On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis 英文参考文献.docVIP

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On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis 英文参考文献.doc

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On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis 英文参考文献

OntheActionofCyclosporineA,Rapamycinand TacrolimusonM.aviumIncludingSubspecies paratuberculosis RobertJ.Greenstein1,2*,LiyaSu2,RamonA.Juste4,SheldonT.Brown3 1DepartmentofSurgery,VeteransAffairsMedicalCenter(VAMC),Bronx,NewYork,UnitedStatesofAmerica,2LaboratoryofMolecularSurgicalResearch,VeteransAffairs MedicalCenter(VAMC),Bronx,NewYork,UnitedStatesofAmerica,3DepartmentofMedicine,VeteransAffairsMedicalCenter(VAMC),Bronx,NewYork,UnitedStatesof America,4InstitutionVascodeInvestigationyDesarrolloAgrarioBerreaga,Derio,Spain Abstract Background:Mycobacteriumaviumsubspeciesparatuberculosis(MAP)maybezoonotic.Recentlythe‘‘immuno-modulators’’ methotrexate,azathioprineand6-MPandthe‘‘anti-inflammatory’’5-ASAhavebeenshowntoinhibitMAPgrowthinvitro.We concludedthattheirmostplausiblemechanismofactionisasantiMAPantibiotics.The‘‘immunosuppressants’’Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of ‘‘autoimmune’’ and ‘‘inflammatory’’ diseases. Rapamycin and Tacrolimusaremacrolides.WehypothesizedthattheirmodeofactionmaysimplybetoinhibitMAPgrowth. Methodology:TheeffectonradiometricMAP 14CO2growthkineticsofCyclosporineA,RapamycinandTacrolimusonMAP culturedfromhumans(DominicUCF4)orruminants(ATCandM.aviumsubspeciesavium(ATCC25291 101)arepresentedas‘‘percentdecreaseincumulativeGI’’(%-DcGI.) PrincipalFindings:Thepositivecontrolclofaziminehas99%-DcGIat0.5mg/ml(Dominic).Phthalimide,anegativecontrol has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants.Cyclosporinehas97%-DcGIby32mg/ml(Dominic),Rapamycinhas74%-DcGIby64mg/ml(UCF4) andTacrolimus43%-DcGIby64mg/ml(UCF4) Conclusions: We show heretofore-undescribed inhibition of MAP growth in vitro by ‘‘immunosuppressants;’’ the cyclic undecapeptideCyclosporineA,andthemacrolidesRapamycinandTacrolimus.Thesedataarecompatiblewithourthesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently