醫(yī)學(xué)期刊的投稿的方法與技巧

AntiretroviralPharmacologyAmandaH.Corbett,PharmD,BCPSClinicalAssistantProfessorUNCSchoolofPharmacyOct19,2007學(xué)分網(wǎng)AntiretroviralClassesNRTIs

(NucleosideORNucleotideReverseTranscriptaseInhibitors,aka“Nukes”)NNRTIs

(Non-NucleosideReverseTranscriptaseInhibitors,aka“Non-Nukes”)PIs

(ProteaseInhibitors)FusionInhibitorsChemokineReceptor AntagonistsIntegraseInhibitorsMechanismofActionofARVsNNRTINRTIProteaseInhibitorIllustrationbyDavidKlemmFusionInhibitor&ChemokineReceptorAntagonistIntegraseInhibitorAntiretroviralDrugApproval:

1987-2007AZTddIddCd4T3TCSQVRTVIDVNVPNFVDLVEFVABCAPVLPV/rTDFT-20ATVFTCFPVTPVDRVMaravirocRaltegravirLiverMetabolism100%3A4CYP100%100%100%50%50%50%25%25%AdaptedfromBrJClinPharmacol1998:46:101-110PgpsmallbowelgutlumensinusoidportalveinhepaticveinNRTIs

MechanismofActionNucleosideanalogs(likeAZTbelow)Analogofthymidine,cytosine,adenine,orguanineTriphosphorylatedinsidelymphocytestoactivecompoundIncorporateintothegrowingHIVviralDNAstrandbyreversetranscriptaseNucleotideanalogCurrentlyonlytenofovir(TDF)DoesNOTneedtobetri-phosphorylatedonlydi-phosphorylatedtoactivecompoundAfterincorporationoftheNRTI,viralDNAsynthesiswillbeterminated.NRTIClassToxicitiesLacticAcidosisDamagetomitochondriaincellsElevatedlactate,lowpH/bicarbonate,N/V,shortnessofbreath,ifuntreatedcanleadtodeathHepatomegalywithSteatosisBuildupoffatdropletsinsidelivercellsEnlargedliverNRTIsDrugStandardDose*DosageformsCommonSideEffectsMetabolism/EliminationZidovudine

(ZDV/AZT)Retrovir300mgbid*300mgtab,100mgcap,iv,oralsolnFatigue,malaise,HAmyalgia,anemia,GIRenalLamivudine

(3TC)Epivir150mgbid*or300mgqd150,300mgtab,oralsolnWelltoleratedRenalEmtricitabine(FTC)Emtriva200mgqd*200mgcapWelltoleratedRenalDidanosine

(ddI)Videx400mgECqd(60kg)250mgECqd(<60kg)*125,200,250,400mgcap,pwdrforsolnPancreatitis,peripheralneuropathy,LA/HSRenal*dosereduceforrenaldysfunctionNote:LacticacidosiscanoccurwithanyNRTIsNRTIsDrugStandardDose*DosageformsCommonSideEffectsMetabolism/EliminationStavudine(d4T)ZeritIR40mgbid(60kg)30mgbid(<60kg)*15,20,30,40mgcap,oralsolnPeripheralneuropathy,Pancreatitis,LA/HS,Lipoatrophy,facialwasting

RenalAbacavir(ABC)Ziagen300mgbid,600mgqd300mgtabs,oralsolnhypersensitivityHepaticbyalcoholdehydrogenaseandglucuronyltransferaseTenofovir(TDF)Viread300mgqd*300mgtabsFewSEs,renaltoxicityRenal*dosereduceforrenaldysfunctionNRTICombinationsDrugStandardDose*DosageformsLamivudine/Zidovudine(COM)Combivir1Tabletbid

*150/300mgtabsAbacavir/Lamivudine/Zidovudine(TZV)Trizivir1Tabletbid*300/150/300mgtabsTenofovir/EmtricitabineTruvada1Tabletqd*300/200mgtabsAbacavir/LamivudineEpzicom1Tabletqd*600/300mgtabsTenofovir/Emtricitabine/EfavirenzAtripla1Tabletqd*300/200/600mgtabs*dosereduceforrenaldysfunctionNon-nucleosideReverseTranscriptaseInhibitors(NNRTIs)Theseagentsdirectlybindtoreversetranscriptase

toinhibittranscriptionNNRTIsdonotrequirephosphorylationtobeactive

RT

XNNRTIsDrugStandardDoseDosageformsCommonAEsMetabolismDelavirdine

(DLV)Rescriptor400mgtid100mgtab,200mgcapRashPotentCYP3Ainhibitor;3A4substrateNevirapine

(NVP)Viramune200mgqdx14dthen200mgbid200mgtabs,OralsuspRash(SJ),hepatotoxicityCYP3Ainducer,autoinducer;3A4,2B6substrateEfavirenz*

(EFV)Sustiva600mgqhs50,100,200mgcap,600mgtabVividdreams,drowsinessorinsomnia,rash(SJ),hyperlipidemiaCYP3A,2B6inducer;2B6,3A4substrate*PregnancyClassDProteaseInhibitors(PIs):

MechanismofActionProteaseenzymecleavesHIVprecursorproteins(gag/polpolyproteins)intoactiveproteinsthatareneededtoassembleanew,matureHIVvirus.PIsbindtoproteasepreventingthecleavageandinhibitingtheassemblyofnewHIVvirusesPIHIV-1Protease

XHIVLipids,InsulinResistance(Lypodystrophy)HypercolesterolemiaUsuallyhypertriglyceridemia,canhaveincreasedLDLanddecreasedHDLTreatwithFibricacidderivativesandcertainHMGCoAreductaseinhibitorsInsulinResistanceTreatwithdiet/exercise,metformin,TZDs,insulin,sulfonylureasLipodystrophyIllustrations“Buffalohump”“Proteasepaunch”“Facialwasting”UseofRitonavirasaP450InhibitorwithPIsProteaseInhibitorsStandardDoseDosageFormsMetabolismCommonAEs**Saquinavir(Invirase)(1)1000/rtv100bidor1600/rtv100qd200mgcaps,500mgtabs3A,Pgpsubstrate;weak3AinhibitorGIintoleranceNelfinavir(Viracept)(1)1250bid,750mgtid250mg,625mgtabs,50mg/goralpwdr2C19(M83A)substrate;weak3AinhibitorDiarrheaLopinavir/ritonavir(Kaletra)(1,2)400/100bid200/50mgtabs,80/20mg/5mLsoln3A,Pgpsubstrate;3Ainhibitor;2C9,2C19inducerDyspepsia,Nausea,vomiting,diarrhea,flatulenceIndinavir(Crixivan)(1-whentakenwithrtv)800/rtv100bid,800mgtid100,200,333,400mgcaps3A,Pgpsubstrate;weak3AinhibitorNephrolithiasisDrink7-8glassesofwaterperday;hyperbilirubinemia(1)TakewithFood(2)Mustberefrigerated**AllPIsexceptatazanavircanincreaselipidsandcauseinsulinresistanceProteaseInhibitorsStandardDoseDosageFormsMetabolismCommonAEs**Atazanavir(Reyataz)(1)400qdor300/rtv100qd100,150,200mgcaps3Asubstrate;3AandUGT1A1inhibitorHyperbilirubinemia,PRprolongationFosamprenavir(Lexiva)(1)1400mgbid;700/100RTVmgbid;1400/200RTVmgqd700mgtabs(Agenerase-APVliqavailable)3A4,Pgpsubstrate;3A4inducer/InhibitorRash,GIintolerance,cautionwithsulfurallergyTipranavir(Aptivus)(1,2)500/200RTVmgbid250mgcaps3A4,Pgpsubstrate;3A4,inducer/inhibitor??;PgpinducerHepatotoxicity,IncreasedbleedingcautionwithsulfurallergyDarunavir(Prezista)(1)600/100RTVmgbid300mgtabs3A4substrate;3A4inhibitorsDiarrhea,nausea,HA,nasopharyngitisRitonavir(Norvir)(1,2)UsedasaPKbooster100-200mg100mgcaps;80mg/mL2D6,3A4,Pgpsubstrate;3A4,PgpinhibitorNausea,vomiting,diarrhea,GIupset(1)TakewithFood(2)Mustberefrigerated**AllPIsexceptatazanavircanincreaselipidsandcauseinsulinresistanceDoseadjustmentstoconsiderRenally-eliminatedNRTIs(exceptAbacavir)AdjustforCrCl<50ml/minordialysisDidanosineEmtricitabineLamivudineStavudineTenofovirZidovudineReference:DrugproductinfoandDHHSguidelines(seetables)HepaticMetabolismNNRTIsPIsAdjustforcertaininducers,substrates,orinhibitorsofP450systemAdjustforinsufficiencyIndinavirFosamprenavirAtazanavirAvoidAmprenaviroralsolnFoasmprenavir(+/-ritonavir)TipranavirNewARVTargetsAgainstHIVFusionInhibitorFuzeon(Enfuvirtide,T-20)SeeKilbyandEron,NEJM2003;348:2228-38Fuzeon:Enfuvirtide(T-20)FDA-approvedfusioninhibitor;36AApeptideRequires106stepstomanufactureDose:90mgsqbidsideeffects:injectionsiterxn,hypersensitivity(rare)resistance:changesingp41(cellsurfaceprotein)HIVTropismChemokineReceptorAntagonistsMarviroc(Selzentry?)CCR5orCXCR4receptorsoncellsurfaceViruswillbindtooneofthe2receptorsSomepatients’viruswillbindtoeitherreceptorMarvirocblocksviralentryatCCR5Dosed300mgBID150mgBIDwithP450inhibitors600mgBIDwithP450inducers

IntegraseInhibitorsRaltegravir(Isentress?)Dosed400mgBID(1tabBID)NoinductionorinhibitiononCYP450enzymesorPgpMetabolizedbyUGT1A1(glucuronidation)OnlyaffectedbydrugsthatinhibitorinduceUGTs(ie,rifampin)DrugInteractionsAntiretroviralMetabolism,Induction,andInhibitionDrugSubstrateInhibitsInducesEfavirenz2B6,3A43A43A4,2B6Nevirapine3A4,2B63A4Ritonavir2D6,3A4,Pgp3A4,2D6,Pgp2D6(athighdosesonly)Saquinavir3A4,Pgp3A4Nelfinavir2C19(M83A4)3A4Amprenavir3A4,Pgp3A4(invitro)3A4(invivo)Fosamprenavir3A4,Pgp3A4(invitro)3A4(invivo)Lopinavir/ritonavir3A4,Pgp3A42C9,2C19,1A2Atazanavir3A4,Pgp3A4,UGT,1A2Tipranavir3A4,Pgp3A4OtherenzymesDarunavir3A4,Pgp3A4Maraviroc3A4,PgpSubstrateInhibitorInducer3A4Macrolides,cyclosporine,CCB,statins,azoles,PDE5inhibitors,aprepitant,midazolam,triazolamCimetidine,Macrolides,FQs,SSRIs,CCB,azoles,aprepitantrifamycins,phenytoin,carbamazepine,St.John’swort,aprepitant,garlic2D6Opiates,nortriptyline,amitriptyline,tramadol,trazodone,paroxetine,metoprolol,propranolol,carvedilolHaldol,SSRIs,cimetidine,amiodaronerifamycins,phenytoin,CBZ,St.John’swort1A2Amitriptyline,clozapine,caffeine,clozapine,imipramine,R-warfarin,theophylline,proprnaololFQs,azoles,macrolides,rifamycins,phenytoin,CBZ,smoking,St.John’swort2C19Omeprazole,phenytoinSSRIs,azoles,fluvastatin,omeprazole,topiramaterifamycins,CBZ,phenytoin2C9S-warfarin,sulfonylureas,phenytoin,carvedilolAmiodarone,SSRIs,azoles,amiodaronePhenytoin,CBZ,rifammycins,aprepitantCytochromeP450:Non-AntiretroviralsProteaseInhibitorsandAcidSuppressionDoNotcombineAtazanavirandProtonPumpInhibitorsMayCombineATVandFamotidinebutdoseadjustmentsareREQUIREDMayuseIndinavirwithPPIsbutONLYifcoadministeredwithRTVMayuseFosamprenavirwithEsomeprazoleSeparateFPVfromH2blockersifusedconcomitantlyDoseAdjustmentsBetweenARVsDrugADrugBRecommendationTenofovirDidanosineDoseddIas250mgQDwithTDF300mgQDTenofovirAtazanavirUseRTV100mgQDwithATV+TDFEfavirenz(Nevirapine)AtazanavirUseRTV100mgQDwithATV+EFVEfavirenz(Nevirapine)FosamprenavirUseRTVwithFPVEfavirenz(Nevirapi