechanismsbehindsuchactivities.Bothinvitroandinvivoaswellas
clinicalstudiesshowedthatpapaverinepossessedconsiderablepharmacologicalproper-
tiesbesidesitsvasodilatoreffects.Asaresult,itisavitalpotentialcandidatebothforthe
discoveryofnoveldrugsandthedevelopmentoftheexistingdrug.Asamaeroffact,its
Molecules2023,28,314920of22
antiviralandanticanceractionsbothexhibituniquemechanismsofactionthatshowcon-
siderablepotentialfortreatingtheirrespectiveillnesses,whichdemonstratesthatpapa-
verineisaprominentcandidateforuseintheresearchanddevelopmentofnewantiviral
andanticancermedications.Inaddition,toxicologicalresearchmustbecarriedouttoes-
tablishthesubstance’ssafetyforuseinotherpharmaceuticalapplications.
Aut h orContributions:Conceptualization,S.A.(SaniaAshrafi),S.A.(SafaetAlam),A.S.,A.R.and
B.K.;investigation,S.A.(SaniaAshrafi),S.A.(SafaetAlam),A.S.,A.R.,N.U.E.,F.T.R.,M.M.and
M.N.P.;writing—originaldraftpreparation,S.A.(SaniaAshrafi),S.A.(SafaetAlam),A.S.,A.R.,
N.U.E.,F.T.R.andT.S.;writing—reviewandediting,S.A.(SaniaAshrafi),S.A.(SafaetAlam),N.U.E.,
T.S.andB.K.;visualization,S.A.(SaniaAshrafi)andB.K.Allauthorshavereadandagreedtothe
publishedversionofthemanuscript.
Funding:ThisresearchwassupportedbyBasicScienceResearchProgramthroughtheNational
ResearchFoundationofKorea(NRF)fundedbytheMinistryofEducation(NRF-
2020R1I1A2066868),theNationalResearchFoundationofKorea(NRF)grantfundedbytheKorea
government(MSIT)(No.2020R1A5A2019413),agrantoftheKoreaHealthTechnologyR&DProject
throughtheKoreaHealthIndustryDevelopmentInstitute(KHIDI),fundedbytheMinistryof
Health&Welfare,RepublicofKorea(grantnumber:HF20C0038),andtheinnovationnetworksup-
portProgramthroughtheINNOPOLISfundedbyMinistryofScienceandICT(2022-IT-RD-0205-
01-101).
InstitutionalReviewBoardStatement:Notapplicable.
InformedConsentStatement:Notapplicable.
DataAvailabilityStatement:Notapplicable.
Acknowledgments:SaniaAshrafiisgratefultoRummanAdibforhiscontinuoussupportandmo-
tivationthroughoutthework.
ConflictsofInterest:Therearenoknownfinancialorresearch-basedconflictsofinterestamongthe
authorsofthisresearchworkandarticle.
SampleAvailability:Notapplicable.
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... Although the in vivo effects of papaverine have not been fully elucidated, it is known to increase cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) levels through the inhibition of phosphodiesterase enzymes. [23] These intracellular secondary messengers play pivotal roles in transmitting various physiological stimuli and regulating numerous physiological processes, including vascular resistance, cardiac output, visceral motility, immune responses, inflammation, neuroplasticity, vision, and reproduction. [24,25] In a study, pirfenidone, a drug with antifibrotic and anti-inflammatory properties currently used in the treatment of idiopathic pulmonary fibrosis, was utilized to prevent tendon adhesion and tendon healing in rats with Achilles tendon damage. ...
... Papaverine is also widely used in urology for diagnosing and treating impotence. [23] Interestingly, a study evaluating the effects of sildenafil, another phosphodiesterase inhibitor used in impotence treatment, on Achilles tendon healing reported positive histopathological effects. [32] In our study, while biomechanical effects were evident in the late period, positive differences were observed in all groups receiving papaverine treatment. ...
The effect of papaverine on tendon healing and adhesion in rats following Achilles tendon repair
Article
Full-text available
  • May 2024
  • EKLEM HAST CERRAHISI
Objectives: The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model. Materials and methods: Forty-eight adult male SpragueDawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15th (early period) or 30th (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15th and 30th days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation. Results: Histopathologically, there were no significant differences among the groups on the 15th day. However, on the 30th day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05). Conclusion: Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings. Keywords: Achilles tendon, healing, papaverine, rat, tendon repair.
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... For the pharmaceutical research community, the process of drug discovery and development presents substantial difficulties. The ADME procedure, which examines how a medication molecule behaves after consumption, is one of the most important ones [216]. Drug metabolism studies are essential for identifying active metabolites for new chemical entities, identifying reactive or toxic metabolites, mitigating safety concerns, ensuring the suitability of animal models for human metabolism, and facilitating precise dose estimations in humans [217]. ...
... For millennia, plants have bestowed us with essential phytochemicals, serving as invaluable resources [220]. These bioactive compounds are crucial in drug research and development, with approximately 80% of existing medications either originating directly from plants or being derivatives of them [216]. Therefore, these substances provide great promise as potential future natural medication candidates. ...
Flavonoids: A treasure house of prospective pharmacological potentials
Article
Full-text available
  • Mar 2024
Flavonoids are organic compounds characterized by a range of phenolic structures, which are abundantly present in various natural sources such as fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. The health advantages of these natural substances are renowned, and initiatives are being taken to extract the flavonoids. Apigenin, galangin, hesperetin, kaempferol, myricetin, naringenin, and quercetin are the seven most common compounds belonging to this class. A thorough analysis of bibliographic records from reliable sources including Google Scholar, Web of Science, PubMed, ScienceDirect, MEDLINE, and others was done to learn more about the biological activities of these flavonoids. These flavonoids appear to have promising anti-diabetic, anti-inflammatory, antibacterial, antioxidant, antiviral, cytotoxic, and lipid-lowering activities, according to evidence from in vitro, in vivo, and clinical research. The review contains recent trends, therapeutical interventions, and futuristic aspects of flavonoids to treat several diseases like diabetes, inflammation, bacterial and viral infections, cancers, and cardiovascular diseases. However, this manuscript should be handy in future drug discovery. Despite these encouraging findings, a notable gap exists in clinical research, hindering a comprehensive understanding of the effects of flavonoids at both high and low concentrations on human health. Future investigations should prioritize exploring bioavailability, given the potential for high inter-individual variation. As a starting point for further study on these flavonoids, this review paper may promote identifying and creating innovative therapeutic uses.
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... A cardiac glycoside that has inotropic effects and is used to manage systolic dysfunction in congestive heart failure (CHF) patients and also work as atrioventricular nodal blocking agent to manage atrial tachydysrhythmias Glycyrrhiza glabra It is used as a remedy for gastrointestinal problems, cough, bronchitis, arthritis and widely used to treat gastritis and peptic ulcers Papaver somniferum An alkaloid used as a vasodilator and direct-acting smooth muscle relaxant [65] Physostigmine ( Fig. 2) Physostigma venenosum A reversible acetylcholine esterase inhibitor in both the periphery and central nervous system. It is used to treat glaucoma and anticholinergic toxicity [66,67] Pilocarpine (Fig. 2) Pilocarpus jaborandi An alkaloid used to treat glaucoma and xerostomia [68] Pseudoephedrine (Fig. 2) Ephedra sinica A sympathomimetic used to treat the symptoms of paranasal sinuses and obstruction in the nasal cavity, in addition to vasomotor rhinitis, allergic rhinitis, and otitis media [69] Quinine (Fig. 2) Cinchona ledgeriana Prevention and therapy of malaria [70] Reserpine (Fig. 2) Rauvolfia serpentina An alkaloid extract used to treat hypertension [71] Scopolamine (Fig. 2) Hyoscyamus niger A natural alkaloid with potent anticholinergic effects that used for the treatment of nausea, vomiting, and motion sickness [72] Sennosides A, B (Fig. 3) ...
Antibacterial activity of medicinal plants and their role in wound healing FJPS s43094-024-00634-0 Online
Article
Full-text available
  • May 2024
Background The study of plant-based medications, or phytomedicine, involves a wide spectrum of biological activi- ties. Due to the existence of secondary metabolites, herbal medicine has been used and practiced throughout history for the treatment of both acute and chronic conditions. Over the past century or so, numerous novel compounds with medicinal potential have been derived from plants. In the age of growing super infections and the emergence of resistant strains, natural medicines are inspiring optimism. Main body of the abstract The review discusses the role of herbal medicine as antibacterial agents and their use in wound care and management of wounds and the critical role of secondary metabolites of herbal plants in fight- ing bacterial infections. Some medicinal plants such as St. John’s wort (SJW) (Hypericum perforatum), Rosemary (Rosmarinus officinalis), Ginger (Zingiber officinale), and nopal cactus (Opuntia ficusindica (L.)) also possess wide range of biological activities and can give a synergistic effect if combined with antibiotics. In addition, natural biopolymers play an important role in the management of wounds as well as the physiological processes of the skin (hemostasis, inflammation, proliferation, and remodelling). Method A narrative review of papers relevant to the use of phytomedicine in treating infections was conducted by using electronic databases PubMed, CrossREF, and Google Scholar. Short conclusion Phytomedicine is one of the top options for the treatment of chronic illnesses for millions of peo- ple around the world. To learn about the bioactive components of medicinal plants, their medical benefits, and their synergistic or additive effects to enhance the action of medications, substantial new studies are still needed.
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... In papaverine, regarding neurodegenerative diseases, such as Alzheimer's disease (8) or Parkinson's disease (9), it has not been specifically investigated or recognized as a potential therapeutic agent for these conditions. However, some studies suggest that papaverine as PDE10 inhibitor primarily breaks down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in cells (10). A study suggests that Tofisopam could modulate cellular processes involved in neurodegeneration and amyloid-beta accumulation (11). ...
In silico screening of drug Bank data base to PDE10: A drug repurposing approach
Article
Full-text available
  • Sep 2023
Drug repurposing has emerged as a promising strategy for expediting drug development by identifying new therapeutic applications for existing drugs. In this study employed in silico screening approach to explore the DrugBank database for potential phosphodiesterase 10 (PDE10) inhibitors with applications in neurological, psychiatric disorders and cancer treatment. PDE10 plays a crucial role in regulating cyclic nucleotide levels in the brain and has been implicated in various diseases, including schizophrenia, Parkinson’s, Huntington’s diseases, and certain types of cancer. Through molecular docking, we evaluated the interactions and energetics of 28 candidate inhibitors with PDE10. Notably, 17 candidates met all selection criteria, presenting excellent potential for further investigation. The theoretical inhibitors demonstrated favorable ADMETx properties, and their adverse effects were comparable or lower than controls. These findings indicate the viability of repurposing existing drugs, such as Nebivolol, Fluvastatin, Pioglitazone and others, for PDE10 inhibition in diverse pathologies. Validation of these candidates in preclinical studies may open new avenues for drug development and clinical applications, addressing unmet medical needs in various disorders and cancer treatment.
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PAPAVER SOMNİFERUM (HAŞHAŞ) BİTKİSİNİN ALKOLOİDLERİNİN FARMAKOLOJİK ve TOKSİKOLOJİK ÖZELLİKLERİ
Article
  • Jan 2024
Endüstriyel ve tıbbi açıdan önemli bir bitki olan Papaver somniferum L. (haşhaş) uzun bir kullanım geçmişine sahiptir. Haşhaş, morfin, kodein, tebain, papaverin, noskapin ve narsein gibi güçlü alkaloidleri üretmektedir. Bu alkaloidler, ağrı kesici (analjezik), öksürük bastırıcı (antitusif) ve bazı durumlarda yatıştırıcı (sedatif) etkilere sahiptir. Morfin, kodein ve diğer alkaloidler, şiddetli ağrıları hafifletmek için kullanılan güçlü analjeziklerdir. Bu nedenle, cerrahi operasyonlar veya şiddetli ağrı durumlarında kullanılmaktadırlar. Uygun şekilde kullanıldığında, ağrıyı hafifletebilirler, ancak kötüye kullanıldığında bağımlılık ve yan etki riski taşırlar. Kodein ise öksürüğü bastırıcı etkisi nedeniyle öksürük şuruplarında sıkça kullanılmaktadır. Bazı alkaloidler, uykusuzluk tedavisinde kullanılabilirler. Bu etkilerinin yan ısıra antioksidan, antimikrobiyal, antikanser etkileri de araştırılmaktadır. Bu derlemede, haşhaş bitkisinin alkaloidlerinin bazılarının farmakolojik ve toksikolojik özellikleri hakkında bilgiler verilmesi amaçlanmıştır.
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Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype
Article
  • Apr 2024
  • GENE DEV
Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR–Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.
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Immunomodulatory Effect of Phytoactive Compounds on Human Health: A Narrative Review Integrated with Bioinformatics Approach
Article
  • Mar 2024
  • CURR TOP MED CHEM
Background Immunomodulation is the modification of immune responses to control disease progression. While the synthetic immunomodulators have proven efficacy, they are coupled with toxicity and other adverse effects, and hence, the efforts were to identify natural phytochemicals with immunomodulatory potential. Objective The objective of this study is to understand the immunomodulatory properties of various phytochemicals and investigate them in Echinacea species extracts using an in silico approach. Methodology Several scientific database repositories were searched using different keywords: “Phytochemicals,” “Alkaloids,” “Polyphenols,” “Flavonoids,” “Lectins,” “Glycosides,” “Tannins,” “Terpenoids,” “Sterols,” “Immunomodulators,” and “Human Immune System” without any language restriction. Additionally, the study specifically investigated the immunomodulatory properties of Echinacea species extracts using gene expression analysis of GSE12259 from NCBI-GEO through the Bioconductor package GEOquery and limma. Results A total of 182 studies were comprehensively analyzed to understand immunomodulatory phytochemicals. The in silico analysis highlighted key biological processes (positive regulation of cytokine production, response to tumor necrosis factor) and molecular functions (cytokine receptor binding, receptor-ligand activity, and cytokine activity) among Echinacea species extracts contributing to immune responses. Further, it also indicated the association of various metabolic pathways, i.e., pathways in cancer, cytokine-cytokine receptor interaction, NF-kappa B, PI3K-Akt, TNF, MAPK, and NOD-like receptor signaling pathways, with immune responses. The study revealed various hub targets, including CCL20, CCL4, GCH1, SLC7A11, SOD2, EPB41L3, TNFAIP6, GCLM, EGR1, and FOS. Conclusion The present study presents a cumulative picture of phytochemicals with therapeutic benefits. Additionally, the study also reported a few novel genes and pathways in Echinacea extracts by re-analyzing GSE 12259, indicating its anti-inflammatory, anti-viral, and immunomodulatory properties.
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Natural and Synthetic Phosphodiesterase Inhibitors in 2023: an Update on the Impact on Neurological and Psychiatric Conditions
Article
  • Oct 2023
  • MINI-REV MED CHEM
This Perspective provides an updated overview on the involvement of phosphodiesterase (PDE) isoforms and of the corresponding inhibitors in neurological disorders, including dementia, Parkinson’s disease, multiple sclerosis, neuropsychiatric conditions and cerebral ischemia. Particular attention has been dedicated to natural and semi-synthetic compounds. Translation into the clinic of preclinical results, toxicity profile and bioavailability represent the challenging aspects in the development of PDE inhibitors. With the aim of providing the latest updates to the reader, the 2023 contributions in the field were considered for the preparation of this Perspective
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Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target
Article
Full-text available
  • Jan 2023
  • INT J MOL SCI
Brown adipose tissue (BAT) is increasingly recognized as the major therapeutic target to promote energy expenditure and ameliorate diverse metabolic complications. There is a general interest in understanding the pleiotropic effects of metformin against metabolic complications. Major electronic databases and search engines such as PubMed/MEDLINE, Google Scholar, and the Cochrane library were used to retrieve and critically discuss evidence reporting on the impact of metformin on regulating BAT thermogenic activity to ameliorate complications linked with obesity. The summarized evidence suggests that metformin can reduce body weight, enhance insulin sensitivity, and improve glucose metabolism by promoting BAT thermogenic activity in preclinical models of obesity. Notably, this anti-diabetic agent can affect the expression of major thermogenic transcriptional factors such as uncoupling protein 1 (UCP1), nuclear respiratory factor 1 (NRF1), and peroxisome-proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) to improve BAT mitochondrial function and promote energy expenditure. Interestingly, vital molecular markers involved in glucose metabolism and energy regulation such as AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21) are similarly upregulated by metformin treatment in preclinical models of obesity. The current review also discusses the clinical relevance of BAT and thermogenesis as therapeutic targets. This review explored critical components including effective dosage and appropriate intervention period, consistent with the beneficial effects of metformin against obesity-associated complications.
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Nigella sativa tea mitigates type-2 diabetes and edema: a case report
Article
Full-text available
  • Jan 2023
Diabetes is a major deadly disease. In 2019 alone, it caused an estimated 1.5 million deaths world-wide. Cases of diabetes are rising rapidly in low- and middle-income countries. Natural remedies that can lower the glucose level would be very useful, particularly to people living in low- and middle-income countries. A 2-year case study was carried out, therefore, to determine if Nigella sativa tea can lower the glucose level in a 72-year-old man with type-2 diabetes, stage 3–4 chronic kidney disease, and congestive heart failure. Changes in body weight, lipids, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) were also studied. N. sativa tea was prepared with N. sativa , barley, and wheat seeds. The 72-year-old drank approximately 50 ml of N. sativa tea daily, in the morning. Results showed that after drinking N. sativa tea daily, hypoglycemia started to occur and occurred more frequently as time went by and that the glycated hemoglobin, HbA1c, was decreasing. Subsequently, the dosages of insulin glargine and insulin aspart were reduced by 33% and 50%, respectively. Results also showed that weight loss led to the 72-year-old cutting back his intake of the diuretic furosemide by at least 50%. His triglycerides level was also lower and there were no changes in his total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels. His eGFR was stable but his UACR was worsening. N. sativa tea is easy to prepare, costs very little, and could be a natural remedy for mitigating diabetes and edema. Many more studies on N. sativa are warranted.
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Amaranthus spinosus (Spiny Pigweed) methanol leaf extract alleviates oxidative and inflammation induced by doxorubicin in male sprague dawley rats
Article
Full-text available
  • Jan 2023
This study evaluated the ameliorative effect of Amaranthus spinosus leaf methanol extract (ASLME) against doxorubicin-induced multi-organ damage in Sprague Dawley Rats. Forty-nine (49) male Sprague Dawley rats were randomly stratified into 7 groups with 7 rats per group. Groups A and B received distilled water for 7 days. Groups C, D, and E were pretreated for 7 days with 200 mg/kg silymarin, 500 and 1000 mg/kg ASLME, respectively followed by intraperitoneal injection of 20 mg/kg doxorubicin (DOX) to groups B, C, D, and E on the 8th day. Groups F and G were orally administered 500 and 1000 mg/kg ASLME respectively for 7 days with an intraperitoneal injection of distilled water on the 8th day. After 48 h of DOX administration, blood was withdrawn by cardiac puncture, and organs were excised for biochemical and histopathological assays. Pretreatment with ASLME decreased the levels of tissues malondialdehyde and nitric oxide as well as serum tumor necrosis factor alpha (TNF-α) with a concomitant (p < 0.05) increase in the levels of serum interleukin-10 (IL-10) and tissues reduced glutathione in a dose-dependent manner compared to group B. The activities of antioxidant enzymes increased significantly (p < 0.05) in the ASLME pretreated groups as well as groups F and G when compared to group B. Administration of doxorubicin induced degenerative hepatic, nephrotic and cardiac biomarkers and histological changes in Group B, while remarkable reversal of these pathological features was observed in groups pretreated with ASLME. Our findings suggest the chemo-protective effect of ASLME against doxorubicin-induced multi-organ damage, by alleviating oxidative stress and inflammation in rats.
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The Biological Relevance of Papaverine in Cancer Cells
Article
Full-text available
  • Oct 2022
Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the Papaverine somniferum plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits phosphodiesterase 10A (PDE10A,) resulting in the accumulation of cyclic adenosine 3′, 5′-monophosphate (cAMP) that affects multiple downstream pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), a mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). The accumulation of cAMP can further affect mitochondrial metabolism through the activation of protein kinase A (PKA), which activates the mitochondrial complex I. Literature has shown that PPV exerts anti-proliferative affects in several tumorigenic cell lines including adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2) cell lines. Cell cycle investigations have shown varying results with the effects dependent on concentration and cell type with data suggesting an increase in cells occupying the sub-G1 phase, which is indicative of cell death. These results suggest that PPV may be a beneficial compound to explore for the use in anticancer studies. More insight into the effects of the compound on cellular and molecular mechanisms is needed. Understanding the effects PPV may exert on tumorigenic cells may better researchers’ understanding of phytomedicines and the effects of PPV and PPV-derived compounds in cancer.
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Isolation, Characterization and Pharmacological Investigations of a New Phenolic Compound along with Four Others Firstly Reported Phytochemicals from Glycosmis cyanocarpa (Blume) Spreng
Article
Full-text available
  • Sep 2022
  • MOLECULES
Plants are serving the mankind with important bioactive phytochemicals from the very ancient ages to develop novel therapeutics against different disease states. Glycosmis cyanocarpa (Blume) Spreng is a plant from the Rutaceae family and a very less explored species from the Glycosmis genus. Thus, this present study was intended to present the chemical and biological investigation of Glycosmis cyanocarpa (Blume) Spreng. The chemical investigation resulted in the isolation of one new phenolic compound to the best of our knowledge which is (4-(3-hydroxy-2-methylpropyl)-2-methoxyphenol) (1) along with four known compounds that are isolated for the first time from this species- 3-methyl-1H-indole (2), Tri-transpoly-cis prenol-12 (3), Stigmasterol (4) and β-sitosterol (5). Their chemical structures were elucidated based on extensive spectroscopic methods, including 1D and 2D NMR, and comparison with the available literature data. Isolated phytochemicals were further investigated to unveil their antioxidant properties with IC50 values (ranged from 9.97–75.48 µg/mL), cytotoxicity with LC50 values (ranged from 1.02–1.92 µg/mL), and antibacterial properties against some selected Gram (+) ve and Gram (−) ve bacteria. Among the compounds, 3-methyl-1H-indole (2) was found to be the most active against Staphylococcus aureus. Moreover, the phenolic compound (1) and the alkaloid (2) revealed the highest antioxidant (9.97 µg/mL) and cytotoxic activities (1.02 µg/mL), respectively. Thus, the isolation of these bioactive phytochemicals from the plant revealed a new perception in the study arena of drug discovery and the findings may ease the development and discovery of novel therapeutics. Further investigations are still recommended to understand their exact molecular mechanism and toxicological impact.
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In Vitro Effects of Papaverine on Cell Migration and Vascular Endothelial Growth Factor in Cancer Cell Lines
Article
Full-text available
  • Apr 2022
  • INT J MOL SCI
Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from Papaver somniferum that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.
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Prospective Asian plants with corroborated antiviral potentials: Position standing in recent years
Article
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  • Apr 2022
Viral diseases are extremely widespread infections caused by viruses. Amongst numerous other illnesses, viral infections have challenged human existence severely. Over the history of mankind, new viruses have emerged and presented us with new tests. The range of viral infections varies from familiar infectious diseases such as the common cold, flu, and warts to severe ailments such as AIDS, Ebola, and COVID-19. The world has been racing to find an effective cure for the newly evolving viruses. Toxic effects, non-selectivity, drug resistance, and high price are the most common complications of conventional treatment procedures. Nature is a marvelous source of phytoconstituents with incredible varieties of biological activities. By tradition, medicinal plants have been utilized for the treatment of countless infectious diseases worldwide, some of which contain a broad spectrum of activities. Modern drug discovery and development techniques offer highly efficient separation techniques, inauguration of vector-based schemes where the original infectious virus is cloned to the non-infectious one for antiviral screening targets. The objective of the review was to gather available data on 20 both cultivated and native plants of Asia giving antiviral activities and provide comprehensive information on the phytochemical analysis of the plants and potential antiviral compounds isolated from these plants.
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Antidiabetic Phytochemicals From Medicinal Plants: Prospective Candidates for New Drug Discovery and Development
Article
Full-text available
  • Feb 2022
Diabetes, a chronic physiological dysfunction affecting people of different age groups and severely impairs the harmony of peoples' normal life worldwide. Despite the availability of insulin preparations and several synthetic oral antidiabetic drugs, there is a crucial need for the discovery and development of novel antidiabetic drugs because of the development of resistance and side effects of those drugs in long-term use. On the contrary, plants or herbal sources are getting popular day by day to the scientists, researchers, and pharmaceutical companies all over the world to search for potential bioactive compound(s) for the discovery and development of targeted novel antidiabetic drugs that may control diabetes with the least unwanted effects of conventional antidiabetic drugs. In this review, we have presented the prospective candidates comprised of either isolated phytochemical(s) and/or extract(s) containing bioactive phytoconstituents which have been reported in several in vitro, in vivo, and clinical studies possessing noteworthy antidiabetic potential. The mode of actions, attributed to antidiabetic activities of the reported phytochemicals and/or plant extracts have also been described to focus on the prospective phytochemicals and phytosources for further studies in the discovery and development of novel antidiabetic therapeutics.
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Papaver Plants: Current Insights on Phytochemical and Nutritional Composition Along with Biotechnological Applications
Article
Full-text available
The genus Papaver is highly esteemed in the pharmacy industry, in the culinary field, and as ornamental plants. These plants are also valued in traditional medicine. Among all Papaver species, Papaver somniferum L. (opium poppy) is the most important species in supplying phytochemicals for the formulation of drugs, mainly alkaloids like morphine, codeine, rhoeadine, thebaine, and papaverine. In addition, Papaver plants present other types of phytochemicals, which altogether are responsible for its biological activities. Therefore, this review covers the phytochemical composition of Papaver plants, including alkaloids, phenolic compounds, and essential oils. The traditional uses are reviewed along with their pharmacological activities. Moreover, safety aspects are reported to provide a deep overview of the pharmacology potential of this genus. An updated search was carried out in databases such as Google Scholar, ScienceDirect, and PubMed to retrieve the information. Overall, this genus is a rich source of alkaloids of different types and also contains interesting phenolic compounds, such as anthocyanins, flavonols, and the characteristic indole derivatives nudicaulins. Among other pharmacological properties, numerous preclinical studies have been published about the analgesic, anticancer, antimicrobial, antioxidant, and antidiabetic activities of Papaver plants. Although it highlights the significant impact of this genus for the treatment of a variety of diseases and conditions, as a future prospect, characterization works accompanying preclinical studies are required along with clinical and toxicology studies to establish a correlation between the scientific and traditional knowledge.
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Novel Drug Targets With Traditional Herbal Medicines: Scientific and Clinical Evidence
Book
  • Jul 2022
This book collects information about the most popular ethnomedicinal plants, which are common in Turkey and around the world. It presents the ethnopharmacological records, in vivo and in vitro studies, side effects, chemical compositions and clinical studies of these medicinal plants. Its special focus is on the novel drug targets for disease and their possible mechanisms of action. It covers botanical descriptions the status of the plants, and food or drug interactions including precautions and warnings about the plants and the available market products. It provides an explanation of recorded and known plant administration dosages. Also, the gap between the traditional practice and scientific/clinical evidences in the use of ethnomedicinal plant is acknowledged.
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