N-acetylcysteine ​​ho mafu a kelello: bopaki ba kalafo bo teng hona joale le mekhoa ea ts'ebetso (2011)

 HO ITHUTA FELA MONA

 Copyright © 2011 Mokhatlo oa Bongaka oa Canada

Olivia Dean, BSc, PhD, Frank Giorlando, MBBS, BMedSc, le Michael Berk, MBBCh, MMed (Psych), PhD

 Dean, Berk - Setsi sa Patlisiso ea Bophelo bo Botle ba kelello, Parkville; Dean, Giorlando, Berk - Lefapha la Saense ea Tleliniki le Bioloedical, Bophelo ba Barwon, Univesithi ea Melbourne, Geelong; Berk - Setsi sa Patlisiso ea Orygen ea Bacha, Parkville, le Sekolo sa Bongaka, Setsi sa Bophelo, Bongaka, Nursing le Boitšoaro ba Bohlale, Univesithi ea Deakin, Geelong, Victoria, Australia

 Litaba tse amanang le: Ngaka O. Dean, Setsi sa Patlisiso ea Bophelo bo Botle ba kelello, 155 Oak St., Parkville, Victoria, Australia; Email: [imeile e sirelelitsoe] '+ reverseAndReplaceString (' ua.gro.htlaehnowrab / ta / daivilo ',' / at / ',' @ ') +' ')} tšoasa (e) {} // ->

 E amohetse la 30 Hlakubele 2010; E ntlafalitsoe ka la 2 Phuptjane 2010; E ntlafalitsoe ka la 22 Phuptjane 2010; E amohetsoe ka la 24 Phuptjane 2010.

inahaneloang

Ho na le lefapha le ntseng le hola la lipatlisiso le etsang lipatlisiso ka melemo ea mefuta e meng ea phekolo ea meriana ea mafu a kelello. N-acetylcysteine ​​(NAC) e hlaha e le moemeli ea ka thusang kalafong ea mafu a kelello. Joalo ka mekhoa e mengata ea phekolo, mantlha a tlholeho a NAC a hole le tšebeliso ea ona ea hona joale ho ts'ebeliso ea kelello. Le ha mekhoa ea NAC e se e qala ho utloisisoa, ho ka etsahala hore NAC e fana ka melemo ho feta ho ba moetapele oa li-antioxidant, glutathione, modulating glutamatergic, neurotropic le pathways. Tlhahlobo ena e bonts'a lingoliloeng tsa hajoale mabapi le ts'ebeliso ea NAC mathateng a kenyelletsang bokhoba ba ho lemalla, mathata a ho qobella le ho ikoetlisa, lefu la kelello le lefu la ho ferekana kelellong. N-acetylcysteine ​​e bonts'itse liphetho tse khothatsang tsa palo ea batho ba nang le mathata ana, ho kenyelletsa le bao ts'ebeliso ea katleho ea kalafo e neng e lekantsoe ho eona pele. Monyetla oa kalafo oa amino acid ena e se o qalile ho hlaha tšimong ea lipatlisiso tsa kelello.

Tšebeliso ea nalane ea nalane ea N-acetylcysteine

N-acetylcysteine ​​(NAC) e sebelisitsoe e le motsoako oa antioxidant ho glutathione (γ-glutamylcysteinylglycine; GSH) kalafo ea paracetamol overdose ka lilemo tse fetang 30.¹ Ha ho utloisisoa haholoanyane ka liketso tsa NAC, lits'ebeliso tsa kliniki le tsona li atile. N-acetylcysteine ​​e se e sebelisoa haholo e le moriana oa kalafo le kalafong ea HIV, 'me e tlaleha ho sebetsa hantle ho lefu le sa feleng la pulmonary le nephropathy.² E ikhethileng mabapi le mathata a bokong, NAC e lekoa ka katleho e itseng ho bakuli ba nang le lefu la Alzheimer.³ Tlhahlobo e teng e tla hlahloba karolo ea NAC kalafong ea maemo a kelello le mekhoa e ka thusang molemong oa mafu ana.

Karolo ea oxidative ea homeostasis

Ts'ebeliso ea NAC ho khutlisetsa maemo a GSH e thehiloe hantle (Feie. 1). Glutathione ke antioxidant ea mantlha ea pele. Glutathione e khelosa oksijene le mefuta ea naetrojene seleng ka ho hasanya ka kotloloho le ka kotloloho. E le antioxidant e ngata haholo ebile e ngata haholo, e na le boikarabello ba ho boloka tekano ea oxidative seleng. Sena se etsahala ka ho tlosoa ka kotlolloho hoa mefuta e sebetsang hape ka ho etsoa le ho phatloha hoa li-adducts mme e boetse e ts'oaroa ke glutathione peroxidase (GPx) ka nicotinamide adenine dinucleotide phosphate (NADPH) -sencence reaction. Li-glutathione tse hlahisoang li tsoa ebe li fokotsoa ke glutathione reductase ho qala potoloho hape.⁴ Lisele tsa Glial li na le maemo a phahameng haholo a GSH ho feta lisele tsa neuronal mme li tšehetsa tlhahiso ea neuronal GSH. Litsebi tsa linaleli li lokolla GSH sebakeng se ka ntle ho sebaka mme γ-glutamyltranspeptidase e theola GSH ho ea dipetlele tsa cysteine-glycine le glutamate. The dipeptide e hydrolyzed ho glycine le cysteine, 'me li-amino acid tsohle tse 3 li se li fumaneha bakeng sa syntonal ea neuronal GSH. Ho hlahisoa ha Neuronal GSH ho lumeloa hore ho kenella hofeta ka ho lokolloa hoa bonohe ba GSH, mme tlhahiso ea GSH ea mohlolo e lekantsoe ke cysteine ​​le enzyme glutamate-cysteine ​​ligase.^4,5

 Ntle le ho fana ka cysteine ​​bakeng sa tlhahiso ea GSH, NAC e bontšitsoe ho hlapolla li-oxidants ka kotloloho, haholo-holo phokotso ea radicxyl radical, · OH le hypochlorous acid.⁶

Tsamaiso ea molomo ea GSH feela ha e buse ka botlalo maemo a GSH. E angoa ka potlako ke sebete le mala,⁷ le ho kenella ka hare ho mali - boko ho haella. Ka mokhoa o ts'oanang, tsamaiso ea molomo ea L-cysteine ​​le eona e bonts'itsoe ha e na le phello e ngata litekanyetsong tsa GSH tsa boko ka lebaka la metabolism ea pele.^8-10 Tsamaiso ea molomo ea NAC e baka maemo a eketsehang a plasma cysteine, 'me qetellong e lebisa keketseho ea plasma GSH.^11,12 N-acetylcysteine ​​e bontšitsoe hore e kenelle ka katleho ho sekhahla sa mali le bokong 'me e phahamise maemo a GSH ea bokong lipapisong tsa liphoofolo.^13-15 e kanna ea sebetsa ho lefu la kelello, moo ho bontšitsoeng liphetoho tse teng bokong GSH le litsela tse ling tsa redox.

Tšebelisano le babuelli ba methapo

Liphetoho ho li-cytokine tsa pro- and anti-inflammatory, ho kenyeletsa le interleukin (IL) -6, IL-1β le tumor necrosis factor (TNF) –α, ho tlalehiloe ka bongata bo nang le khatello ea maikutlo, le ho isa tekanyong e tlase, ho ferekana ha kelello le lefu la kelello.^16,17 Li-cytokine tsena tse nang le tšoaetso li na le monyetla oa ho kenya letsoho pathophysiology e ka tlase ea mafu ana. N-acetylcysteine ​​e bontšitsoe hore e na le thepa e khahlanong le ho ruruha (Feie. 1) tse hokahaneng le litsela tsa oxidative, tse ka fanang ka mokhoa o mong oa ts'ebetso molemong oa NAC ho ts'ebetso ea kelello.

N-acetylcysteine ​​e bontšitsoe ho fokotsa maemo a IL-6 ho bakuli ba hemodialysis,¹⁸ leha ho se phetoho mehatong ena e tlalehiloeng kamora kalafo ea NAC ka mohlala oa maqeba a ho lemala ha boko.¹⁹ Ka lehlakoreng le leng, litekanyetso tse eketsehileng tsa TNF-α le IL-1β li ile tsa fokotsoa kamora kalafo ea NAC mefuteng ea likotsi tsa boko bo utloisang bohloko le ischemia ea kelello.^19,20 N-acetylcysteine ​​e boetse e bontšitsoe ho ntlafatsa sephetho mefuteng ea lipopolysaccharide ea ho ruruha. Ho ts'oaroa ha feberu le NAC ho thibetse khatello ea maikutlo le ho lahleheloa ke bokhoni ba nako e telele kamora ho pepesetsoa ts'oaetso ea prenatal.²¹ Ho feta moo, kalafo ea lipopolysaccharide e baka nts'etsopele ea lesigodendroglial ea cell e thibelitsoeng le myelination e fumanoang ke tsamaiso ea NAC litsong tse kopaneng tsa glial.²²

Phokotso ho li-cytokine tse fokolisang ke kalafo ea NAC e kanna ea ba mochine o ka sebelisang mekhoa eo NAC e fetotsang matšoao a mafu a kelello. Sena se ka amahanngoa ka kotloloho le tsela ea ts'oaetso, kapa ho sebetsa ka lits'ebetso tsa oxidative tse amanang le ho ruruha. Ho hlokahala patlisiso e eketsehileng ho hlakisa mekhoa ena.

Litlamorao ho neurotransication

Glutamate

 Ntle le litlamorao ho ho leka-lekana ha li-oxidative, liphetoho tse maemong a cysteine ​​le tsona li bontšitsoe ho feto-fetola mekhoa ea neuro-transmitter, ho kenyelletsa glutamate le dopamine (DA; Feie. 1).^23,24 Cysteine ​​e thusa ka taolo ea phapanyetsano ea neuronal intra- le extracellular exchange of glutamate ka antiporter ea cystine-glutamate. Le ha antiporter ena e le makhethe ho mefuta eohle ea lisele, bokong e fumaneha ka ho khetheha liseleng tsa glial.²⁵ Leseli, cystine, le nkeloa ke linohe tsa linaleli ebe le fetoloa bakeng sa glutamate, e ntšoang sebakeng sa kantle ho naha. Mofuta ona oa mahala oa glutamate o bonahala o susumetsa li-receptor tse thibelang metabotropic glutamate li-terminals tsa methapo ea kutlo ea glutamatergic ebe ka tsela eo li fokotsa ho lokolloa ha glaptamate.²⁶ Ka lebaka la kamano eo, palo ea cysteine ​​tsamaisong hammoho le tlhahiso ka tlhahiso ea GSH ka li-neuron e ka laola ka kotloloho palo ea glutamate e teng sebakeng sa extracellular. Ho feta moo, GSH ka boeona e bonts'itsoe ho arabela karabo ea mokokotlo oa N-methyl-d-aspartate ea receptor ho glutamate ho likhoto.^27,28 Liphetoho maemong a neuronal GSH li kanna tsa se fetole maemo a teng a glutamate feela, empa hape li ka ba le litlamorao tse tobileng ts'ebetsong ea glutamatergic.

 Dopamine

 Ntle le ho fetolela maemo a glutamate ka antiporter ea cystine-glutamate, NAC e boetse e bontšitsoe ho fetola tokollo ea DA. Kamora kalafo ea amphetamine ho etsa likhoto tsa striatal, NAC e bonts'itsoe ho thusa ho lokolla masapo a DA ka litekanyetso tse tlase ho li-striatal neurons le ho thibela ho lokolloa ha methapo ea methapo.²⁹ Ho litšoene, NAC e bontšitsoe ho sireletsa khahlanong le phokotso ea maemo a transporter a DA kamora tsamaiso ea methamphetamine e pheta-phetoang,³⁰ fana ka tlhahiso ea mokhoa o le mong moo ho eketsang tokollo ea DA ho ileng ha khothalletsoa thutong e fetileng. Glutathione e boetse e bontšitsoe ho eketsa glutamate agonist-e tsitsitse ho lokolloa ha DA ho li-neur striatal neurons.²³

Sebelisa ho mafu a kelello

 Ho na le 'mele o ntseng o eketseha oa lingoliloeng o ntseng o hlahloba ts'ebeliso ea NAC kalafong ea mafu a kelello. Ho na le bopaki ba nakoana ba hore mosola o ka ba teng oa NAC maemong a mangata a ferekaneng. Bongata ba mathata ana a na le likhetho tse fokolang tsa kalafo kapa liphetho tse fokolang. Tlhahlobo ea hona joale e bonts'a ts'ebeliso ea bongaka ea NAC ho mafu a kelello (kakaretso in Lethathamo 1).

 lemalla ntho e

 Ho na le lingoliloeng tse ngata tse hatisang tlhekefetso bokhobeng.^47,48 Haufinyane tjena, ho ntse ho hlaha lintlha tse fanang ka maikutlo a karolo ea khatello ea ts'oaetso ho pathophysiology ea ho lemalla lithethefatsi tsa tlhekefetso.^32,49-51 Patlisiso e hlokometse ho feto-fetoha ha litsela tsa glutamatergic tsa NAC ka mehlala ea pele ho tleliniki.^52,53 N-acetylcysteine ​​e bontšitsoe ho khutlisa ho fokotseha hoa phallo ea cystine-glutamate ka cypine-glutamate antiporter 'me ka hona e thusa ho khutlisetseng lits'ebetso tsa glutamatergic ka ho lemalla.^32,52 Thepa ena e entse hore e be le tebello ea monyetla oa kalafo ea bokhoba ba tahi. Bongata ba lingoliloeng tse latelang li thehiloe litekong tse nyane tsa tlhahlobo ea bongaka, lingoloa tse sa sebetseng kapa litlaleho tsa linyeoe, empa li ts'episa ho fana ka maikutlo a tlhoko ea lithuto tse kholo tse entsoeng hantle.

Ho itšetleha ka Marijuana

Phuputso ea morao-rao e entsoeng ke Gray le basebetsi mmoho³¹ ba fuputse ts'ebeliso ea NAC (2400 mg / d) thutong e bulehileng ea basebelisi ba matekoane ba 24 ba tlalehileng ba nang le thahasello ea ho fokotsa ts'ebeliso ea bona. Kamora kalafo, basebelisi ba tlaleha liphokotso matsatsing / bekeng ea tšebeliso le "palo ea likotsi." Ka lehlakoreng le leng, mehato ea "cannabinoid" ea moroto ha ea ka ea fetoha haholo nakong ea kalafo, leha bangoli ba re maemo a moroto oa cannabinoid ho basebelisi ba 13 a lutse a phahame ho feta tlhahlobo ea tlhahlobo, ka hona a fana ka sephetho se makatsang mabapi le ho fokotseha ha ts'ebeliso. Ntle le ts'ebeliso e akaretsang, phokotso ho ts'ebetso e tlalehiloeng, ho nkeha maikutlo le sepheo mabapi le tšebeliso ea matekoane (e lekantsoeng le Marijuana Craving Questionnaire) ho tlalehiloe, ho bonts'ang ntlafatso maemong a 3 ho a mane a sekhahla.³¹

Bokhoba ba Nikotine

N-acetylcysteine ​​le eona e fuputse e le kalafo bakeng sa ho lemalla joala ba nicotine. Ntle le phetolo ea glutamate ho fokotsa litakatso le boits'oaro ba moputso, NAC e kanna ea ba le karolo ea ho ba antioxidant bothateng moo khatello ea oxidative e tšoaeang. Ho bile le thuto e laoloang ke placebo e le 'ngoe (n = 1) ho fuputsa 29 mg / letsatsi la NAC e le kalafo bakeng sa ho khaotsa ho tsuba.³² Phuputso ena e tlaleha litekanyetso tsa motho ea nkang karolo le litakatso hammoho le mehato ea biochemical ho netefatsa tšebeliso e tlalehiloeng. Ha ho na phapang e kholo palong ea lisakerete tse tsubang kapa tsa carbon monoxide lipakeng tsa NAC le lihlopha tsa placebo. Ho latela kalafo le kalafo ha lia ka tsa tlalehoa. Bangoli ba hlokometse hore joala e ne e le "covariate ea bohlokoa", mme kamora ho tlosoa ha barekisi ba babeli ho latela ts'ebeliso ea lino tse tahang le ts'ebeliso e mpe ea nicotine, ho ne ho ena le ts'ebetso ea morao ho ho theoha ha palo ea lisakerete tse fokotsehileng tsa tsuba sehlopheng sa NAC, mme sena se ne se sa tsamaisane le litekanyetso tsa carbon monoxide tse fokotsehileng. Ka lebaka la ho nka karolo ha barupeluoa tlhahlobisong le ho fapana ha sampole ho latela lintlha tse kathoko ka tšebeliso ea joala, sampole ea phuputso ena e ne e le nyane haholo hore e ka etsa liqeto tse hlakileng.

Ho na le phuputso e 'ngoe e nyane e kenyelletsang batho ba tsubang bao ba neng ba sa rera ho tlohela, e leng ba ileng ba fuputsa barekisi ba biomark ho batho ba tsubang kamora kalafo ea NAC.³³ Liphetho tsa thuto e ne e le ho lekola litlamorao tsa NAC ho likarolo tse kotsi tsa biophysical tsa ho tsuba. Barupeluoa ba ile ba abeloa ka lihlopha tsa placebo kapa NAC (1200 mg / d) mme ba phekoloa likhoeli tse 6. Phuputso e fumane hore sehlopheng sa NAC, ho ne ho fokotsehile liphatlalatsong tsa DNA tsa lipophilic lipakeng tsa motheo le ntlha ea qetello. Hape, maemo a 8-OH-dG a ne a fokotsehile ka bobeli pakeng tsa motheo le ntlha ea pheletso, mme a bapisoa le sehlopha sa placebo. Lintlha tsena li bontša ho fokotseha ha tšenyo ea DNA nakong ea thuto. Ntle le moo, ho bile le palo e fokotsehileng ea micronuclei e teng ka mucosa ea molomo sehlopheng sa NAC kamora kalafo ha e bapisoa le motheo.

Bokhoba ba koae

Phuputsong e nyane ea crossover (n = 13), e etselitsoeng ho khetholla mamello le polokeho, barupeluoa (bao hona joale ba hanelang tšebeliso ea koae) ba fuoe 2400 mg ea NAC kapa placebo ho feta matsatsi a 2.³⁴ Matsatsi a mane hamorao, barupeluoa ba ile ba tšeloa letsoho le leng. Le ha ho ne ho se na liphetoho lipakeng tsa sehlopha sa phokotso ea litakatso ha li bapisoa le placebo, tlhahlobo ea sehlopha sa ka hare e bonts'itse hore sehlopha sa NAC se na le phokotso e kholo litakatsong, ho tlosoang le ts'ebelisong e tlalehiloeng le ha ho bapisoa le motheo, o sa bonoeng sebakeng sa placebo sehlopha. Le ha thuto ena e ne e sa ikemisetsa ho etsa patlisiso, ho ile ha fumanoa pontšo e fanang ka bopaki bo bong ba ho netefatsa lipatlisiso tse ling.

Phuputsong e latelang, sampole e ts'oanang e ile ea alafshoa ka 2400 mg ea NAC.³⁵ Liphetho tsa boithuto bona li bonts'itse hore, ho ipapisitse le li-slice tsa cue-reacaction, NAC e theotse takatso le takatso ea cocaine, hape ea fokotsa nako e sebelisitsoeng ho sheba li-slide tse amanang le koae.

Kamora lithuto tsena, sehlopha sena sa lipatlisiso se ile sa tsoela pele ho etsa liteko tse kholo tse bulehileng tsa NAC li sebelisa tekanyetso tse 3 ho feta libeke tse 4.³⁶ Qalong, barupeluoa ba 8 ba amohetse 1200 mg / letsatsi la NAC. Kamora ho thehwa ha mamello ho lethal dose lena, barupeluoa ba bang ba 9 ba amohetse 1800 mg / letsatsi la NAC, mme qetellong barupeluoa ba 6 ba amohetse 3600 mg / letsatsi la NAC. Le ha e se lipalo-palo, phuputso ena e fumane phokotso ea chelete e sebelisitsoeng ho koae, palo ea matsatsi a ts'ebeliso le lintlafatso e ipapisitse le Tlhahlobo ea Kaka ea Seoa ea Cocaine. Bafuputsi ba hlokometse hore boithuto bona bo matlafalitsoe mme bo hloka moralo o laoloang ke placebo ho etsa likhakanyo tsa konkreite mabapi le ho sebetsa hoa NAC kalafong ea ho lemalla koae. Ka lebaka la liphetho tsena, ho hlokahala liteko tse kholo tse lokiselitsoeng hantle.

Papali ea papali ea chelete

Phuputsong e bulehileng ka ho akaretsa barupeluoa ba 29 ba nang le temallo ea methapo ea kelello ea ho becha, Grant le basebetsi mmoho³⁷ e tsamaisoa 1800 mg (lethal dose) ea NAC ho feta libeke tse 8. Teko e sa hlophisoeng ea ba arabileng ka 13 e ile ea etsoa libeke tse 6 tse latelang (lethal dose le sa khaotseng la 1800 mg / kg ea NAC ha e bapisoa le placebo). Nakong ea thuto e bulehileng, barupeluoa ba 16 ba ile ba fokotseha haholo litloaelong tsa papali ea chelete. Ho bao, ba 13 ba ile ba lumela ho nka karolo ho ithuteng e sa reroang. Kamora libeke tse ling tse 6 tsa kalafo ea NAC, 83% ea sehlopha sa NAC e ne e ntse e nkuoa e le ba arabelang, e le 28% feela sehlopheng sa placebo.

Boloetse bo qhekellang - bo qobellang

Ho tšoana ho teng har'a libaka tsa boko tse kenyelletsang tlatsong le bokhobeng bo sa bonahaleng (OCD), ho kenyelletsoa le li-nucleus accumbens le cortex ea anterior.^54,55 Ho bile le litlaleho tsa khatello ea ts'oaetso ea oxidative bathong ba nang le OCD, ho kenyelletsoa le lipid peroxidation;^56-59 vithamine E e fokotsehile,⁵⁸ catalase, GPx le selenium;⁵⁹ ho tepella ho hoholo ha superoxide;⁵⁹ le diphetoho maemong ohle a nang le oxidative.⁶⁰ Tse ling tsa liphetoho tsena li hokahane le matšoao a thata.^57,59

Mekhoa ea kalafo ea mantlha e tloaelehileng ea OCD ka kakaretso e kenyelletsa motsoako oa li-serotonin reuptake inhibitors (SRIs) le psychotherapy. Le ha ho na le katleho e itseng ka mofuta ona oa kalafo, ho fihlela batho ba 20% ba nang le OCD ha ba na kalafo mme ba fumana molemo o fokolang.⁶¹ Ho na le bopaki bo bong ba ho fana ka maikutlo a tlhekefetso ea glutamatergic ho batho ba nang le OCD; leha ho le joalo, ts'ebetso e 'ngoe e hlokahala ho fumana hore na ena ke sepheo sa mantlha, sephetho kapa sehlahisoa sa hypermetabolism le neurotransuction e fetotsoeng litseleng tse ling.⁶²

Hajoale, ho na le tlaleho ea nyeoe e le 'ngoe feela mabapi le ts'ebeliso ea NAC ho bakuli ba nang le OCD.³⁸ Tlaleho ena e bonts'a melemo e ntle ho motho ea neng a hana phekolo. Morupeluoa o ile a fumana molemo o itseng ho tsoa kalafong ka fluvoxamine, mme a tsoela pele fluvoxamine nakong ea teko ea libeke tse 13 ea 3 g ea NAC (ho kenyelletsa le tekanyetso ea karolo ea 3 g). Nakong ea liteko, morupeluoa o ile a ntlafala maemong a Yale-Brown Obsessive Compulsive Scale le Hamilton Rating Scale bakeng sa lintlha tsa khatello ea maikutlo. Pheko e tsoelang pele ka fluvoxamine le NAC e lebisitse ntlafatsong e kholo taolong ea ho hlatsuoa ka mokhoa o qobelloang le lisosa tse bonoang.

Trichotillomania le mathata a ho ikoetlisa

Kamano e makatsang pakeng tsa OCD le trichotillomania (TTM) e ea hlalosoa, 'me ho tlalehiloe ho sebetsa hoa li-SRI ho TTM, joalo ka OCD.⁶³ Leha ho le joalo, karabelo ea kalafo le li-SRI ho batho ba nang le TTM ha e lumellane.⁶⁴ Papiso lipakeng tsa TTM le mathata a bokhoba le tsona li se li entsoe, ka lebaka la hore ts'usumetso ea moputso le ts'ebeliso e mpe ea ts'ebeliso ea litšebeliso li ka sebetsa ka mefuta ena e 'meli ea pherekano,' me ho bile le molemo o itseng oa ho alafa TTM ka bahanyetsi ba opioid.⁶⁵ Trichotillomania e kanna ea ba le tlholeho, e na le sehlotšoana se le seng se ts'oanang le OCD le sehlotšoana se seng se ts'oanang le tlhekefetso.⁶⁶ Liphuputso tse peli li bontšitse melemo ea kalafo ea NAC ho batho ba nang le TTM.³⁹ Ba pele ba ne ba ama monna ea lilemo li 28 'me oa bobeli e le mosali ea lilemo li 40. Bangoli bana ba tlalehile hore 1800 mg ea NAC (e kentsoe nako e fetang libeke tse 'maloa) e ntlafalitse ho hula moriri.

Ho bile le teko e laoloang habeli ea mahlo, e laoloang ke placebo bakeng sa kalafo ea TTM.⁴⁰ Thutong ena, batho ba 50 (basali ba 45 le banna ba 5) ba ile ba fuoa 1200 mg ea NAC kapa placebo bakeng sa libeke tse 6, ba lateloa ke libeke tse ling tse 6 tsa 2400 mg tsa NAC kapa placebo. Halofo ea sampole e ne e ntse e nka meriana ka nako e tšoanang, ho kenyelletsa le li-SRIs, serotonin-noradrenaline reuptake inhibitors le li -vuser. Barupeluoa ba bane ba ne ba fuoa kalafo ea kelello. N-acetylcysteine ​​e ile ea fanoa hammoho le liphekolo tsena. Ha thuto e ntse e tsoela pele, kalafo ea NAC e ile ea fumanoa e fokotse matšoao a TTM ha e bapisoa le placebo. Boholo (88%) ea barupeluoa ba qetile thuto ea libeke tse 12. Litlamorao tsa kalafo li ile tsa bonoa ka beke ea 9 mme tsa tsoela pele ho pholletsa le thuto kaofela. Ka kakaretso, NAC e ne e bonahala e sebetsa hantle kalafong ea TTM.

Ntle le TTM, ho tšepisa sephetho sa ts'ebetso ea pele ho fana ka maikutlo a tlhoko ea lithuto tse laoloang mathateng a mang a boikoetliso, ho kenyelletsa ho loma kezipu le ho ts'oaroa ha letlalo.^39,41 Tlaleho ea nyeoe e ile ea phatlalatsoa mabapi le motho ea nang le boits'oaro bo bobeli ba TTM le maqeba a ho luma, eo ho luma ha hae ho ileng ha emisa kamora libeke tse 9 tsa kalafo ea NAC.³⁹ Morupeluoa o ile a oela hape kamora hiatus kalafong, empa ho pheta hape ha NAC ho felletse ka tokiso ea matšoao.³⁹ Ho fumanoe serendipitous ea melemo ea kalafo ea NAC phokotsong ea ho longoa ke lipekere thutong e atileng ho fuputsa NAC (2000 mg / d) kalafong ea mathata a maikutlo.⁴¹ Barupeluoa ba bararo ba nkileng NAC ba tlaleha ho fokotseha hoa bohlokoa ha ho longoa ke lipekere nakong ea thupelo ea likhoeli tse 6. Barupeluoa bohle ba bararo ba ne ba ntse ba sa thibele ho loma lipekere khoeli e le 'ngoe ka mor'a ho felisoa ha NAC.

Kamora nako, ho na le tlaleho ea nyeoe mabapi le ho khetha letlalo le kalafo ea NAC.³⁹ Ho mosali ea neng a sa fumane ts'ebetso ea meriana, ho ile ha tsamaisoa tšebetso ea 600 mg / letsatsi la NAC. Ho feta libeke tse 4 tse latelang, lethalinyana le ile la eketsoa ho 1800 mg / ka letsatsi, kamora moo boits'oaro bo habeli le boits'oaro bo nepahetseng mabapi le ho ts'oaroa ha letlalo bo ne bo tlohile ka botlalo.

Schizophrenia

Litla-morao tsa dopaminergic esale nalane e ntse e le ka pele joalo ka sepheo sa lipatlisiso bakeng sa schizophrenia, leha lits'ebetso tse ling tsohle tse kholo tsa neurotransmitter, ho kenyeletsa γ-aminobutyric acid, serotonin, acetylcholine, glutamate le noradrenaline le tsona li bile le tshusumetso.⁶⁵ Ho eketseha ha metaboliki ea dopaminergic ho striatum ho tlalehiloe. Sebaka sena sa hyperdopaminergic se bontšitsoe hore se lumellana haholo le hypodopaminergia sethaleng sa pele. Liphetoho tsena ho lumeloa hore li tsamaisa liphetoho lipakeng tsa tšebetso e phahameng le matšoao a mangata a pherekano ena.

Ho baahi ba nang le schizophrenia, ho hloka taolo ho metabolism ea glutamate le ho fokotseha ha maemo a glutamate ho cortex ea pele ho nako ho tlalehiloe.⁶⁸ Ho kenyelletsoa ha cysteine ​​ho bontšitsoe ho fetolela maemo a glutamate ka phapanyetsano ea glutamate-cystine, mme GSH e bonts'itsoe ho hlophisa ho tlama ha glutamate ho li-receptors tsa N-methyl-d-aspartate.⁶⁹ N-acetylcysteine ​​e kanna ea ba molemo ho phekolo ea lefu la kelello ka ho tsepamisa maikutlo le khatello ea kelello ka habeli, e fana ka maikutlo a hore phenotype ke litholoana tsa ts'ebelisano ea methapo e mengata ea methapo ea methapo ea methapo.⁷⁰ e sebetsanang le lits'ebetso tsa oxidative le ts'oaetso, tse eketsang tlatsetso bothateng.

Ho na le 'mele o ntseng o eketseha oa bopaki o bonts'ang khatello ea oxidative e etsahala ho batho ba nang le lefu la kelello,' me ho na le likhokahano lipakeng tsa lets'oao la ho sithabela ha oxidative le subtype ea ho hlahloba.^45,71-74 Hore na litlamorao li tsamaellana le phetoho ea methapo ea kutlo kapa sephetho sa tlhekefetso ena ho hloka lipatlisiso tse ling. Bopaki ba karolo ea khatello ea oxidative bathong ba nang le schizophrenia bo kenyelletsa li-polymorphisms ho liphatsa tsa bohlokoa tsa tsela ea GSH le maemo a fetotsoeng a li-antioxidants (ka kamano pakeng tsa maemo le botebo ba matšoao).⁷⁵ Matšoenyeho a nang le oksijene a ka lebisa ho liphetoho liphumeng tsa lipid, ho se sebetse hantle ha mitochondrial le liphetoho lipuisanong tsa DNA le liprotheine. Bathong ba nang le lefu la kelello, ho lumeloa hore ha ho na le liphetoho tse fokolang ho 'mele ea lisele tsa neuronal, lihokelo le ho phatloha ha dendritic ho ka ameha. Ona ke mokhoa o ka sebelisang khatello ea maikutlo mabapi le ts'oaetso ena. Ka mokhoa o ts'oanang, liphetoho tsa ts'ebetso ea mitochondrial li tlalehiloe, mme khokahano ea ho hlahisa matla e ka fana ka leseli ho lefu le thellang la lefu la kelello la schizophrenia. Ho feta moo, likhokahano pakeng tsa khatello ea oxidative le neurotransmission ho mafu a mafu a kelello li se li qala ho tsejoa.

Ho entsoe thuto e kholo ea ho etsa lipatlisiso tsa Nac e le mofuta oa kalafo ea adjunctive ea schizophrenia,⁴² e sebelitseng mofuta oa 1000 mg, regimen ea bi-day letsatsi le leng le le leng (ho bapisoa le placebo) ho kenyelletsa meriana e teng likhoeli tse fetang tse 6. Ka kakaretso, barupeluoa ba 140 ba ile ba nka karolo molekong ona o foufetseng habeli, o laoloang ke placebo, o sa reroang. Ho tsena, 60% e phethile teko ea kalafo ea likhoeli tse 6. Lintlafatso li ile tsa bonoa matšoao a seng matle, a lekantsoe ho Positive and Negative Syndrome Symbale. Ntle le moo, ho bile le lintlafatso ts'ebetsong ea lefats'e le ho sisinyeha ho sa tloaelehang ha mesebetsi, haholo akathisia. Mefuta ena ea phello e ne e lekane, 'me lintlafatso li ile tsa lahleha kamora khoeli e le ngoe kamora ho khaotsa kalafo. Mohlala ona o ne o nkuoa e le mokhoa oa ho phekola, 'me nako ea ho kula e le lilemo tse 1 mme batho ba fetang 12% ba kenya letsoho thutong ea letlalo. Ha re fuoa sena, liphetho tsa kenyelletso ea NAC li bohlokoa. Litla-morao tsa ka mpeng li ne li tlalehoa haholo; le ha ho le joalo, lihlopha tsa NAC le li-placebo ha lia fapana ka lipalo.

Liphumano tsena li ile tsa tšehetsoa hape ke tlhahlobo ea boleng ba lintlha tsa barupeluoa. Tlalehong ena, ho sebelisoa mokhoa oa ho ngola, tlhahlobo ea boleng ba litlaleho tsa bakuli le lipatlisiso tsa baoki li entsoe ka tsela e foufalitsoeng, mme li-NAC le lihlopha tsa placebo li bapisoa. Litaba tse hlahang li bonts'a hore barupeluoa ba ileng ba tšoaroa ke NAC ba bonts'itse ntlafatso ea temohisiso, boitlhokomelo, tšebelisano ea sechaba, tšusumetso, boikemelo, botsitso ba kelello le botsitso ba maikutlo.⁷⁶ Khethong e tlase ea thuto ea mantlha, NAC e ile ea hlaha e lekola ts'ebetso ea methapo ea kutlo, e lekantsoeng e sebelisa ho se sebetse hantle, letšoao la ts'ebetso ea glutamatergic le endophenotype ea psychosis. Ha ho bapisoa le taolo e phetseng hantle, batho ba nang le lefu la kelello ba ile ba bonts'oa ba fokolitse ho se sebetse hantle ha mantlha. Kamora libeke tse 8 tsa kalafo ea NAC (2000 mg / d), ho se tsotelle ho ile ha bontšoa ho ntlafala haholo.¹² Tlaleho ea linyeoe tsa morao-rao e boetse e bonts'itse ntlafatso ea bohlokoa matšoao a latelang 600 mg / letsatsi la NAC ho mosali e monyane ea nang le schizophrenia e hananang le kalafo. Leha ho le joalo, lintlha ha li fanoe ka botlalo.⁴³

Lefu la ho ferekana kelellong

Liphetoho tsa metabolism ea oxidative le tsona li hlalositsoe bathong ba nang le lefu la ho ferekanya kelello.^61,77 E tšoanang le schizophrenia, liphetoho maemong a antioxidant, matšoao a eketsehang a lipid peroxidation le carbonylation kaofela li tlalehiloe kaofela. Liphetoho tsena li shebahala li amana le naha, haholo mania, moo khatello ea oxidative e bonahalang e bonahala e bonahala. Sena se lumellana le litlaleho tsa linaha tsa hyperdopaminergic nakong ea liketsahalo tsa manic.⁴⁶ Ntle le moo, likamano pakeng tsa boemo ba oxidative le nako ea bokuli le tsona li fumanoe.⁷⁸

Ho ile ha etsoa tlhahlobo ea NAC e sa boneng mahlo ka bobeli, e sa reroang, 'me ea laoloa ke placebo ho barupeluoa ba 75 ba nang le lefu la ho ferekana.⁴⁴ Teko ena ea likhoeli tse 6 e kenyelletsa kenyelletso ea 2000 mg / d ea NAC kapa placebo kalafong joalo ka mehleng. Nakong ea likhoeli tse 6 ho ne ho se na phapang lipakeng tsa lihlopha ka litefiso tsa ho theoha, ka 64% ea sampole e felletseng ea liteko. Lintlha tsa tekanyetso ho Montgomery-Åsberg Depression Rating Scale (MADRS) le Bipolar Depression Rating Scale e bontšitse ho fokotseha ho hoholo ha matšoao a nyahamisang (lintlha tse 9 ho li-MADRS pakeng tsa lihlopha tsa NAC le li-placebo qetellong). Akin tekong ea schizophrenia, lintlafatso li ile tsa bonoa ntlafatsong ea lefatše, botebo le sekala sa tšebetso; leha ho le joalo, litlamorao tsena li ne li le kholo ka tekanyo, li le boholo bo boholo ka mehato e mengata. Kamora hore ho khaoloe kalafo ea NAC, ho bile le khokahano pakeng tsa lipalo tsa NAC le lihlopha tsa placebo, ho bonts'a tahlehelo kamora ho hlatsoa.

Puisano

N-acetylcysteine ​​e bonahala e tšepisa kalafo ea mafu a 'maloa a kelello. Mathata a mangata a kelello a hlalositsoeng a bontšitse feela tlhaiso-leseling mabapi le ho sebetsa hoa NAC kalafong ea bona, 'me ho hlokahala lipatlisiso tse ling. Leha ho le joalo, NAC e bonahala e le sepheo se ts'episang sa kalafo mme e fana ka monyetla oa monyetla oa kalafo tšimong eo kalafo ea hona joale e fokolang kapa e sa luleng e le ngata.

Ho haella ha ho hlaka ha NAC lithutong tsa pele hoa makatsa ebile ho fana ka maikutlo a hore e kanna ea ba liphofu tsa litsela tse atileng ho pholletsa le mathata; khatello ea maikutlo ea oxidative e bonahala e le ho se fumane ho sa tsotelleng ho fumanehang ha mefuta e mengata ea li-psychopathologies, le taolo ea glutamate, litsela tsa ts'oaetso le DA li tlalehiloe ka mokhoa o tšoanang. Ha ho nahanoa hore lits'ebetso tsa ho hlahloba hona joale li thehiloe ka mokhoa o makatsang, le hore ha ho na lefapha le leng la bongaka le sebetsanang le lefu la pathophysiology ka mokhoa o amanang, sena se ka bonts'a sekhahla sa mokhoa oa rona oa ho khetholla. Sena se hlakisoa ke taba ea hore ho na le mefuta e mengata ea phekolo le lihlahisoa tsa biomarkers ho pholletsa le mathata. Ha 'mele oa bopaki o ntse o le teng bakeng sa likhathatso tse ngata, ha motheo oa bopaki o ntse o eketseha, ho ka etsahala hore ts'ebetso e sebetsang e ka bonahala e le kholo libakeng tse ling ho feta tse ling. Ntle le moo, tekanyetso e nepahetseng ea NAC e ntse e tlameha ho thehoa ka nepo. Boithuto ba ho fumana moriana bo ka supa katleho e kholo ho litekanyetso tse phahameng kapa ho sebetsa hantle ho litekanyetso tse tlase. Le ha molaetsa oa mamello ea NAC o bonahala e le bobebe, o hloka ho hlakisoa hore ha ho na bopaki bo pharaletseng ba bopaki bo teng ka tšebeliso ea nako e telele. Liketsahalo tse ling tse mpe, joalo ka khatello ea mali ea methapo ea methapo ea methapo e tlalehoa lithutong tsa phoofolo e phahameng haholo, empa ha li e-so bonoe lithutong tsa batho.⁷⁹ Athe NAC e bonahala e le antiepileptic ka tekanyetso e tlase,⁸⁰ ho ts'oaroa ho tlalehiloe ka overdose.⁸¹ Ho hlokahala hore u falimehe.

Kaha boholo ba mathata ana a na le litsela tse ngata tse tsamaellanang tsa pathophysiological, ho hlokahala lipatlisiso tse eketsehileng ho tseba hore na Nac e fana ka melemo joang. Letšoao la bio le li-platform tsa neuroimaging li na le matla a ho bonesa litaba tsena. Mathateng a kang ho lemalla, glutamate e bile khetho ea mantlha bakeng sa ts'ebetso ea ts'ebetso, athe litekong tsa kelello le maikutlo, maikutlo a GSH ke 'ona a phatlalalitsoeng e le mokhoa oa ts'ebetso oa NAC. Leha ho le joalo, ha ho fanoa ka tšebelisano lipakeng tsa glutamate, methapo e mengata haholo ea methapo, le litsela tse ling tsa neurotransmitter, ho kenyelletsa le DA le serotonin, batho ba nang le mathata a kang khatello ea maikutlo le schizophrenia ba ka rua molemo ka ho feto-fetoha ho sa amaneng ha litsela tsena ka liphetoho tsa tšebetso ea glutamatergic. Khokahano e tloaelehileng ts'ebetsong ea kalafo e ka ba khatello ea oxidative, e bonts'itsoeng e fetotsoe boholo ba mathata ana. Leha ho le joalo, ho ts'ebeliso ea koae ea koae, boholo ba lipatlisiso tse shebileng mekhoa ea ts'ebetso bo ts'oarelletsa phetoho ea antiporter ea cystine-glutamate ke NAC e le eona sesosa se ka bang molemo.^26,82,83 Le ha ho e-na le ho tšoana ho pholletsa le mathata ana ka liphetoho tsa biology ea oxidative le neurotransication, le liphetoho lipapatsong tsa nako e telele tse tlatselletsang ho glutamate le boteng ba neuronal,⁸⁴ mohlomong heterogeneity ea methapo ea methapo e ka tlas'a lefatše, haholo-holo libakeng tsa ts'ebetso ea boko, e ka lebisa ho tšenolo ea liketso tse fapaneng tsa NAC ho latela moferefere.

Ka mokhoa o ts'oanang, phetisetso ea lits'oaetso tsa ts'oaetso e kanna ea bapala karolo molemong oa melemo e bonoang kamora kalafo ea NAC. Karolo ea ho ruruha khatello ea maikutlo e amohetse tlhokomelo e kholo ka ho fetisisa; leha ho le joalo, litsela tsa ho ruruha li na le tšusumetso ho etiology ea mafu a mang, joalo ka schizophrenia. Joalo ka antipsychotic ea atypical, e nang le data e ncha e bonts'ang mefuta e fapaneng ea ts'ebetso, ho kenyelletsa le ho ruruha,⁸⁵ boko-derived neurotrophic factor⁸⁶ le khatello ea maikutlo⁸⁷ katleho e ka fetoha tšebelisano e akaretsang ea litlamorao litseleng tse fapaneng.

Ka kakaretso sesebelisoa sena se sa lebelloang sa kalafo se hlahisa mekhoa ea lipale e le liphofu tse ka sebetsang tsa kalafo. Sena se bula tsela bakeng sa nts'etsopele ea mefuta e meng e metle ea kalafo, e amanang le hypothesis. Hore NAC e bonahala e bolokehile, e mamelleha ebile e theko e tlase ebile e fumaneha habonolo ebile e eketsa thahasello ea eona.

Mongolo o botlaaseng ba leqephe

Lithahasello tsa tlholisano: Mosebetsi ona o tšehelitsoe ke chelete ka chelete e tsoang ho Lekhotla la Patlisiso la Bophelo le Bongaka la Australia (OD le MB, NHMRC No. 509109) le Melbourne Research Scholarship (FG) ho ea Univesithing ea Melbourne. Ngaka Berk o phatlalatsa hore esale e le moeletsi oa AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen Cilag le Servier; setheo sa hae se amohetse lithuso ho tsoa ho Setheo sa Patlisiso ea Bongaka sa Stanley, MBF, Lekhotla la Sechaba la Bophelo le Lipatlisiso tsa Bongaka, Beyond Blue, Setsi sa Boithuto sa Bophelo sa Geelong, Bristol Myers squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma le Servier; o amohetse honaria ho Astra Zeneca, Eli Lilly, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvay le Wyeth; mme o na le chelete ea ho etela e tsoang ho Janssen Cilag, Astra Zeneca, Wyeth le Pfizer.

 Ba fanang ka Tlhahiso: Barekisi. Dean le Berk ba qapile thuto. Dr. Dean o fumane tlhaiso-leseling eo mme a e sekaseka le Drs. Giorlando le Berk. Bangoli bohle ba ngotse le ho hlahloba sengoloa mme ba lumellana le phatlalatso ea sona.

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