褪黑素能类药物治疗睡眠障碍的研究进展_

··黄流清,赵忠新[　]　,、。,,。(、/、),、、。[]　;,;/;;[]　R971.3　　　[]　A　　　[]　1671-2838(2010)03-0166-05AdvanceinresearchontreatmentofsleepdisorderswithmelatonergicdrugsHUANGLiuqing,ZHAOZhongxin＊(DepartmentofNeurology,ChangzhengHospital,SecondMilitaryMedicalUniversity,Shanghai200003,China)[ABSTRACT]　Sleepdisordersisrefractorytomostmedications.Thereisdemandsforthedevelopmentofmoreeffective,bet-tertoleranceandnewerhypnoticdrugs.Melatoninisahormonesynthesizedprincipallyinthepinealgland.Itiscentrallyin-volvedinmaintainingcircadianrhythmicityandregulatingsleep,mediatedbymelatoninreceptors.Itisofimportantsignifi-cancetodevelopmelatonergicdrugsandmelatoninreceptoragonistsasdrugsfortreatingsleepdisorders.Inthisreview,me-latonin,melatoninreceptoragonists,suchasramelteon,tasimelteonandagomelatine,whicharecurrentlybeingresearchedintreatingsleepdisordersarereviewed.[KEYWORDS]　melatonin;receptor,melatonin;melatoninanalogsandderivatives;sleepinitiationandmaintenancedisorders;review[PharmCareRes,2010,10(3):166-170]　(08411950700)　(),,,.E-mail:[e-mail]:,E-mail:[e-mail]　200003,　　,、。、、,。(melatonin),、,,[1]。(、/、)[1,2],。1　　　()———(su-prachiasmaticnucleus,SCN),SCN。,、[3]。(1～2),、。、,。　　。G,SCN、、、、、、,、、、、、。cAMP、cGMP、Ca2+、C(proteinkinaseC,PKC)、。MT1、MT2MT3。MT1SCN、,;MT2;MT3。。2　　　。1/10。、·166·　PharmCareRes　2010Jun;10(3),.、[3,4],。,2007(Circadin)55,、,,,[1]。Garzón[5](5mg/d)2,2265(15,7),(NHSMI)。149。Gehr-man[6]、22:0010mg(8.5mg,1.5mg)10d,(24),,(17),(agitatedbehaviorratingscale)Cohen-Mansfield、,。　　,、,[2]。。Sadeghniiat-Haghighi[7]、、,30min5mg8624～46,,,。[8]。　　。9183,(34min),50min,[9]。VanderHeijden[10]36mg4,6～12(atten-tion-deficit/hyperactivitydisorder,ADHD)105,,(26.9±47.8)min,(10.5±37.4)min(P0.0001)。(dimlightmelato-ninonset,DLMO)(44.4±67.9)min,(12.8±60.0)min(P0.001)。(19.8±61.9)min,(13.6±50.6)min(P0.05)。、。1h(chro-nicobstructivepulmonarydisease,COPD)3021d,21,(Pittsburghsleepqualityindex,PSQI)(),[11,12]。Bourne[13]21:0010mg244d,、,,8:00。　　(10min),,20,,。3　3.1　雷美尔通(ramelteon)　MT1、MT2,84%,1～2.6h,(CYP1A2)。M-II,MT1、MT2,。,,30min8mg,、[2]。(19.4%)、(9.4%)、(7.9%),(18.3%、2.3%、1.5%)。,、[14]。3.1.1　治疗慢性原发性失眠　、、46[11]、、,30min8mg4516,1、1、3、56(P0.05)。Mini[15]、、,8mg1395,1、3、5、6(polysom-nogram,PSG)50%(131),15。8mg16mg18～64248965,61(clinicalglobalimpressions,CGI),、[16]。、、、8mg16mg405·167·　PharmCareRes　2010Jun;10(3),.5,,1、,[17]。Mini[18]8297d,8mg5(157,72.7,87),(170,72.3,111),1(≥60min)(-23.2minvs-7.5min;P0.01),3(-33.7minvs-19.8min;P0.01)5(-37.4minvs-17.1min;P0.001)。Wang-Weigand[19]4、、8mg566,556。1、266.9min30.2min43.3min,-13.1min(P0.001)。,8.9%vs8.8%,3.5%vs0.7%。　　、、、PSG,289[20]8mg(12.2min)、(436.8min),(19.7min419.7min,P0.01)。16mg433.1min(P0.05)。,,。Roth[21]173(9),100(37)4mg、8mg23(5～12d),PSG,4mg(28.7minvs38.4min,P0.001);8mg(30.8minvs38.4min,P0.01)。、,Postsleep,4mg,8mg(P0.05)。、、()Postsleep()。3.1.2　治疗睡眠时相异常　10%[22],。75(18～45)6d5,5h。3pg/ml(,dim-lightmelatoninoffset,DLMoff)。30min(1、2、4、8mg)1/d,4d。1、24mgDLMoff-88.0、-80.5-90.5min,。8mgDLMoff-27.9min(-7.1min),1、24mg/d,[22]。3.1.3　治疗其他睡眠障碍　Kryger[23]26(ob-structivesleepapneasyntrome,OSAS)30min16mg,PSG(11.4vs11.1)、(SaO2)(95.1%vs94.7%),。Kryger[24]8mg25≥40(chronicob-structivepulmonarydisease,COPD),(389.0minvs348.4min)(81.0%vs72.6%)(P0.05);(23.1minvs56.9min),(P0.05)。SaO2(92.2%92.5%),、。,208mg6,、。,、,、、[25]。16mg、,。、、[26]。Kry-ger[27]、、16mg()26COPD。,SaO2(92.9%vs92.9%),,(9.0vs8.3)。,,(P0.05)。3.2　特斯美尔通　(tasimelteon,VEC-162)。、、、,Ⅱ3910、20、50、100mg,、。·168·ISSN1671-2838　PharmCareRes　　2010Jun;10(3)　[e-mail]/[e-mail]　Phn/Fax[phone]　　　　　。Ⅲ19,41130min20、50、100mg(100、102、106、103)。,、,,[28]。4　5-HT2C　　(agomelatine)MT1MT2、5-HT2C,,、。MT1MT2Ki6.15×10-112.68×10-11,5-HT2C。2006,2007SFDA。Montgomery[29]3357,25～50mg(-17,HAMD-17≥25)(P0.05)。,5-HT2C。　　,、、(slow-wavesleep,SWS)、(rapideyemovementsleep,REMsleep)。、。5-HT,5-HT,,[30]。、5-HTREM,(NREM)。5-HT2,、()、。、,。,。、10～75mg/kg。,。Quera-Salva[31]15(HAMD≥20)25mg/d42d,PSG,SWS(1)、SWS、、δ,REM、。Lemoine[32]33225～50mg/d(75～150mg/d)6、,、、HAMD,1,。25～50mg1,Leeds,。192、,,1。、,。25～50mg/d(121)12,Leeds(P0.05)[33]。　　,,。、,。【】[1]　SrinivasanV,SpenceDW,Pandi-PerumalSR,etal.Jetlag:therapeuticuseofmelatoninandpossibleapplicationofmelatoninanalogs[J].TravelMedInfectDis,2008,6(1-2):17-28.[2]　ArendtJ,VanSomerenEJ,AppletonR,etal.Clinicalupdate:melatoninandsleepdisorders[J].ClinMed,2008,8(4):381-383.[3]　SrinivasanV,Pandi-PerumalSR,TrahktI,etal.Melatoninandmelatonergicdrugsonsleep:possiblemechanismsofaction[J].IntJNeurosci,2009,119(6):821-846.[4]　ZisapelN.Controlledreleasemelatonin(Circadin)inthetreatmentofinsomniainolderpatients:efficacyandsafetyinpatientswithhistoryofuseandnon-useofhypnoticdrugs[J].Harefuah,2009,148(5):337-341,348.[5]　GarzónC,GuerreroJM,AramburuO,etal.Effectofmelatoninadministrationonsleep,behavioraldisordersandhypnoticdrugdiscontinuationintheelderly:arandomized,double-blind,placebo-controlledstudy[J].AgingClinExpRes,2009,21(1):38-42.[6]　GehrmanPR,ConnorDJ,MartinJL,etal.Melatoninfailstoimprovesleeporagitationindouble-blindrandomizedplacebo-controlledtrialofinstitutionalizedpa