Bartilmaameedka Nidaamka Glutamaterigga ee Lagu Daweeyo Khamaarka Cudurka: Calaamadaha Xaadirka ah iyo mustaqbalka mustaqbalka (2014)

  • Biomed Res Int. 2014; 2014: 109786.
  • Waxaa lagu soo daabacay 2014 Jun 12. doi:  10.1155/2014/109786

PMCID: PMC4075088

Maqaalkani wuxuu ahaa ku qeexay maqaalada kale ee PMC.

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aan la taaban karin

Xanuunka khamaarka ama khamaarka ee khalkhalka waxaa lagu qeexay DSM-5 sida takoorka akhlaaqda. Ilaa waqtigeeda, fayaqrigu maahan mid gebi ahaan la fahmi karo mana jiraan wax daweyn ah oo FDA ah oo la ogolaaday oo loogu talagalay xanuunada khamaarka. Glutamate waa madaxa neurotransmitter ee xanuunka ku jira habdhiska dareenka waxaana ugu dambeyntii ku lug lahaa baaritaanka dabeecad daroogada. Warqaddan, waxaan dib u eegeynaa suugaanta hadda ee fasalka daroogada kuwaas oo u dhaqma sidii nidaamka glutamate ee PG. Wadar ahaanshaha 19 ayaa lagu daray, iyada oo la raacayo shuruudaha ka-saarista iyo ka-saarista. Dacwada qalliinka iyo kiisaska la isticmaalayo daawooyinka glutamatergic (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, iyo modafinil) ayaa loo soo bandhigi doonaa si loo ogaado waxtarka ku saabsan dabeecadaha khamaarka iyo qiyaasta daaweynta , iyo calaamadaha garashada) ee bukaanka PG. Natiijooyinka ayaa looga dooday si ay u yeeshaan aragti dheeraad ah oo ku saabsan fayaqabka iyo daaweynta PG. Gebogebada, wax ka qabashada glutamatergic neurotransmission waxay u muuqataa mid rajo leh in lagu horumariyo wakiilada daaweynta ee wanaajinta daaweynta xanuunka khamaarka. Daraasado dheeraad ah ayaa loo baahan yahay. Ugu dambeyn, waxaan soo jeedineynaa tilmaamaha iyo caqabadaha mustaqbalka ee cilmi-baarista.

1. Taariikhda

Khamaarka nafsadda (PG) wuxuu calaamad u yahay dabeecad khamaaraya oo aan habooneyn, taas oo qofku uu ku dhaco xaalado badan oo soo noqnoqonaya oo khamaaraya inkastoo ay jirto cawaaqib xun [1]. Xanuunka khamaarka ayaa saameynaya 0.2-5.3% dadka waaweyn ee adduunka ku nool; dhibaatooyinka ba'an ee khalkhalka dabeecada ah ayaa badanaa keena dhaawac halis ah nolosha bukaanka iyo qoysaskooda. Ilaa imminka, ma jirto daaweyn FDA-ansax ah oo loogu talagalay PG, inkasta oo toboneeyo sano oo ah cilmi-baaris culus, iyo istaraatijiyado wax ku ool ah oo tayo leh ayaa weli ah mid aad u dhib badan. Ugu dambeyntii, PG waxaa lagu daray qeybta cudurka dabiiciga ah ee isticmaalka mukhaadaraadka iyo xanuunka halista ah ee daabacaadda 5th ee bukaanka Diagnostic iyo Statistics ee Xanuunka Dhimirka (DSM-V).

Glutamate (Glu) waa madaxa neurotransmitter-ka ee naqshadda nidaamka dareenka. Waxaa dhawaan la soo jeediyay in fara-gelinta loo arki karo natiijada awoodda liidata ee la xakameynayo daroogada raadinta ee ka jawaab celinta xaaladaha degaanka, taas oo ay ugu wacan tahay isbeddelka Glu-homeostasis, oo wadajir ah oo lagu kiciyo dopamine (DA) iyo N-methyl-d- aspartate (NMDA) qaboojiyeyaasha glutamatergic [2]. Xayiraadda sii deynta Glu ayaa ka hortagey dabeecadaha raadinta maandooriyaha ee xayawaanka iyo sidoo kale bukaanada qaba dhibaatooyinka isticmaalka maandooriyaha [3, 4]. Isdhexaadyada daaweynta iyo bayoolojiga ee ka dhexeeya PG iyo maandooriyaha maandooriyaha [5] waxay soo jeedinayaan in bukaanada PG-da ay ka faa'ideysan karaan daawooyinka loo isticmaalo daaweynta mukhaadaraadka daroogada iyo in qaababka nafsaaniga ah ee daroogada maandooriyaha ay sidoo kale muhiim u tahay PG.

Warqaddan, waxaan dib u eegnaa suugaanta hadda ee daroogooyinka u bedelaya glutamaterigic neurotransmission in PG. Waxa kale oo aanu soo koobnaa qiyaasaha hadda jira ee ku saabsan neurobiology ee PG, diiradda saarista glutamatergic neurotransmission iyo isdhexgalka ay la leeyihiin neurotransmitters kale. Dhibaatooyinka klinikada iyo kiisaska taxan ee isticmaalaya daawooyinka glutamatergic ayaa loo soo bandhigi doonaa si loo caddeeyo waxtarka ku saabsan dabeecadaha khamaarista iyo cabbirada kiliinikada ee la xariira (xuriyad, ciribtir, iyo garashada garashada) ee bukaanka PG. Natiijooyinka waxaa looga doodi doonaa si loo helo aragti dheeraad ah oo ku saabsan fayaqabka iyo daaweynta PG. Ugu dambeyn, waxaan soo jeedineynaa tilmaamaha iyo caqabadaha mustaqbalka ee cilmi-baarista.

2. Hababka

Laba dib-u-fiiriye ayaa si gooni ah uga shaqeynayey dib-u-eegidgan, ka dib markii la sameeyay raadinta bibliographic raadinta iyo qawaaniinta xogta. Baaritaanka bibliographic waxa uu ka koobnaa baaritaanka kombiyuutarada ee Medline, Scopus, iyo Google Goobaha macluumaadka ee Janaayo 2014. Kaliya maaddooyinka luuqada Ingiriisiga ee la daabacay tobankii sano ee la soo dhaafay ayaa dib loo eegay. Waxaan u isticmaalnay su'aalaha soo socda: "gambl *" oo lagu daray "glutamate" iyo liis ay ku jiraan liiska glutamatergic neurotransmission-modulating oo ay ku jiraan N-acetylcysteine, memantine, amantadine, acamprosate, topiramate, lamotrigine, baclofen, gabapentin, pregabalin, modafinil, riluzole, dizocilpine, LY354740, D-cycloserine, metadon, iyo dextromethorphan. Baadhitaankii hore wuxuu keenay natiijooyinka 99. Ka dibna waxaan raadinay tixraacyada lagama maarmaanka ah ee maqaal kasta, oo ay ku jiraan daraasado hore oo mowduucan ah.

99 maqaalada, 19 ayaa lagu daray (Jaantuska 1) sida waafaqsan shuruudaha soo socda: (a) dhibaatada bartilmaameedku waa PG; (b) Abstract waa la heli karaa; (c) Daabacaadu waa warqad asal ah, marka laga reebo dib u eegista; (d) daraasaddan waa cilmi-baaris ku salaysan neerobiological ama cilmi baaris oo ku saabsan maaddooyinka PG.

Jaantuska 1 

Nidaamka Bibliographic.

Shaxda 1 waxay muujinaysaa xogta ku jirta qoraalada ku jira daraasaddan: daroogada loo isticmaalo, qiyaasta, naqshadeynta daraasadda, cabbirka saamiga iyo dadka la beegsaday, hababka, natiijada garashada, iyo raadinta ugu muhiimsan ee natiijada khamaarka.

Shaxda 1 

Xanuunnada caafimaadka iyo taxanaha kiis ee la isticmaalayo daawooyinka glutamatergic si loo daaweeyo khamaarka noolaha.

3. Gudbinta Glutamaterka ee Habdhaqanada Khatarta ah: Kala-xulashada Khamaarka Cudurka

Glu waa neurotransmitter-ka ugu badan ee lagu daaweeyo CNS, ficilkana waxaa lagu xakameynayaa laba nooc oo soo dejiyey: ionotropic (iGlu) iyo qaboojiyaha metabotropic (mGlu). Raajatada ionotropic waa ion channels kuwaas oo, marka Glu xiraya, kordhiyo qulqulaya of sodium iyo potassium caatada taas oo keenta kaydinta of membrane [19]. Waxay u kala qaybsamaan saddex qaybood: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid (AMPA), iyo kainate. Qaybaha soo-saarka metabotre waa G protein-ku duuban oo waxay u kala qaybsamaan saddex kooxood (I, II, iyo III) oo ku saleysan habka isku-dabiiciga ah ee isdaba-joogga, habka is-beddelka signal-celinta, iyo doorashadooda farshaxanka [20]. Qalabka qabatimaytka metabotic ayaa ku yaal meelaha ugu horreeya ee goobaha limbic iyo goobaha, kuwaas oo si gaar ah ugu lug leh hababka mukhaadaraadka. Gaar ahaan, qolooyinka soo ururinta waxaan u muuqdaa inay kaalin muhiim ah ka qaataan xakameynta saamaynta sii xoojinta ee daroogooyinka, halka nooca II ee soo dhaweeyayaashu ay ku jiraan isbeddellada 'synaptic' ee ka dhacda natiijada muddada dheer ee soo-gaadhista daroogada iyo calaamadaha xanuunka [21]. Ka dib xadgudubka walax kasta, gudbinta glutamatergic wuxuu ku dhacaa nidaamka limbic iyo kortex doorbidiisa oo u muuqda inay mas'uul ka yihiin, marka hore iyo ugu horreynba, sii deyn dheeraad ah ee DA, iyo sidoo kale saameynta DA-ku-tiirsanaan. Gaar ahaan, halka ay dhacdo sida dareen-celinta, rabitaanka, dib-u-dhiska, iyo xoojinta waxay ku xiran tahay isbeddelada nidaamyada dopaminergic iyo glutamaterkic ah, mawduuc gaar ah iyo dabeecadaha xaaladaha leh ee la xiriira isticmaalka maandooriyaha inta badan waxay ku xiran tahay qaababka glutamatergic [22]. Guud ahaan, nidaamka glutamatergic-dopaminergic (ee nukleus accumensis) ayaa ka masuul ah bilawga ah "daroogada raadsata," halka dib-u-soo-kabashada kaliya ay ku lug leedahay nidaamka glutamatergic [23]. Hoos u dhigidda heerarka glacamate ee ka baxsan goobaha limbic ayaa u muuqda inay si aad ah ula xiriiraan cilladda ka soo noqoshada maskaxda; Dhibaatooyinka jidh-dilka jirka ee metabotropic glutamate waxay u muuqdaan inay awoodi karaan inay yareeyaan xishoodka iyo ka-hortagga dib-u-celinta iyada oo loo marayo qaab magdhow. Sidoo kale, antagonistayaasha xayawaanka metaboterta ayaa caqabad ku ah saamaynta dhaqanka ee kookeynta, nicotin, iyo aalkolada, iyo NMDA antagonists waa musharaxiin suuragal ah in lagu daaweeyo cudurrada aalkolada, khamriga,24].

PG ayaa loo maleynayaa in lagu beddelo inta badan maskaxda DA iyo Glu, inkastoo natiijooyinka ay ka soo horjeedaan. DA waxaa lagu soo koobay dabeecadaha abaalmarinta, xoojinta, iyo dabeecadaha la qabatimay. Isticmaalka maandooriyaha maandooriyaha, xogtu waxay taageertaa jiritaanka gobolka hypodopaminergic heerarka heerarka daawooyinka iyo kuwa loo yaqaan "25]. Inkastoo DA sii deyntu sii xoojin karto barashada [26, 27], Glu waxaa laga yaabaa in lagu dhejiyo nuujinta dheeriga ah ee wareegga corticostriatal kaasoo matalaya substrate-ka neerfaha ee sababa dhimista jilicsanaanta soo noqoshada [2]. Glu wuxuu ku hawlan yahay barashada iyo xasuusta waxaana laga yaabaa in uu dhaqdhaqaaqo noocyada kala duwan ee Glu reseptors, oo ay ku jiraan receptors NMDA oo lagu soo bandhigay gobollada maskaxda oo ka kooban wareega abaalmarinta [2]. Heerarka Glu ee gudaha nukleus waxay u dhigantaa habdhaqanka abaal-marinta dhexdhexaadinta [2]. Khamaarayaasha nafsadda waxay soo tebiyaan dareenka euphoric inta lagu jiro xaaladaha khamaarka, oo loo barbardhigo "sare" isticmaalka maandooriyaha, sidaas awgeed iyaga ayay u sii nugul yihiin khamaarista sii socota. Intaas waxaa sii dheer, warbixinno hordhac ah ayaa muujiyay hoos u dhaca awoodda khatarta ah ee ka jawaab celinta dareemada sida caadiga ah loo arko sida abaalmarin [28]. Marka la sii wado khamaarka, saliibiyada ku xiran habdhaqanka ayaa la xoojiyaa waxayna keenaysaa jawaab celin cuna oo sababi karta dhacdooyin isdaba-joog ah iyo in laga yaabo inay sii kordhiso DA neurotransmission. Ugu dambeyntii, khamaarista joogtada ah iyo isbeddelka xayeysiinta ee DH-da 'DA neurotransmission-ka ee ku-meel-gaadhka ah ayaa keeni kara in la sameeyo xanuunka neurootiga ee waddooyinka mesolimbic-prefrontal glutamatergic [29]. Qaadashada daawada dabadheeraad ah waxay la xiriirtaa neuroterapia oo lagu magacaabo glutamatergic neurotransmission oo ku jirta stjiatum iyo kortex limbic [30]. Intaa waxaa dheer, in la ogaado cue-ka ayaa lagu ogaaday in ay ku xiran tahay saadaalinta xooggan ee maskaxda glutamatergic ee ka soo baxa kiliyaha horay loo soo geliyay nukleus accumens [31]. Dabeecadaha soo noqnoqda oo si dhow ula socda abaalmarinta kordhinta heerarka "Glu"32]. Mid ka mid ah daraasaddan, heerka dheecaanka cerebrospinal (CSF) ee heerarka glutamic iyo aspartic acid, labaduba waxay ku xidhan yihiin dukaamada NMDA, waxay sare u kaceen bukaanka PG marka loo eego maadooyinka kontaroolka [33]. Iskudhin la'aanta Glu homeostasis waxay isbeddel ku sameeyaan isbeddelka neuroplasticity taas oo u keenta isgaadhsiin ka dhexeysa kortex laabtada hore iyo nucleus accumens, sidaas daraadeed ujeedada ka-qaybgalka dabeecadaha abaal-marinta, sida PG [34].

4. Istaraatiijiyada Daaweynta Glutamaterigic ee Khamaaraha Biyoolojiga

Daaweynta glutamatergic neurotransmission waa jiid yar oo laakiin jahwareer leh si loo horumariyo wakiillada daaweynta ee wanaajinta daaweynta daroogada iyo mukhaadaraadka akhlaaqda [10, 35]. Caddayn badan ayaa soo ururay caddaynta in lammaaneyaasha ku lug leh gudbinta glutamatergic ay sidoo kale ka faa'iideysan karaan daaweynta maandooriyaha maandooriyaha, iyo sidoo kale noocyo kala duwan oo loo isticmaalo sida khamaarka noolaha. Caddeynta kobaca waxay soo jeedinaysaa in nidaamka glutamaterka uu udub dhexaad u yahay neurobiology iyo daaweynta xanuunka niyadda [36] iyo in ay u noqon karto bartilmaameed qiimo leh ee PG leh xaaladaha isku-dhafan [37].

4.1. N-Acetylcysteine

N-Acetylcysteine ​​(NAC), Primer Cysteine ​​iyo amino acid, waxay kordhin kartaa heerarka dheeraadka ah ee Glu-diirinta ee xajmiga nucleus wuxuuna muujiyay wax-qabadka hordhaca ah ee daaweynta walxaha maaddooyinka [38, 39]. NAC waxay kicin kartaa habka daaweynta guluubka ah ee guluubka, oo laga yaabo inay keento hoos u dhigista sii-deynta glutamate. Daraasado ku saabsan dadka roodhiga ah waxay muujinayaan in NAC ay wax ku ool u tahay yaraynta dhaqanka-raadinta abaalmarinta [40] iyo xogaha hordhaca ah ee PG ayaa dhiirigelinaya.

NAC waxaa loo arkay in uu yahay mid wax ku ool ah ee yareynta qulqulatooyinka iyo dabeecadaha (Dhibcaha hoose ee Yale-Brown Obsessive Compulsive Scale oo loogu talagalay PG-da (PG-YBOCS))14]. Toddobaatan iyo toddobo maadi PG (haweenka 12) ayaa la daweeyey toddobaadyo XNUM leh NAC (celcelis ahaan qiyaasta 8 ± 1476.9 mg / maalin). Jawaabayaasha ayaa lagu kala saari waayey 311.3-todobaadkii laba-indhoole-joojin la'aanta (NAC vs placebo). Qeybo aad u sarreeya oo maadooyinka lagu daaweeyo NAC ayaa weli la kulma shuruudaha jawaab celinta dhammaadka daraasaddan (6% ee NAC oo ka soo horjeeda 83.3% ee kooxda placebo). Intaa ka sokow, RCT-da dhowaan ayaa xaqiijisay waxtarka NAC ee soo koobidda daaweynta dabeecadda ee daaweynta PG [15]. Daraasada waxaa lagu fuliyay maadooyinka 28 iyada oo la adeegsanayo nikotiin ku tiirsan nikotiin iyo PG. Waxay heleen daaweyn dabeecadeed oo lagu kala soocay si ay ugu kiciyaan NAC (illaa 3,000 mg / maalin) ama placebo oo ku jira tijaabo laba-indhoole ah. Xilliga koontaroolka 3-da, waxaa jiray faa'iido dheeraad ah oo loogu talagalay NAC oo ka soo horjeeda xakameynta khatarta khamaarka (PG-YBOCS).

Dhawr arrimood ayaa weli aan la xalilin. Qiyaasta ugu wanaagsan ee NAC ee loogu talagalay PG weli wali lama yaqaan. Qiyaasta loo isticmaalo soo-saarista-RCT waxay aad uga sarreysaa tan loo isticmaalo daraasaddii hore. Marka la eego xogta hore ee jiirka, miisaanka hoose ee NAC wuxuu joojiyaa gudbinta Glu ee nucleus xuddunta xarigga marka xajmiga sare uu ka soo horjeedo saameyntan [41]. Marka la eego sifooyinka NAC glutamatergic iyo doorka glutamate ee barashada iyo xusuusta hababka balwada leh42], isticmaalkeeda ayaa loo soo jeediyay bukaannada soo sheegaaya inay ku qoslaan khamaarka iyo kuwa iyagu sidoo kale ku lug leh faragelinta nafsaaniga ah ee ku salaysan soo-gaadhista.

4.2. Memantine

Memantine, oo ah mid aan loo tartamin oo ka soo horjeeda NMDA oo leh astaamaha neerfaha, ayaa loo oggol yahay cudurka Alzheimers waxaana sii kordhaya in lagu barto noocyo kala duwan oo cudurada maskaxda ah43]. Xubnaha PG ee maqaarka ayaa hoos u dhacay dhibcaha PG-YBOCS iyo waqtigii khamaarka lagu kharash gareeyey, sidoo kale waxay sare u qaadaan shaqada neurocognitiga ee la xiriira dabacsanaanta garashada [11]. Laba iyo sagaal maaddo ayaa lagu diiwaan geliyay maxkamad 10 todobaadkii. Ka dib markii la daaweynayo daaweynta xasaasiga ah (10-30 mg / day), dhibcaha PG-YBOCS iyo saacadaha khamaarka si weyn u yaraatay. Waxaa intaa dheer, maadooyinka waxay horey u mariyeen qiimeynta garashada iyo dib u dhigista qiimeynta fahamka iyadoo la adeegsanayo hawlaha joogtada ah iyo hawlaha isku-xirnaanta (IDED) ee loo yaqaan 'IDED' si loo qiimeeyo isdhexgalka iyo dabacsanaanta garashada, siday u kala horreeyaan. Dhamaadka dhammaadkii waxbarashada, horumar weyn ayaa ka muuqatay waxqabadka IDED, laga yaabee inay sababto isbedelka xasaasiga ah ee isku-gudbinta glutamaterka ee PFC [44]. Si kastaba ha noqotee, xaddiga uu xasaasiga ahi ku hayo saameynta uu ku leeyahay dabeecadaha khamaarista iyada oo loo marayo saameyn ku yeelanaya isdhexgalka ama qasab ma wali caddayn [45].

Daraasad kambiyuutar ah ayaa ka warbixisa wax ku oolnimada xasaasiga ah ee daaweynta bukaanka 23-sano jir ah oo leh jirro qasab ah oo isdaba-joog ah, jirro dysmorphic, iyo PG daran [12]. Jawaab-celin caafimaad ayaa la arkay ka dib markii todobaadyadii 8 ee daaweynta xasaasiga ah, ayadoo la sii xakameynayo khamaarista iyo xiisad yar iyo rajo-darro.

Memantine waxay u muuqataa in ay yareeyso xiisaha Glu iyo in ay hagaajiso go'aan qaadashada. Waxaa intaa dheer, waxay muujinaysaa balanqaad ku saabsan daaweynta calaamadaha garashada iyo is dulqaadashada ee bukaanka PG [11, 45].

4.3. Amantadine

Amantadine, waa dawada loo yaqaan 'antiglutamatergic' oo leh talaabooyin dheeri ah oo ku saabsan dopaminergic neurotransmission, ayaa lagu qiimeeyay daaweynta PG iyo dabeecadaha kale ee qasabka ah ee shakhsiyaadka qaba cudurka Parkinson [9, 46]. Xog is khilaafsan ayaa laga soo sheegay isticmaalka amantadine ee bukaanka cudurka Parkinson.47]. Waxaa la ogaaday in ay tahay mid ammaan ah oo wax ku ool ah bukaanada 17 oo leh PG, yaraynta ama joojinta qulqulatooyinka iyo dabeecadaha [9]. Daraasad iswaydaarsi ah oo ku salaysan 'amantadine' waxaa lala xiriiriyay PG iyo cudurrada kale ee kantaroolka ah [48].

Waxaa intaa dheer, daraasad kiis ah ayaa soo jeedisay suurtagalnimada faa'idada suurtagalka ah ee daaweynta bukaanka PG [8]. Horumar xoog leh oo ku saabsan calaamadaha khamaarka ayaa tilmaamaya in habka daaweynta glutamaterka iyo dopaminergic-ka ee isku marna ay yareeyn karaan khamaarka PG, laga yaabo inay ka laabato isbeddellada pathogaraamka ee neef-ba'an ee lagu garto dabeecadaha khatarta ah [2].

4.4. Topiramate

Topiramate waa mujtamaca glutamatergic iyo daroogada pro-GABAergic taasoo si weyn u yareyneysa dhaqanka diidmada iyo qasabka. Waxaa la baaray waxaana lagu ogaaday in ay tahay mid waxtar leh oo ka soo horjeeda jirro kufilan oo ay ka mid tahay ciriiri darida iyo xiisa gelinta qaababka muhiimka ah, sida cabbitaanka khamriga, ku tiirsanaanta kookaynta, bulimia nervosa, iyo cuncunka cuntada cunta. Waxaa intaa dheer, waxaa dhawaan la soo jeediyey in topiramate ay sidoo kale tahay antagonist of AMPA duubayaasha, nooc ka mid ah Glu receptor ah oo dhexdhexaad ah dabeecadaha soo noqnoqda-sida iyo waxaa laga soo xigtay isbedelka neuroadaptive ee soo saaray daroogada xadgudubka iyo sidoo kale [49].

Toddobaadkii 14, randomized, laba-indhoole, tijaabo xakamaynta kontoroolka kontoroolka ah ayaa baaray keyiramate ee PG [17]. Inkastoo aysan jirin farqi weyn oo u dhexeeya kooxda xuubka iyo kooxda daaweynta topiramate-la daaweeyay ayaa lagu arkay iyada oo la tixraacayo tallaabooyinka aasaasiga ah ee natiijooyinka (isbeddelka qaddar-dhimista ee PG-YBOCS), kor u kicinta hoos u dhiganta (gaar ahaan muraayada iyo qulqul la'aanta), sida lagu cabbiray Qiyaasta Barratt Impulsiveness (BIS). Qorayaashu waxay soo jeedinayaan in topiramate ay faa'iido u yeelan karto qaybaha hoose ee PG oo lagu garto heerar sare oo isdaba-joog ah. Dannon et al. [16] marka la barbar dhigo waxtarka loo yaqaan "topiramate" iyo "fluvoxamine" ee daaweynta PG ee toddobaadkii 12, tijaabinta is barbardhigga indho-la'aanta. In kasta oo ay qorayaashu soo gabagaboobeen in labada koronka iyo daawada fluvoxamine monotherapies ay waxtar u yeelan karaan daaweynta PG, horumarinta PG-CGI ee fluvoxamine ma gaadhin muhiimadda tirakoobka. Sidoo kale, tiro yar oo ka mid ah ka tanaasulka ayaa lagu soo warramey kooxda kor ku xusan.

Intaa waxaa dheer, bukaanka qaba cudurka laba-cirifoodka iyo isdhaafsiga PG, Nicolato et al. [18] waxay soo sheegeen in si buuxda looga xanibay xad-gudubka iyo dhaqanka khamaarka ka dib markii loo yaqaan 'topiramate' lagu darey daaweynta lithium ee caadiga ah.

4.5. Acamprosate

Acamprosate (calcium acetylhorauraurinate) waa nooc ka mid ah taurin iyo gaabis aan aheyn GABA agonist kaasoo kor u qaada dheelitirka u dhexeeya neurotransmitters (Glu iyo GABA). Waxay si gaar ah ugu xiran tahay garsoorayaasha GABAB waxayna u muuqataa inay joojinayso soo celinta Glu iyo in la joojiyo calaamadaha glutamatergic ee hyperactive [50]. Inkasta oo ay jiraan cadaymo isku-dhafan oo soo jeedinaya in caddaynta rasmiga ah ay faragalinayso nidaamka Glu iyadoo la hor-marinayo dhaqdhaqaaqa NMDA [51], qaabkeeda waxqabad weli weli ma cadda. Natiijooyinka dhowaan waxay soo jeedinayaan ka qayb qaadashada waddooyinka kalsiyum-dhexdhexaad ah [52]. Is-beddeladaani waxaa laga yaabaa inay la xiriiraan arrimaha sida gobolka maskaxda la baaray, hal-abuurka isuduwaha NMDA, xaalad xanuunka neuronal, iyo jiritaanka NMDA daaweeye nuromodulators NMDA sida polamines [50, 53]. Acamprosate ayaa loo ansixiyay FDA-da si loogu isticmaalo khamriga. Dib u soo kabashada isku dheelitirka u dhaxeeya neurotransmissions-ka ee niyadjabinta iyo xanuunka nuurotransmission ee ay keento khamriga raagay [53], waxaa la ogaaday in kor loo qaado heerka khamriga joogtada ah oo labanlaabaya maalmaha isku-dhaafka ka yimaada khamriga [54].

Natiijooyinka ka soo horjeeda ayaa lagu soo warramey isticmaalka daaweynta PG [55]. Toddobaadkii 8, maxkamad furan oo lagu magacaabo 2-toddobaadkii, ayaa si rasmi ah ugu guuleystay horumarinta PG-YBOCS iyo Dhibcaha Qiimaynta Cilmi-baarista ee G-SAS (G-SAS), labadaba CGI, iyo tirada khamaarka [6]. Laba iyo lixdan bukaan ayaa la siiyay daawada (xaamuuska 1,998 / maalin). Qiyaasta waxtarka aasaasiga ah waxay ahayd PG-YBOCS. Qiyaasaha waxqabadka sare ee ka midka ah G-SAS, Maqnaanshaha Caalamiga ah ee Korjoogteynta (CGI) ee Miisaaniyadda Horumarinta iyo Dhowmaanta, qiimeynta caalamiga ah ee qiimeynta caalamiga ah, Iskeelka Heerka Nafaqada ee Hamilton (HDRS), Maqnaanshaha Naafada ee Sheehan (SDS), iyo waqtiga jadwalka dambe (TLFB).

Taa bedelkeeda, daraasad is barbardhac ah ayaa ku guuldareysatay in ay xaqiijiso wax ku oolnimada dhaqanka khamaarka [7]. Daraasaddan furan ee buug-yarahan, khamaarayaasha pathologist 8 ee lagu daaweeyay xamiin 999 mg / maalin ayaa la qiimeeyay bishiiba bilaha 6 si loo qiimeeyo soo noqoshada. Midkoodna ma helin bilooyin 6, oo lagu qeexay maqnaanshaha dabeecadda khamaarka inta lagu jiro bisha ka horeysa booqashada dabagalka. Dhibcaha VAS-da ee aasaasiga ah, kadib bilihii 1, iyo dib-u-soo-kabashada ayaa muujin waayay farqiga u dhexeeya garashada. Maqnaansho lagama maarmaan ah ayaa loo shaqeynayey si loo ogaado waxtarka loo yaqaan "acamprosate" ee ciyaaraha khamaarka iyo xishoodka.

4.6. Baclofen

Baclofen (beta- (4-chlorophenyl) -GABA) waa GABAB oo loo yaqaan 'GABAB Agonist' kaas oo lagu ogaaday in lagu xakameynayo dabeecadaha cabbitaanka khamriga ee ku jira jiirka iyo qaadashada khamriga maalinlaha ah ee khamriga khibrada leh. Iyada oo la xakameynayo tiro badan oo laga sii daayo terminaalka presynaptic, waxay hoos u dhigtaa calaamadaha Gluffic synaptic [56] waxayna xakameysaa Ca2 + daaweyn ka yimaada NMDA reseptors. Jiirka, waxa kale oo ay xakameynaysaa sii deyn-dheecaanka kobcinta dopamine ee qolofta nukleus accumens [57].

Maxkamad furan oo furan [7], Bukaanada 9 ee qaata baclofen ayaa la qiimeeyay bishiiba si loo qiimeeyo tallaabooyinka hagaajinta joogtada ah (ie, ka-dhaafitaan) iyo dib-u-soo-kabasho. Midkoodna ma helin bilooyin 6, oo lagu qeexay maqnaanshaha dabeecadda khamaarka inta lagu jiro bisha ka horeysa booqashada dabagalka; kaliya hal bukaan ah oo qaata baclofen ayaa helay 4 bilo qalad ah. Dhibcaha VAS-da ee aasaasiga ah, kadib bilihii 1, iyo dib-u-soo-kabashada ayaa muujin waayay farqiga u dhexeeya garashada.

4.7. Gabapentin iyo Pregabalin

Anticonvulsants, sida gabapentin iyo pregabalin, waxay leeyihiin qaabab badan oo ficil ah, oo ay ku jiraan xakamaynta farsamooyinka gaaska Na + iyo Ca2 +, taasina waxay joojinaysaa soo noqoshada neurotransmitters oo ay ku jiraan glutamate. Gabapentin wuxuu u dhigtaa GABAergic iyo glutamatergic neurotransmissions labadaba. Qaar ka mid ah qorayaasha ayaa baaray isticmaalka gabapentin ee xaaladaha isticmaalka maandooriyaha. Gabapentin waxay ka soo horjeedaa GABA iyo Gluus badan oo loo maleynayo in ay hoos udhacaan khamriga iyo horey u-dhaafsiga. Waxay yaraynaysaa isticmaalka aalkolada iyo xurmeynta, taas oo fududeyneysa in la joojiyo [58]. Pregabalin waa qaabka qaab-dhismeedka GABA, oo la mid ah ubapentin. Waxa kale oo ay yareyneysaa sii deynta nuurotransmitter-ka iyo xagjirnimada postsynaptic. FDA waxay ogolaatay pregabalin qayb ka mid ah suuxdinta qaybta, xanuunka neuropathic, iyo cudurada guud ee walwalka. Intaas waxaa sii dheer, pregabalin ayaa si baaxad leh loo bartey khamriga iyo ku tiirsanaanta benzodiazepin [59]. Diiwaanka 6-bishii ayaa horay u baaray suurtogalnimada isticmaalka suurtagalka isticmaalka bukaankooda PG-da (bukaannada 6 waxay heleen pregabalin; bukaanada 4 waxay heleen gabapentin), iyadoo la yareeyo khamaarka khamaarka sida lagu cabbiray G-SAS [10]. Sidoo kale, pregabalin ayaa loo isticmaalay in lagu daaweeyo xaalad citalopram-la xiriirto khamaar [60]. Daraasadaha mustaqbalka waa in ay baaraan isticmaalka gabapentin iyo pregabalin ee daaweynta PG, iyada oo daroogadaasi ay u muuqato in si gaar ah loogu bartilmaameedsado sifooyinka ugu muhiimsan ee dareenka, walwalka, iyo xiisa gelinta.

4.8. Modafinil

Modafinil waa kiciyaha dareenka ah, oo asal ahaan loogu talagalay inuu kor u qaado wacyigelinta iyo feejignaanta daaweynta nikololeediga waxaana mararka qaar lagu qoraa daaweyn calaamad ah oo loogu talagalay xanuunka dareenka / maqnaanshaha / maqnaanshaha (ADHD). In kasta oo farsamooyinka ficilka aan si buuxda loo fahmin, modafinil uma muuqato in uu u dhaqmo sida mashiinka monoamine sida kiiska loogu talagalay kiciyaasha amphetamine-sida. Taas beddelkeeda, modafinil wuxuu ku dhaqmi karaa kicin α-drenoceptors, xakamaynta sii-deynta GABA, si liidata u joojiya qaadaha dopamine, ama kicinta hypothalamic orexin-ku jirta nuuroon [61, 62]. Inkastoo daraasadaha intooda badani ay soo jeedinayaan dopaminergic ku saabsan saameynta kicinta [63], modafinil ayaa lagu muujiyey kor u kaca heerka glacamate ee gobollada maskaxda badan ee ay ka midka yihiin storatum dorsal, hippocampus, iyo diencephalon iyada oo aan waxyeello u dhejin gogameey [35, 64]. Warbixinno badan oo kiliinikarin ah ayaa muujiyey in modafinil uu muujinayo saamaynta ay ku yeelan karto daaweynta cocaine cocaine [62].

Zack iyo Poulos [13], oo lagu tijaabiyay tijaabo-koontaroolo indho-indhoole ah, isku dayay in la ogaado haddii maadada 'modafinil' (celcelis ahaan 200 mg / maalin) waxay yareyneysaa saameynta sii kordheysa ee mashiinka loo yaqaan 'slot machine' oo ku jira maaddooyinka PG iyo haddii tani ay ka xoog badan tahay miisaanka hoose ee hooseeya (N = 20). Cabbirka darajada ayaa si isku mid ah hoos u dhac ku yimid kaqeybgalayaasha sare iyo kuwa hooseeya ee qaata modafinil. Ka qaybgalayaasha sare ee niyad-jabka, modafinil wuxuu yareeyaa rabitaanka khamaarka, kalsoonida ereyada khamaarka, kicinta, iyo go'aanka khatarta ah. Ka qaybgalayaasha hooseeya, modafinil ayaa kor u qaaday buundooyinkan. Natiijooyinka waxay muujiyeen in modafinil uu leeyahay saameyn laba dhinac ah oo labada kooxood ah. Mid ka mid ah muunada bukaanka ayaa dib loo qiimeeyay daraasad mustaqbalka ah, iyadoo natiijooyinka bukaan-socodka ay tilmaamayaan in modafinil uu ka niyad-jebin karo khamaarayaasha pathologists ee ka-hortagaya khasaaraha laakiin waxay sidoo kale ku dhiirigelinayaan inay sii wadaan sii-deyntooda, halkii ay joojin lahaayeen inta ay horay u socdaan [65]. Sidoo kale, waxaa la soo wariyay kiis xiriirin ah oo xiriir ah oo u dhaxeeya daaweynta modafinil iyo khamaarista pathological ee bukaan 39-sano jir ah oo leh taariikh taariikhda nikolepsiga iyo xayawaanka la xiriira [66].

5. Wadahadal

Waxaa jira cadeymo la taaban karo oo muujinaya in daaweynta daaweynta farqiga daaweynta glutamatergic ay tahay ka faa'iideysiga daaweynta daroogada maandooriyaha. Marka la eego natiijooyinka neurobiological waxay tilmaamayaan in PG iyo daroogada maandooriyuhu ay wadaagaan wadooyinka wadaagga ee etiopathological [5, 45], daawooyinka la beegsanayo gudbinta glutamaterka waxay noqon kartaa mid loo isticmaalo daaweynta dabiicada akhlaaqda (ie, PG).

Macluumaadka waxay u muuqdaan inay xaqiijinayaan isticmaalka habka loogu talagalay nidaamka glutamaterka ee daaweynta PG, gaar ahaan iyada oo uur-ku-qaadista iyo kordhinta daaweynta daaweynta [10, 15]. Daawooyinka Glutamaterigic xaqiiq ahaan, waxay xaqiiqooyinka bixin karaan faa'iidooyin ka hortagga soo noqoshada [4]. Waxaa dhawaan la soo jeediyey in cabashooyinka loo arko inay tahay natiijada awoodda liidata ee la xakameynayo daroogada raadinta ee ka jawaab celinta xaaladaha degaanka, taas oo ay ugu wacan tahay isbeddelka ku yimaada Glu homeostasis, iyadoo wadajir ah oo lagu kicinayo qalabka DA iyo NMDA glutamatergic reseptors [2]. Daawooyinka Glutamatergic waxay xakameyn karaan isdhexgalka isku dhafan ee ka dhexeeya nidaamyada glutamaterigga iyo dopaminergic, isla mar ahaantaana si siman labada nidaam, hababka loo baahan yahay in si fiican loo baadho.

Cilmi-baarisyada laga wada-hadlayo ma aha kuwo ku lug leh shuruudaha loo isticmaalo si loo qiimeeyo wax-ku-oolnimada daaweynta fayo-dhawrka ee PG. Dhab ahaan, daraasadaha qaarkood waxay tixgelinayaan maqnaanshaha dabeecada khamaarka sida natiijada asaasiga ah iyada oo la fiirinayo qiyaasaha daaweynta ee muhiimka ah oo ay ku jiraan calaamadaha niyad-jabka iyo ka-noqoshada. Waxa xiiso leh, cilmi baarista daawooyinka glutamatergic waxay muujineysaa muhiimada ay leedahay in la tuso dareenka daaweynta si loo ogaado iyo daaweynta calaamadaha garashada [29]. Khamaarayaasha cudurku waxay muujinayaan qaab go'aamineed oo si joogta ah u dhibaateeynaya cawaaqib xumo mudo dheer ah si loo helo daweyn degdeg ah ama gargaar deg deg ah oo ka imaanaya dawlad aan raaxo lahayn oo la xidhiidha qabatinka. Noocyada fahamka iyo dareenka ee kala duwan ayaa saameeya go'aan qaadashada [11]. Isbeddeladan (sida, garashada garashada) waxay gacan ka geysan kartaa doorasho madaxbannaan ee bukaanka PG iyo dayactiridda xanuunka, si aan toos ah u xaqiijin waxtarka suurto galka ah ee daaweynta garashada ee diiradda saareysa isbeddelidda garashada khamaarka aan caqli-gal ahayn [67]. Bartilmaameedka bukaan-socodka, dhammaan hab-dhaqameedka daaweynta nidaamka glutamaterka, wuxuu noqon karaa daaweyn wax ku ool ah oo u baahan baahida waxbarasho dheeraad ah.

Daroogooyinka sii kordhiya awoodda go'aan qaadashada iyo awoodda waxqabadka fulinta ayaa ah mid aan si fiican loo garaneyn sababtoo ah kakanaanta hawlahaas oo ka kooban hoos-u-marisyo kala duwan (sida, abaal-marin, dareen ciqaabeed, iyo dareen diidmo). Si kastaba ha noqotee, waxaa lagu doodi karaa in wakiilada lagu beegsanayo subaxdii soo socota ay kor u qaadi karaan go'aan qaadashada sidoo kale. Intaa waxa dheer, kor uqaadayaasha garashada sida modafinil waxaa kale oo laga yaabaa in ay leeyihiin saameyn faa'iido leh, gaar ahaan maadooyinka dareenka badan [13].

6. Xogta mustaqbalka

Xogta waxay u muuqataa inay xaqiijinayso kor u qaadista nidaamka geedka glutamaterka ee daaweynta PG, gaar ahaan adigoo ku shaqeynaya adoo adeegsanaya garashada iyo garashada garashada (isdhexgalka iyo garashada garashada). Inkastoo daaweynta loo adkeeyay ee PG ay leedahay heerar kala duwan oo taageero ah, wax yar ayaa la ogyahay farsamooyinka ficilkooda ama sida daaweynta gaarka ahi u shaqeyn karto shakhsiyaadka gaarka ah. Daraasado dhowr ah ayaa la sameeyay si loo tijaabiyo waxtarka daawooyinka opioid ee daaweynta xanuunka, iyo saadaal hidde ah ama taariikh qoys ee khamriga ayaa la qiimeeyay si loo xakameeyo jawaabta loo yaqaan 'opioid antagonists' kooxaha dhexdhexaadka ah [68]. Sidoo kale, daraasadaha mustaqbalka waa in ay baaraan astaamaha nafleyda iyo nafsiyaadka ee bukaanka PG kuwaas oo daaweynta glutamatergic ku habboon tahay. Iyada oo ku saleysan aqoonta hadda jirta, waxaan u soo jeedinnaa aalado caafimaad iyo dhibaatooyin isku dhafan kuwaas oo gacan ka geysan kara in ay hagaan dhakhaatiirta xulashada xeeladaha daaweynta daaweynta glutamaterka ee habboon (Jaantuska 2). Tilmaamahan wuxuu bixin karaa aasaaska iyo ujeedada si uu u hagto xulashada daawooyinka farmasiyada ee kooxo ka mid ah bukaanada PG. Baadhitaano dheeraad ah ayaa loo baahan yahay si loo xaqiijiyo algorithm daaweynta aan soo jeedino.

Jaantuska 2 

Mawduucyo caafimaad iyo dhibaatooyin isku-dhafan oo ku saabsan xulashada xeeladaha daaweynta glutamatergic si loo daaweeyo khamaarka noolaha.

Ka dib markii maamulka cocaine-ka, uu carqaladeeyey Glu's homeostasis ee nucleus xajmiga asaasiga ah ayaa la arkay. Astaamaha khalkhalka gurmadka degdega ah waa hoos u dhac ku yimaadda ficil ahaanta iyo u shaqeynta gaadiidka waaweyn ee Glu, GLT-1 [69]. Daraasadaha mustaqbalka waa inay baaraan doorka ay ka leeyihiin PG iyo suurtagalnimada isticmaalka daroogooyinka u shaqeynaya si ay u bedelaan muujinta Glu neurotransmitter-ga oo loo marayo dhaqdhaqaaqa hidaha (ie, ceftriaxone) [70].

Ka sokow Glu iyo DA, arrimo kale, sida walxaha neerotrophic ee maskaxda (BDNF), waxay ku lug lahaan karaan talaabada glutamatergic agents ee PG [71]. Waxyaabaha loo yaqaan 'neurotrophic factors' ayaa lagu muujiyay in la beddelo dhacdooyinka deegaanka ee xaalado kala duwan ee cilmi nafsiga ah [72], kaalintoodana waxaa lagu xaqiijiyay fayaqabka PG [73]. Daraasadaha mustaqbalka waa in ay ka caawiyaan fahamka kaalinta suurtagalka ah ee qaabeynta glutamaterka ee heerarka neurotrophins ee bukaanka PG.

Baaritaannada mustaqbalka waxay ka faa'iideysan doonaan tijaabooyinka kiliinikada lagu xakameynayo si ay u muujiyaan faa'iidooyinka dhabta ah ee daawooyinka glutamatergic ee daaweynta PG. Intaa waxa dheer, cilmi-baarista mustaqbalku waxay faa'iido ka yeelan kartaa ciladaha fayloserka ee lagu daro farsamooyinka neuroimka si ay u iftiiminayaan kaalinta Glu ee fayadhowrka maskaxda ee PG. Cilmi-baarista cusub ee PGD waa in lagu daraa kontaroolka la isku daray, xisaabtanka arrimaha keena, iyo kala-takooridda doorashooyinka khamaarka. Baadhitaannada kooxo yaryar oo gaar ah, ayaa la rajeynayaa, inay si dheeraad ah u siiyaan fikrado badan oo ku saabsan jirroyinka cudurada ee kooxahan iyo waxay u horseedi karaan daaweyn dheeraad ah oo tayo sare leh. Daraasadaha mustaqbalka waa inay sidoo kale diirada saaraan xiriirka ka dhexeeya dopaminergic iyo glutamatergic, si loo iftiimiyo hababka adag ee neurobiological ee hoosta ka ah horumarinta dabeecada khamaarka.

Soo Gaabiyey

PG:Khamaarka nafsadda
Calool:Glutamate
DA:dopamine
NMDA:N-methyl-d-aspartate
AMPA:α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid
GABA:Gamma-aminobutyric acid
CSF:Dheecaanka cerebrospinal
NAC:N-acetylcysteine
RCT:Maxkamad aan haboonayn
PG-YBOCS:Yale-Brown Nidaamka Iskuduwida Isbedelka ee PG
G-SAS:Khamaarista Qiimaynta Cilmi-badeedka.
 

Iskuduwida xiisaha

Qorayaashu waxay cadeynayaan in aysan jirin wax khilaaf ah oo ku saabsan danta ku saabsan daabacaadda warqadan.

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