Liphello tsa Monoamine Stabilizer (-) - OSU6162 ka ho lakatsa Batho ba nang le lithethefatsi tse tahang: Thuto ea Batho ba Lipatlisiso (2015)

Khemiri, Lotfi le al. European Neuropsychopharmacology

Lotfi Khemiri, Hape Steensland, Joar Guterstam, Olof Beck, Arvid Carlsson, J.Franck, Nitya Jayaram-Lindström

DOI: http://dx.doi.org/10.1016/j.euroneuro.2015.09.018

Pale ea Sehlooho

  1. 1. Selelekela
  2. Mekhoa ea Teko
    1. 2.1. Barupeluoa
    2. 2.2. Moralo oa ho Ithuta
    3. 2.3. Likarolo tsa Teko ea Takatso ea Tahi
    4. 2.4. Mehato ea bongaka
    5. 2.5. Mosebetsi oa ho itlosa bolutu
    6. 2.6. Tlhahlobo ea Statistical
  3. 3. Liphetho
  4. 3.1. Barupeluoa
  5. 3.2. OSU6162 ha ea ka ea fumana litekanyetso tse ikhethileng tsa litakatso tsa cue tse susumetsang
  6. 3.3. OSU6162 litekanyetso tse kenyellelitsoeng tsa litabatabelo tse theotsoeng pele
  7. 3.4. Bokhoni ba OSU6162 ba ho fumana takatso ea joala bo entsoe ke batho ba nang le ts'usumetso e phahameng ea mantlha
  8. 3.5. OSU6162 ha ea ka ea ba le phello e kholo ho noeng, ho lakatseng kapa mokong nakong ea kalafo
  9. 3.6. Litlamorao
  10. 4. Puisano
  11. Lichelete le ho senola
  12. phehisa
  13. Mohloli oa lichelete
  14. Sehlomathiso A. Lintho tse tlatsetsang
  15. References

inahaneloang

Ho itšetleha ka joala ho amana le moputso oa dopamine system modulating moputso, takatso le kelello. The monoamine stabilizer (-) - OSU6162 (OSU6162) e ka loants'oa bobeli ba hyper- le hypo-dopaminergic, mme haufinyane re bonts'itse hore e fana ka boits'oaro bo kopaneng le joala litsing tsa nako e telele tsa ho noela. Boithuto ba hona joale ba Phase II ea tlhahlobo ea maqhubu ea batho bo ile ba etsa lipatlisiso ho tsebo ea rona ka lekhetlo la pele litlamorao tsa OSU6162 litakatsong tsa cue- le tsa ho phahamisa ba lakatsang joala.

Batho ba itšetlehileng ka joala ba mashome a mahlano a metso e ts'eletseng ba ile ba khethoa ka mokhoa o sa fetoheng nako ea matsatsi a 14 ea phekolo ea OSU6162 kapa placebo kamora hore maemo a bona a ho thella a thehiloe ka ts'ebeliso ea "Sign Signal Task". Ka letsatsi la 15, barupeluoa ba ile ba kenngoa tlhahlobo ea takatso ea joala ea laboratori e nang le lithuto tse khothaletsoang ke: i) mafolofolo - litekanyetso tse khethehileng tsa joala, ii) ho hlohlelletsa ho hloka toka le iii) ho ts'oara joala - joala ba joala (0.20 g ethanol / kg bodyweight) .

Litekanyetso tse kenelletseng tsa litakatso tsa joala li ile tsa hlahlojoa ho sebelisoa mofuta o khutsufalitsoeng oa Desire for Alcohol lipotso le sekala sa analogue (VAS). Phekolo ea OSU6162 e ne e se na phello e matla litakatsong tse bakoang ke joala, empa e ile ea atleha haholo litakatsong tse susumetsang. Tlhahlobo e hlalosang e senotse hore phello ena e ne e tsamaisoa ke batho ba nang le ts'usumetso e phahameng ea mantlha. Ntle le moo, OSU6162 e fupere haholo ho rata ts'ebetso ea joala bo tahiloeng (VAS). Leha nako ea kalafo ea matsatsi a 14 e sebelisitsoe, e bonts'itse hore OSU6162 e bolokehile 'me e mamellehile hantle, tlhahlobo ena ea tlhahlobo ea mahlale ea batho e ne e sa etsetsoa ho lekola ts'ebetso ea OSU6162 ho ama ts'ebeliso ea joala. Kahoo teko ea bongaka e sebetsanang le tšebeliso ea matla ea placebo e matlafalitsoeng e hlokahala ho tsoelapele ho lekola bokhoni ba OSU6162 e le moriana o fumanehang oa ho itlopa joala.

Keywords:

ho noa joala, lemalla ntho e, Ho lakatsa, Ho se tsitsisehe, Dopamine e tsitsisa, OSU6162

1. Selelekela

Sistamine ea mesolimbic dopamine ke sistimi e ithutileng hantle ea phepo e ntle ho nts'etsopele le ho boloka ts'ebeliso ea lithethefatsi le joala. Litlamorao tse matlafatsang tsa lithethefatsi tse lemalloang, ho kenyeletsa le joala, li kenella ka karolo ka ho lokolloa ha dopamine ka har'a li-nucleus accumbens (Boileau et al., 2003, Di Chiara le Imperato, 1988, Imperato le Di Chiara, 1986), e sebetsang ea dopamine D2 receptors (Joaleak et al., 2000). Ho batho ba itšetlehileng ka joala, lithuto tse nahanang ka bokong bo sebelisang positron emission tomography (PET) li hlahisitse phokotso ea ho fumaneha ha li-receptor tsa dopamine D2 tse khothalelitsoeng ho bonts'a taolo e tlase ea tahlehelo e bakoang ke tšebeliso e mpe ea joala e amanang le kotsi ea morao-rao ea ho khutla hape. (Heinz et al., 2009, Heinz et al., 2005, Volkow et al., 1996). Ntle le moo, bothata ba dopamine bo hlokometsoeng lithutong tsa batho bo ile ba kopanngoa le ho teba ha litakatso tsa joala le ts'ebetso e eketsehang libakeng tsa bongoana ha li pepesetsoa lintlha tse amanang le joala, tse bonts'ang tlhokomelo e hlakileng litekong tse ikhethileng le kotsi ea ho khutla hape (Heinz et al., 2004). Ntle le moo, haufinyane ho bontšitsoe hore batho ba itšetlehileng ka joala ba fokotse litekanyetso tsa dopamine hape ho "cortex" (Narendran et al., 2014), ho fana ka tlhahiso ea hore bofokoli ba cortical dopamine bo ka tlatsetsa ho senyeheng hoa kelello (mohlala, taolo e fokolisitsoeng ea tšusumetso le tlhokomelo) tse bonoang ho batho ba ts'ehetsoeng joala. (Goldstein le Volkow, 2011, Stavro et al., 2012). Ebile, liphuputso tsa morao tjena li fuputse moelelo oa likhokahano tsa neural tse amanang le phetoho tsamaisong ea dopamine le boits'oaro bo sa tsotelleng, ho utloisisa bohlokoa ba bona ba ts'ebeliso ea joala. Liphetho li bonts'a botsoalle lipakeng tsa tšebeliso ea joala, ho ts'oaroa ho hoholo, karabelo e phahameng ea ho itjella joala (Leeman et al., 2014) le litekanyetso tse eketsehileng tsa dopamine (Boileau et al., 2003), ho fana ka maikutlo a hore ho hloka toka (Dick et al., 2010) le karabelo e ikhethileng ea joala (Crabbe et al., 2010) ke lintho tse kotsing ea ho lemalla joala.

Sisteme ea dopamine e kile ea hlahlojoa e le sepheo sa kalafo se ka bang teng bakeng sa ts'ebeliso ea lino tse tahang, leha ho le joalo, lithuto le bahanyetsi ba dopamine ba setso li bile li nyahamisa (Swift, 2010). Ts'ebeliso ea li-antoponist tsa dopamine (ke hore, li-neuroleptics) e boetse e fokotsoa ke litla-morao tse matla ho kenyelletsa anhedonia le karabelo ea extrapyramidal e hlahisoang ke thibelo e feteletseng ea dopaminergic. Le ha ho le joalo, haufinyane tjena modafinil (modopin transporter modulator) le aripiprazole (k'homphieutha e entsoeng ka thekiso e thehiloe holima karolo e tsoang ho D2-agonist (-) - 3PPP (Carlsson le Carlsson, 2006) e bontšitsoe hore e fokotse tšebeliso ea joala le ho lakatsa ho itšireletsa ho batho ba lemalloang joala (Joos et al., 2013, Martinotti et al., 2009, Martinotti et al., 2007, Myrick et al., 2010, Schmaal et al., 2013, Voronin et al., 2008). Liphetho tsena li bonts'a hore li-dopamine agents ntle le ho qhekella kapa ho ts'oaroa ka botlalo ke ts'episo ea kalafo e sebetsang ea ts'ebeliso ea lino tse tahang.

The monoamine stabilizer (-) - OSU6162 (OSU6162) (Carlson et al., 2004, SONerson et al., 1994,, ke nts'etsopele e 'ngoe e tsoang ho (-) - 3PPP e nang le bokhoni ba ho tsosa, ho hatella kapa ho bonts'a phello mosebetsing oa dopamine ho latela molumo o teng oa dopaminergic. Mohopolo ona o phatlalalitsoe ho latela phuputso ea PET ho litšoene tsa rhesus moo OSU6162-infusions e bakileng phello e itšetlehileng ka dopaminergic ka phokotso ea sekhahla sa Lri [11C] DOPA sekhahla sa litšoene tse nang le litheko tse phahameng tsa motheo le L-striatal L- [ 11C] Sekhahla sa tlhaselo ea DOPA ho liphoofolo tse nang le melao ea motheo ea tlase (Tedroff et al., 1998). Mokhoa oa ts'ebetso leha ho le joalo ha o utloisisoe ka botlalo, mme leha ho le joalo a vitro liphuputso li bonts'a hore OSU6162, joalo ka aripiprazole, e sebetsa joalo ka karolo e ikhethileng ea maemo a bophelo ho D2-receptors (Kara le al., 2010, Seman le Guan, 2007), lithuto tsa boits'oaro li sitiloe ho bonts'a mesebetsi efe kapa efe e makatsang ea komporo (Natesan et al., 2006, SONerson et al., 1994). Sebakeng seo ho fanoe ka maikutlo a hore OSU6162 e hlahisa litlamorao tse sebetsang ka ho sebetsa e le mohanyetsi ho li-presoreaptic autoreceptors ka bobeli le li-postynaptic D2 receptors (Carlson et al., 2004, Lahti et al., 2007, Rung et al., 2008, SONerson et al., 1994) OSU6162 e bonahala e bolokehile tliliniking e nang le litla-morao tse bobebe tsa baithaopi ba phetseng hantle (Rodríguez et al., 2004) le bakuli ba nang le mohlala Huntingtons lefu le ho tepella kelellong ho latela ho tetebela le khatello ea kelello (Johansson et al., 2012, Kloberg et al., 2014, Tedroff et al., 1999). Kahoo menyetla ea OSU6162 ha e bapisoa le bahanyetsi ba setso ba D2, e kanna ea ba khaello ea karabelo ea extrapyramidal (Carlsson le Carlsson, 2006).

Re sa tsoa tšoaea OSU612 e le moriana o sa fumaneheng oa ho itlopa joala ka ho bonts'a hore e fana ka tahi e ikemiselitseng ho itlopa joala, ho ts'oara joala, ho khaola le ho tsosa / ho tsosa-joala le ho khothaletsa joala bo batlang likhoebong tsa nako e telele tsa ho noela (Steensland le al., 2012). Ho feta moo, menyetla ea OSU6162 ea ho shebella sisteme ea dopamine libakeng tsa boko tse amehang bakeng sa ts'ebeliso ea joala e tšehetsoa ke phuputso ea morao-rao ea PET ea motho e bonts'ang hore OSU6162 e rata pele ho D2 / D3-receptors ho striatum (Tolboom et al., 2014) le boithuto ba rona ba morao-rao ba Microphotoal bo bonts'ang hore komporo e ka loants'a 'muso oa hypodopaminergic litheong tsa nako e telele tsa ho nooa (Feltmann, et al., Addiction Biology, 2015). Ho latela liphetho tsena, boithuto bo teng hona joale bo ile ba lekola litlamorao tsa OSU6162 litakatsong tsa cue- le tsa ho phahamisa litheko ho batho ba its'episang joala thutong ea mahlale ea batho e laoloang ke sebaka sa II. E ipapisitse le 'mele o ntseng o hola oa lipatlisiso o bonts'ang phallo e kholo ea methapo pakeng tsa ho qhekelloa le ts'ebeliso ea joala (Dick et al., 2010, Lejuez et al., 2010) le tsebo ea hore ho haella ke pherekano ea bohlokoa ea sephetho sa kalafo (Joos et al., 2013, Schmaal et al., 2013, Voronin et al., 2008) re boetse re batlisisitse hore na ts'usumetso ea mantlha e reretsoe ho iphetola ha lintho le karabelo ea kalafo ho OSU6162.

Mekhoa ea Teko

2.1. Barupeluoa

Batho ba mashome a mahlano a metso e ts'eletseng ba batlang joala ba batlang joala ba ile ba khethoa lipapatsong tsa sechaba. Ngaka ea thuto e fane ka tlhaiso-leseling e mabapi le mekhoa, pele a batla tumello e ngotsoeng. Batho ba qetileng thuto le ketelo e latelang ba ile ba buseletsoa ka 1500 Sweden Crown (hoo e ka bang 180 USD). Boithuto bona bo amohetsoe ke boto ea tlhahlobo ea melao ea boitšoaro tikolohong e Stockholm le Setsi sa Lihlahisoa tsa Bongaka tsa Sweden, tse ngolisitsoeng ho European Clinical Trials Database (EudraCT; 2011-003133-34), e beiloe leihlo ke Karolinska Trial Alliance mme e entsoe ho latela Ts'ebetso e Ntle ea Clinical le Phatlalatso ea Helsinki.

Kamora puisano e khutšoane ea mohala, bao e neng e tla ba karolo ba ile ba memeloa Setsing sa Stockholm bakeng sa Dependency Disorder outpatient research hospital, Karolinska University Hospital (KUH) bakeng sa ketelo e hlahlobang e nang le tlhahlobo ea 'mele, tlhahlobo ea kelello, liteko tsa mali, phefumoloho, tlhahlobo ea moroto le electrocardiogram (ECG) , Mortara Instrument ELI150c). Ka bokhutšoanyane, ho kenyelletsoa batho ba neng ba le pakeng tsa lilemo tse 20 ho isa ho tse 55, ba neng ba phethahatsa litekanyetso tsa DSM-IV tsa ts'ebeliso ea lino tse tahang, ba bile le matsatsi a 45 a ho nwa haholo (HDD; a hlalosoa e le letsatsi le noang bonyane lino tse 5 kapa 4 tse tloaelehileng) (tse hlalositsoeng joalo ka 12 g joala ka seno se nooang bakeng sa banna le basali, ka ho tšoanang) matsatsing a 90 a khalendara ho tloha ho kenyelletsoa mme o ne a sa jella joala bonyane matsatsi a mane, le nako e telele ea matsatsi a 14 pele ho kenyelletsoa, ​​ho netefalitsoeng ke Time Line Follow Back (TLFB) puisano ((Sobell le Sobell, 1992) le breathalyzer. Ka bokhutšoanyane, litekanyetso tsa ho kenyelletsa e ne e le phethahatso ea mekhoa ea DSM-IV bakeng sa mofuta ofe kapa ofe oa bothata ba tšebeliso ea lithethefatsi (ntle le nicotine), litekanyetso tsa DSM-IV tsa schizophrenia, lefu la ho ferekana kelellong, khatello e kholo ea maikutlo kapa ho ba teng ha lefu le leng le le leng la pelo la tlhekefetso e bohlokoa ea ECG. Litekanyetso tse felletseng tsa ho kenyelletsoa le ho khetholloa li fanoe ka tlhaiso-leseling e tlatselletsang (SI)).

2.2. Moralo oa ho Ithuta

Thutong ena e sa boneng mahlo, e laoloang ke placebo, barupeluoa ba ile ba fuoa monyetla oa ho fumana li-OSU6162 kapa matlapa a placebo (Galenica AB, Malmö, Sweden) nakong ea phekolo ea matsatsi a 14 mme ba laetsoe ho nka meriana ho latela kemiso e latelang: Letsatsi 1–5: 10 mg × 2; Letsatsi la 6 - 10: 15 mg × 2; Letsatsi 11: 14: 30 mg × 2. Bolelele ba nako ea kalafo bo thehiloe khotellong e tsoang ho Sweden Medical Products Agency kaha thuto ea hona joale e bile ea pele ea ho hlahloba OSU6162 ho baahi ba lemaletseng joala. Ts'ebetso ea khethollo (bona SI bakeng sa lintlha) e etsoa ke Mokhatlo oa Teko oa Karolinska, ntle le ho nka karolo ha basebetsi ba lipatlisiso mme moriana o ile oa isoa kliniking ea lipatlisiso ke k'hemiste ea KUH. Phuputso e kenyelelitse maeto a lateloang a mararo nakong ea phekolo ea matsatsi a 14 le karolo ea liteko ea tai e ipapisang le joala ea laboratori ka letsatsi la 15 (letsatsi la liteko). Maeto a latelang a kenyeletsa ECG, pokello ea sampole ea mali le urine, ho ajoa ha meriana, tlhahlobo ea phefumoloho le ho tlaleha ho nooa, maikutlo le liketsahalo tse bohloko. Barupeluoa ba ile ba laeloa ho hana ho nwa nakong ea kalafo, leha ho nooa e ne e se lebaka la ho qheleloa ka thoko. Leha ho le joalo, ho itlopa joala pele ho letsatsi le pele ho letsatsi la Teko (le netefalitsoeng ka TLFB le breathalyzer) ho ile ha fella ka kantle ho karolo ea ho lakatsa ea liteko ho thibela leeme ho boiphihlelo bo bobe ba ho lakatsa.

Letsatsing la tlhatlhobo barupeluoa ba fihlile tleliniking ea lipatlisiso hoseng, mme ba nkile tekanyetso ea ho qetela ea meriana ea ho ithuta ka pel'a basebetsi ba lipatlisiso. Nikotine le caffeine e ne e lumelloa pele e fihla, empa eseng nakong ea Teko. Kamora ho qeta lithuto tsa liteko tse matla, barupeluoa ba ile ba fumana lijo tsa mots'eare le ho hlonepha 'me ba lula tleliniking ea lipatlisiso ho fihlela ba hlaphohetsoe. Barupeluoa bohle ba ile ba fuoa phetisetso ea kalafo kahare ho Setsi sa Stockholm bakeng sa Bofokoli ba ho Kula.

2.3. Likarolo tsa Teko ea Takatso ea Tahi

Linako tsa liteko tsa laboratori tsa batho li fetotsoe ho tloha (Hammarberg et al., 2009), mme lits'ebetso li hlalositsoe ka botlalo ho SI. Ka bokhutšoanyane, tlhahlobo e kenyeletsa likarolo tse tharo tsa litakatso tse susumetsoang ke: i) mafolofolo - litekanyetso tse khethehileng tsa joala, ii) ho hlohlelletsa maikutlo le iii) ho phahamisa - ho ja seno se tahang (0.20 g ethanol / kg bodyweight).

Taelo ea lenane-thuto (cue -ikao le mafolofolo a sa jeleng paate) e ile ea hlophisoa ka nepo le ho leka-lekana pakeng tsa barupeluoa, hara sehlopha ka seng sa kalafo. Sebokeng se seng le se seng, litekanyetso tse ikhethileng tsa litakatso tsa joala li ne li bokelloa pele, hang kamora 'metsotso e 5 le 10 kamora ho hlahisa polelo (moelelo oa lintlha tse peli tsa morao-rao li hlalositsoe e le litekanyetso tsa "post-cue"). Ho lakatsa ho ile ha hlahlojoa ho sebelisoa phetolelo e khutsufalitsoeng ea Sweden ea Desire for Alcohol Questionnaire (Short-DAQ) (Rata et al., 1998) e nang le lintho tse robeli (Letlapa la S1) e filoe lintlha tse supileng tsa Likert, moo 1 le 7 li bonts'ang "Se lumellane ho hang" le "Ho lumellana ka botlalo", ka tatellano hammoho le ntho e le 'ngoe ea Visual Analogue Scale (VAS, e pakeng tsa 0 ho ea ho 100) " U lakatsa ho noa joala hakae hajoale? ”.

Romella linako tsa thupelo, 'me thuto e ile ea etsoa nakong eo morupeluoa ka mong a neng a nka seno se le seng sa hae sa joala seo a se ratang pele a qeta ho se noa. Litekanyetso tse lakatsang tsa ho lakatsa li ile tsa bokelloa: pele, hang kamora, esita le metsotso e 5, 10, 25 le 40 kamora ho qeta ho noa joala (moelelo oa lintlha tse 'ne tsa morao-rao li hlalositsoe e le litekanyo tsa "ho noela" le ho hlahlojoa ka Nakoana -DAQ le VAS joalo ka ha ho hlalositsoe kaholimo. Ho nka litlamorao hang kamora ho nooa ka lekhetlo la pele, lintho tsa VAS tsa "ho lakatsa", "ho tšoenyeha" le "ho tsosa" li ile tsa bokelloa. Ntle le moo, ntho ea VAS ea "ho rata" e kenyelelitsoe e le phetoho ho protocol kamora barupeluoa ba pele ba 15.

2.4. Mehato ea bongaka

Tlhatlhobo ea kelello e entsoe ho hlahlojoa ho sebelisoa lipotso tse hlophisitsoeng tsa Clinical Clinical bakeng sa DSM-IV (Mokhatlo oa Mahlale oa Amerika, 2000). Mood le ho lakatsa nakong ea kalafo li ile tsa hlahlojoa ho sebelisoa Montgomery-Åsberg Depression Self Rating Scale (MADRS-S) (Svanborg le Asberg, 2001) le Penn Alcohol Craving Scale (PACS) ea Penn AlcoholFlannery et al., 1999), ka ho latellana. Tšebeliso ea joala e ile ea emisoa e le phetoho lipakeng tsa ho kenyelletsoa le letsatsi la Teko liperesente tsa HDD (TLFB ea boits'oaro) le litekanyetso tsa serum tsa phosphatidylethanol (S-PEth) (e hlahliloeng ke laboratori ea k'hemistri ea bongaka, KUH). Boteng ba lithethefatsi tse seng molaong mohlala, amphetamine, cocaine, cannabis (THC) kapa opiates li ile tsa hlahlojoa maetong a latelang a beke le beke li sebelisa dipstick tsa moroto. Ho netefatsoa ha sampole e ntle ho ile ha etsoa laboratoring e sa tsoa boleloa. Ts'ebetso ea OSU6162 e ne e lekantsoe ka meeli ea plasma (mokhoa oa ho hlahloba ho SI) ketelong ea bobeli ea tlhahlobo le Letsatsi la Teko, le lipalo tsa lipilisi maetong a mang le a mang. ECG e ile ea tlalehoa ea ba ea hlahlojoa ke ngaka ea methapo ea maikutlo e le mohato oa polokeho ketelong ea bobeli le tlhahlobo ea tlhahlobo.

2.5. Mosebetsi oa ho itlosa bolutu

Nakong ea ketelo e kenyellelitsoeng (pele ho tšebeliso ea meriana ea ho ithuta), barupeluoa ba ile ba etsa mosebetsi oa Stop Signal Task (SST, bona SI bakeng sa lintlha tsa mokhoa), tlhahlobo ea ts'ebetso ea ts'ebetso ea ts'ebetso ea k'homphieutha e sebelisoang haholo joalo ka mokhoa o itseng oa ho susumetsa (Aron et al., 2003, DeVito et al., 2009). Sephetho sa thahasello e ne e le nako ea ho emisa ea lets'oao la ho emisa (SSRT) -khato ea bokhoni ba barupeluoa ho thibela karabelo e sa le pele. Morupeluoa e mong le e mong o ne a hlalosoa e le ea phahameng kapa ea sa qobelloang ho its'etleha, a ipapisitse le karohano e lipakeng tsa lintlha tsa SSRT ho latela lithuto tse fetileng ho batho ba itšebelisang joala.Joos et al., 2013, Schmaal et al., 2013).

2.6. Tlhahlobo ea Statistical

Liphetho tsa mantlha e ne e le (i) kakaretso ea DA-Short le (ii) lintlha tsa VAS, ka ho latellana, bakeng sa ho lakatsa nakong ea liteko tsa liteko tsa laboratori. Lintlha li ile tsa hlahlojoa ho sebelisoa li-ANOVA tse nang le kalafo (OSU6162 kapa placebo) joalo ka ntlha-pakeng. Lintho tse ka hare ho taba e ne e le Boemo (bo sebetsang, bo sa nkeng lehlakore) le Nako (pele, hang ka mor'a le ka morao ho cue) bakeng sa liboka tse tlatsellelitsoeng ka cue le Nako (pele, hang kamora ho noha le ho noela) bakeng sa seboka sa ho qala. Tšusumetso ea bohlokoa ea Phekolo kapa Boemo le litšebelisano li ile tsa hlahlojoa hape ka ho sebelisa liteko tsa moithuti tse sa lefelloang kapa tsa paired, moo ho loketseng. Lintlha tse tsoang linthong tsa VAS kamora hore ho qhaloe liteko tsa pele tsa joala (priming-session) li ile tsa hlahlojoa ke liteko tse sa lefelloeng tsa Thupelo ea Liithuti, ho bapisa lintlha lipakeng tsa lihlopha tsa kalafo.

Ka tlhahlobo ea tlhahlobo ea sepheo se ikemiselitsoeng pele, li-ANOVA tse arohaneng li ile tsa etsoa ho lekola tšusumetso e ka bang teng ea sepheo sa mantlha (ke hore, ho phahama kapa ho tlase ho ipapisang le karohano ea SSRT)Joos et al., 2013; Schmaal et al., 2013)), mabapi le sephetho ho tsoa litekong tsa tlhahlobo ea cue- le ea priming-indueding, ka tatellano. Phapang taolong ea joala (HDD le Peth), ho lakatsa (PACS) le mohatsela (MADRS-S) lipakeng tsa kenyelletso le letsatsi la liteko li ne li bapisoa pakeng tsa lihlopha tsa kalafo tse sebelisang liteko tsa liteko tsa tlelase tsa seithuti.

Boithuto bona ba laboratori ea batho ke ho tsebo ea rona boithuto ba pele ba ho hlahloba litlamorao tsa OSU6162 ho bakuli ba ts'ehetsoeng joala, ba sebelisa litekanyetso tse peli tse fapaneng empa li tsepame haholo tsa litakatso tse kenang. Kahoo, kotsi ea mofuta oa phoso ea 1 e ne e nkuoa e se na mathata ho feta liphoso tsa mofuta oa 2, mme boemo ba alpha bo behiloe ho0.05, tse peli-tailing, tse sa lokang. Tlhahisoleseling e ile ea hlahlojoa bakeng sa tlhahlobo ea tlhahlobo ea maqhubu hammoho le liteko tsa tlhahlobo ea Shapiro Wilks mme ea hlahlojoa ho sebelisoa lipalo tsa IBM SPSS (mofuta oa 21.0, SPSS inc., Chicago, Illinois). Haeba tekano ea liphapang e hataketsoe (e hlahlojoa ke liteko tsa Levenes), ho tlalehiloe sephetho sa tlhahlobo ea Welch. Greenhouse-Geisser diphetho li ile tsa sebelisoa haeba monahano oa bophahamo o tlotsoe (ho hlahlojoa ho sebelisoa liteko tsa Mauchlys). Melao e lahlehileng ha ea ka ea nkeloa sebaka. Haeba e sa boleloe ka tsela e 'ngoe, ho bolela hore boleng ba de mekhoa e khelohileng e tlalehiloe.

3. Liphetho

3.1. Barupeluoa

Ho hira boithuto ho qalile ka Loetse 2012, mme ketelo ea ho nka karolo e ne e le ka Mots'eanong 2013. Lihlopha tsena tse peli tsa kalafo li ne li se na sepheo mabapi le semelo sa sechaba, mekhoa ea joala, takatso le maikutlo (Lethathamo 1). Ho ba 56 ba neng ba sa hlophisoa, morupeluoa a le mong sehlopheng sa placebo o ile a akheha kamora ho oela hape ka matla ka Letsatsi la 1. Kahoo, barupeluoa ba 55 ba qetile nako ea kalafo ea 14 le ho fana ka datha mabapi le tšebeliso ea joala, ho lakatsa, maikutlo le litlamorao. Barupeluoa ba supileng ba ile ba qheleloa ka thoko ho liteko tsa takatso ea joala ka lebaka la: tšebeliso ea joala letsatsi le fetileng (n= 3), e sa lumellaneng le lits'ebetso tsa ho ithuta nakong ea letsatsi la liteko (n= 1) kapa ho hlahisa sampole ea moroto e loketseng li-opiate (n= 2) kapa THC (n= 1). Thutong ea pele-pele, barupeluoa ba bararo ha baa ka ba latela ts'ebetso ea ho ithuta ka mor'a ho noa lino tse qalang, kahoo ba fane ka lintlha tsa mantlha le lintlha tsa pele tsa nako. Sehlopheng sa OSU6162, li-sampuli tsa mali tse hlahlobiloeng li ne li fumane litekanyetso tsa plasma tsa OSU6162 ka Letsatsi la 7 (38.9 ± 24.7 ng / mL) le letsatsi la Teko (105.0 ± 73.8 ng / mL). Ha ho OSU6162 e fumanoeng ka nako efe kapa efe ea methapo ea mali ho tsoa sehlopheng sa placebo.

Lethathamo la 1Bakena karolo nakong ea kenyelletso. Ha ho na phapang e kholo lipakeng tsa OSU6162- kapa lihlopha tse tšoaroang ke placebo bakeng sa efe kapa efe ea liphetho. Ho fapana ho tsoelang pele ho hlahisoa e le ho bolela (ho kheloha ho tloaelehileng). Maelefatso: MADRS-S-Montgomery-Åsberg Depression Boemo ba Boemo ba Tekanyetso; PACS-Penn Alcohol Alla Caleving Scale.

 

OSU6162 (n = 28)

PLACEBO (n = 28)

Bohlokoa

Tse tona / Tse tšehali

14 / 1416/12p = 0.60

Age

47.3 (6.5)45.3 (7.7)p = 0.30

Lilemo tsa thuto

13.3 (2.5)14.1 (2.8)p = 0.26

O nyetse / Molekane

54%54%P = 1.0

Mosebetsi oa nako eohle

78.6%71.4%P = 0.54

Mosebetsi oa nakoana

7.1%17.9%P = 0.23

Ha ba sebetse

14.3%7.1%P = 0.39

Sick leave / Ho tlohela mosebetsi

0%3.6%P = 0.31

Tšebeliso ea nikotine ea letsatsi le letsatsi (%)

68%64%P = 1.0

Litekanyetso tsa DSM-IV tsa ts'ebeliso ea joala

5.2 (1.1)5.1 (1.4)P = 0.62

Ho nwa haholo ho qetela matsatsi a 90 (%)

73%68%P = 0.29

Ho nooa ka letsatsi matsatsi a 90 a fetileng

5.8 (2.2)5.7 (2.4)P = 0.88

Lintlha tsa MADRS-S

9.2 (6.8)7.9 (6.7)P = 0.46

PACS e lakatsang lintlha

11.1 (6.5)10.4 (6.0)P = 0.70

3.2. OSU6162 ha ea ka ea fumana litekanyetso tse ikhethileng tsa litakatso tsa cue tse susumetsang

Likarolong tse lakatsehang tsa ho ba le takatso ea ho tseba 'nete (Short-DAQ; Feie. 1), ho bile le phello e kholo ea Boemo (F (1,45) = 76.5;p<0.001) le Nako (F (2,90) = 21.1;p<0.001) empa ha ho na tšusumetso e kholo ea Phekolo (F (1,45) = 2.1;p= 0.154). Ntle le moo, ho ne ho na le Nako ea bohlokoaasterisk e tlaseHo sebelisana ha maemo (F (1.7,76.2) = 22.5;p<0.001) empa ha ho na kalafo ea bohlokoaasterisk e tlaseBoemo (F (1,45) = 1.3;p= 0.262) kapa Nakoasterisk e tlaseboemoasterisk e tlaseTšebelisano 'moho ea kalafo (F (2,90) = 1.1;p= 0.320). Kahoo, ho ipapisitse le ho haella ha litlamorao tsa kalafo, ho ile ha etsoa tlhahlobo ea post hoc ho hlahloba phapang lipakeng tsa likarolo tse mafolofolo le tse sa jeleng paate ho sa tsotelehe kalafo. Ho ne ho na le boemo bo phahameng haholo ba ho lakatsa ho latela takatso ea mantlha hang kamora ho hlahisoa ha cue ea mafolofolo (24.0 ± 8.6) ha ho bapisoa le sepheo sa ho se nke lehlakore (17.3 ± 8.9; t (46) = - 8.0;p<0.001) hape le papiso le pele (18.9 ± 9.2; t (46) = - 6.0;p<0.001) le tlhahiso ea poso ea sehlahlo se sebetsang (19.8 ± 9.3; t (46) = 5.7;p<0.001). Boemong ba ho se jele paate, ho ne ho se na phapang e kholo maemong a takatso e ikemetseng lipakeng tsa lintlha tse lekantsoeng tsa nako (Pele: 17.8 ± 8.8; Hanghang kamora: 17.3 ± 8.9 le Post: 17.1 ± 8.8). Lintlha tsa takatso ea VAS li hlahisitse litlamorao ho takatso ea takatsoSetšoantšo sa S1) tse ts'oanang le sephetho sa Short-DAQ (bona SI bakeng sa tlhahlobo e felletseng).

Feiga 1 e bula setšoantšo se seholo

Feie. 1

OSU6162 ea monoamine stabilizer ha ea ka ea hlahisa litekanyetso tse ikhethileng tsa takatso ea cue-e kentsoeng ho bakuli ba lemaletseng joala. Ho bolela ho lakatsa lintlha tse felletseng phetolelong e khutsufalitsoeng ea Desire for Alcohol Questionnaire (Short-DAQ) nakong ea karolo ea (A) e sa nke lehlakore le (B) e mafolofolo ea sepheo sa khopiso. Ha ho na phapang e kholo ea lipalo ea ho lakatsa lipakeng tsa OSU6162- le lihlopha tse tšoaroang ke placebo nakong ea likopano tsa cue tse sa nke lehlakore kapa tse sebetsang, ka ho latellana. Tlhahiso-leseling e ne e bokelletsoe lintlheng tse latelang tsa nako: pele, hang ka mor'a metsotso e 5 le 10 kamora ho hlahisa polelo (moelelo oa lintlha tse peli tsa morao-rao li hlalositsoe e le litekanyo tsa "post-cue"). Melao ea boleng e hlahisoa joalo ka mean sem

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3.3. OSU6162 litekanyetso tse kenyellelitsoeng tsa litabatabelo tse theotsoeng pele

Nakong ea litakatso tsa takatso ea pele ea ho lakatsa, nako ea ho qeta ho nooa e ne e le metsotso e 8.6 (ho tloha metsotso e meraro ho isa ho e 18 lipakeng tsa lithuto) ho se na phapang e kholo lipakeng tsa lihlopha tsa kalafo. (t (42) = - 0.09;p= 0.927). Ha re sekaseka data e khutšoane ea DAQ ho bile le phello e kholo ea Nako (F (1.5,63.6) = 13.7;p<0.001) le Phekolo (F (1,43) = 4.1;p= 0.050) empa ha ho na Nako ea bohlokoaasterisk e tlaseTšebelisano 'moho ea kalafo (F (1.5,63.6) = 1.4;p= 0.255). Tlhahlobo ea post hoc e senotse hore batho ba tšoeroeng ke OSU6162 ba ne ba le litakatso tse tlase haholo ha ba bapisoa le placebo hang kamora ho qeta ho noha joala (ka karolelano ho ile ha nka metsotso e 9 ho qeta seno). Leha ho le joalo, ha ho phapang e kholo e fumanoeng pakeng tsa lihlopha tse fapaneng tsa kalafo pele kapa kamora ho qeta ho noa (ho bolela nako ea lintlha tsa 5, 10, 25 le 40; Feie. 2A). Bakeng sa data ea VAS (Feie. 2B) ho bile le phello e kholo ea Nako (F (1.6,70,2) = 29,2;p<0.001) le mokhoa o lebisang bohlokoa ba kalafo (F (1,43) = 3.3;p= 0.075) empa ha ho na Nako ea bohlokoaasterisk e tlaseHo sebelisana ka kalafo (F (1.6, 70,2) = 0.85;p= 0.412).

Feiga 2 e bula setšoantšo se seholo

Feie. 2

OSU6162 ea monoamine stabilizer e kenyellelitseng litekanyetso tse kenelletseng tsa litakatso tse khothatsang tse lebisang ho bakuli ba ts'ebelisang joala. Bontša lintlha tse felletseng ho (A) mofuta o khutsufalitsoeng oa Desire for Alcohol potso (Short-DAQ) le (B) ntho e lakatsang nakong ea takatso le sepheo sa ho lakatsa le (C) VAS-lintho tsa "ho lakatsa", rata "," matšoenyeho "le" ho tsosa "kamora ho nooa ka lekhetlo la pele. Sehlopha se phekotsoeng sa OSU6162 se kentse tekanyo e tlase haholo litakatsong tse khutšoane (DA -6162Q) hang kamora ho qeta ho nwa joala ha se bapisoa le sehlopha se phekotsoeng sa placebo (A) mme ho bile le ts'ekamelo ea ho fokotseha ha litakatso tsa OSU6162- ha ho bapisoa le sehlopha se tšoaroang placebo se sebelisang le VAS ka nako e ts'oanang-ntlha (B). Sehlopha sa OSU5 se ekelitse likhetho tse tlase haholo, le mokhoa o lebisang takatsong e tlase, kamora ho nooa ha pele (C). Tlhahiso-leseling e ile ea bokelloa ka nako e latelang-lintlha: pele ho seno, kamora ho nooa pele, hang kamora ho qeta ho nooa, hape le metsotso e 10, 25, 40 le XNUMX ho nooa joala (moelelo oa nako e mene ea morao-rao. -pisi li ne li hlalosoa e le litekanyo tsa "joala ba posta". Melao ea boleng e hlahisoa joalo ka mean sem; *p<0.05 ha e bapisoa le sebaka se tšoanang.

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Kamora ho nooa ka lekhetlo la pele ho seno se tahang (Feie. 2C), OSU6162 batho ba phekotsoeng ba tlalehiloe ka mokhoa o tlase ba ratang ho ts'oaroa joala (t (31) = - 2.27;p= 0.031) le mokhoa o lebisang litakatsong tse tlase (t (46) = - 1.88;p= 0.066) bapisoa le placebo, ha ho ne ho sena phapang ea bohlokoa lipakeng tsa lihlopha tsa kalafo mabapi le makhopho (t (46) = - 1.29;p= 0.205) kapa matšoenyeho (t (46) = - 0.24;p= 0.814).

3.4. Bokhoni ba OSU6162 ba ho fumana takatso ea joala bo entsoe ke batho ba nang le ts'usumetso e phahameng ea mantlha

Ka bomong phahameng motheo oa ts'usumetso, tlhahlobo ea data e khutšoanyane ea DAQ ho tsoa lithutong tse ts'oaroang ke takatso ea cue e senotse phello e kholo ea kalafo (F (1,22) = 4.5;p= 0.044), empa ha ho na Phekolo ea bohlokoaasterisk e tlaseHo sebelisana ha maemo (F (1,22) = 1.4;p= 0.248) kapa Nakoasterisk e tlaseboemoasterisk e tlaseTšebelisano 'moho ea kalafo (F (1.5,32.2) = 0.93;p= 0.377). Tlhahlobo ea hoc ea hoc e senotse hore batho ba tšoaroang haholo ke OSU6162 ba thathamisitse takatso e tlase kamora nako, mme ba romella (ho bolela lintlha tse 5 le tse 10) tlhahiso ea sethala se sa jeleng paate ha se bapisoa le batho ba tšoaroang ke placebo. (Feie. 3A, sethala sa leqele). Sebokeng se sebetsang sa cue, ho bile le phokotso e kholo litakatsong tse ikhethileng ho OSU6162-, ha ho bapisoa le batho ba tšoaroang ke placebo ba hlahisang polelo ea 'nete ea mora-ea-nnete (Feie. 3A, phanele e nepahetseng). Ka bomong tlaase ts'usumetso ea mantlha, leha ho le joalo, ho ne ho se na phello ea bohlokoa ea kalafo (F (1,21) = 0.16;p= 0.695), mme ha ho na Phekolo ea bohlokoaasterisk e tlaseBoemo (F (1,21) = 0.152;p= 0.701) kapa Nakoasterisk e tlaseboemoasterisk e tlasePhekolo (F (2,42) = 0.275;p= 0.761) tšebelisano (Feie. 3B). Lintlha tsa VAS li hlahisitse litlamorao tse kholo litakatsong tse matla tsa cue ho batho ba phahameng le ba fokolang ba ts'oanang le liphetho tsa Short-DAQ (bona lintlha ho SI; Setšoantšo sa S2).

Feiga 3 e bula setšoantšo se seholo

Feie. 3

OSU6162 ea monoamine stabilizer e tsosang takatso e matla ea batho ba ikemiselitseng joala ba nang le ts'usumetso e matla ea mantlha. Ho bolela ho lakatsa lintlha tse ngata lenaneong le khutsufalitsoeng la Desire for Alcohol Questionnaire (Short-DAQ) ho (A) e phahameng le (B) batho ba its'elang joala ba ts'epahalang nakong ea litakatso tsa bona. (A) OSU6162 e fokotse takatso e matla ea batho ba noang joala haholo ha ba bapisoa le placebo hang kamora, le tlhahiso ea polelo e sa jeleng paate, le tlhahiso ea tlhahiso ea seneke. (B) Ha ho na phapang ea ho lakatsa ho fumanoeng lipakeng tsa OSU6162 le sehlopha sa placebo har'a batho ba ts'ehelitsoeng joala haholo ba sa tsubeng. Tlhahiso-leseling e ne e bokelletsoe lintlheng tse latelang tsa nako: pele, hang ka mor'a metsotso e 5 le 10 kamora ho hlahisa polelo (moelelo oa lintlha tse peli tsa morao-rao li hlalositsoe e le litekanyo tsa "post-cue"). Melao ea boleng e hlahisoa joalo ka mean sem; *p<0.05 ha e bapisoa le sebaka se tšoanang.

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Kopanong ea litakatso tse matlafatsang tse tsoakiloeng, tlhaiso-leseling ea lintlha tse bokhuts'oane ba DAQ ho tsoa ho batho ba nang le phahameng ho ikemela ha mantlha ho bontšitse phello e kholo ea kalafo (F (1,20) = 9.8;p= 0.005) le Nako (F (1.3,26.0) = 8.8;p= 0.004) empa ha ho na Nako ea bohlokoaasterisk e tlaseTšebelisano 'moho ea kalafo (F (1.3,26.0) = 2.5;p= 0.116). Tlhahlobo ea post hoc e senotse hore sehlopha sa OSU6162 se thetsitse takatso e tlase ho feta sehlopha sa placebo ka linako tsohle tse lekantsoeng (Feie. 4A, sethala sa leqele). Ka lehlakoreng le leng, ho batho ka bomong tlaase khatello ea mantlha ea mantlha (Feie. 4B, sethala sa leqele), ho bile le phello e kholo ea Nako (F (2,42) = 4.3;p= 0.021) empa ha ho na phello ea bohlokoa ea kalafo (F (1,21) = 0.12;p= 0.731) kapa Nakoasterisk e tlaseTšebelisano 'moho ea kalafo (F (2,42) = 0.428;p= 0.639). Lintlha tsa VAS li hlahisitse litlamorao tse kholo ho ho lakatsa ho lakatsa-ho qhekella ho batho ba phahameng le ba tlase ba ts'oanang le ba tšoanang le liphetho tsa Short-DAQ (Feie. 4A le B, likharetene tse bohareng; Bona SI bakeng sa tlhahlobo e phethahetseng ea lipalo).

Feiga 4 e bula setšoantšo se seholo

Feie. 4

Bokhoni ba OSU6162 ba ho ba le bokhoni ba ho tsilatsila ba ho lakatsa joala ka likhoka ba ne ba khannoa ke batho ba nang le ts'usumetso e matla ea mantlha. Ho bolela ho lakatsa lintlha tse felletseng ho mofuta o khutsufalitsoeng oa Desire for Alcohol Questionnaire (iDemo-DAQ) le ntho e lakatsang ea VAS ho (A) e phahameng le (B) batho ba its'elang joala ba ts'epahalang nakong ea litabatabelo tsa ho lakatsa. (A) OSU6162 e fokotse takatso e matla ea batho ba noang joala haholo ha ba bapisoa le placebo nakong ea moetlo oa ho lakatsa, ho kenyelletsa le ho lakatsa kamora ho nooa ha pele. (B) Ha ho phapang e kholo ea ho lakatsa e fumanoeng ka nako efe kapa efe pakeng tsa OSU6162- le sehlopha se tšoaroang ke placebo sehlopheng se ikemetseng se sa ts'epa joala. Tlhahiso-leseling e ile ea bokelloa nakong e latelang ea lintlha-tse latelang: pele ho seno, kamora ho nooa pele, hang kamora ho qeta ho nooa, hape le metsotso e 5, 10, 25 le 40 ho nooa joala (moelelo oa nako e mene ea morao-rao. -Meko e ne e hlalosoa e le litekanyo tsa "seno se nooang". *p<0.05 le **p<0.01 ha e bapisoa le sebaka se tšoanang.

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Kamora ho nooa ha pele ka joala, batho ba tšoaroang ke OSU6162 ba nang le maemo a phahameng, empa eseng a tlase, ba ile ba beha tekano e tlase haholo nthong ea takatso ea VAS ha e bapisoa le placebo (High: t (22) = 2.9, Feie. 4A, sebaka se nepahetseng; E tlase: t (22) = - 0.45, Feie. 4B, phanele e nepahetseng). Ha ho phapang e kholo lipakeng tsa lihlopha tsa kalafo ho efe kapa efe ea ntho e 'ngoe ea VAS e hlahlojoang ka mor'a ho nooa ka lekhetlo la pele ho batho ba phahameng kapa ba sa tsubeng.Feie. 4A le B, liphanele tse nepahetseng).

3.5. OSU6162 ha ea ka ea ba le phello e kholo ho noeng, ho lakatseng kapa mokong nakong ea kalafo

Nakong ea phekolo ea matsatsi a 14, sehlopha sa OSU6162 se fokotsitse tšebeliso ea bona ho tloha liperesente tse 73 ho isa ho tse 19 tsa HDD (t (27) = 9.9;p<0.001) e ts'oanang le phokotso e kholo maemong a serum PEth ho tloha 0.83 ho ea 0.60 (t (27) = 2.7;p= 0.012). Sehlopha sa bohlokoa sa placebo se fokotsa ho nwa ha bona ho tloha ho liperesente tse 68 ho isa ho tse 10 tsa HDD (t (26) = 15.9;p<0.001) le ho tloha 0.69 ho isa 0.54 maemong a serum PEth (t (26) = 2.5;p= 0.020). Leha ho le joalo, ho ne ho se na phapang e kholo ea lipalo pakeng tsa lihlopha tsa kalafo mabapi le phetoho liperesente tsa HDD (OSU6162: −54.6 ± 0.29; Placebo: −57.6 ± 0.19; t (46.4) = - 0.45;p= 0.658), litekanyetso tsa serum PEth (OSU6162: −0.23 ± 0.45; Placebo: −0.15 ± 0.31; t (48.4) = - 0.77;p= 0.447), lintlha tsa PACS (OSU6162: −4.9; Placebo: −4.2; t (53) = - 0.541;p= 0.591) kapa lenane la MADRS-S (OSU6162: −3.6; Placebo: −2.9; t (53) = - 0.641;p= 0.524) nakong ea kalafo. Kamora moo, ha ho na litlamorao tse kholo tsa kalafo ho noo efe kapa efe, ho lakatsa kapa ho ba le sepheo sa maikutlo nakong ea kalafo ha barupeluoa ba arotsoe ka batho ba phahameng le ba sa thellang (Bona. SI bakeng sa lintlha tsa lipalo).

3.6. Litlamorao

Phekolo ea OSU6162 ka kakaretso e ne e mamelletsoe hantle ntle le litlaleho tsa litla-morao tse mpe mme ha ho na phapang ea bohlokoa khafetsa ea litlaleho tsa litla-morao (mohlala, ho opeloa ke hlooho, matšoao a mpa, ho tepella le vertigo) ha ho bapisoa le sehlopha sa placebo (Letlapa la S2). Ho bapisoa ha ECG ha ho hlahlojoa ha letsatsi ho bapisoa le letsatsi la liteko ho bontšitse hore sehlopha sa OSU6162 se ne se fokotsehile haholo ka sekhahla sa pelo ha se bapisoa le sehlopha sa placebo (OSU6162: −7.6; placebo: −0.15; t (52) = - 2.6; p= 0.013). Ha ho phapang e kholo ea liphetoho tsa QTc e fumanoeng pakeng tsa lihlopha tsa kalafo (OSU6162: −1.8 ms; Placebo: −3.9 ms; t (48) = 0.32; p= 0.752).

4. Puisano

Boithuto ba hona joale ba laboratori ea batho ke hore, tsebong ea rona, tlhahlobo ea pele ea phello ea monamine stabilizer OSU6162 liphetho mabapi le litlamorao tse amanang le tšebeliso ea lino tse tahang, joalo ka ho lakatsa, ho batho ba ts'ebelisang joala. Liphetho tsa mantlha e ne e le hore OSU6162, ha e bapisoa le placebo, e ts'oants'a haholo "ho rata" joala bo tahiloeng le takatso ea peleho, sephetho se tsamaisoang ke batho ba nang le maemo a phahameng a ho hloka ts'ebetso ea mantlha. Hammoho le liphetho tsa rona tsa pejana tse bonts'ang hore OSU6162 e bonts'a boits'oaro bo kopaneng le joala litsing tsa nako e telele tsa ho noa (Steensland le al., 2012), liphetho tsa hona joale li bonts'a hore moralo oa dopamine o tsoetseng pele oa bongaka o ka ipaka o le molemo ho fetoleng mekhoa e meng e tlisoang ke moputso molemong oa ts'ebeliso ea joala le hore OSU6162 e kanna ea ba le mokhoa oa ho ba moriana o mocha oa ho itlopa joala.

OSU6162 ha e na phello e matla litakatsong tsa takatso ea joala tse tahiloeng, empa e fokolisitse takatso e matla ea batho ba ts'epahalang. Ho haella ha phello ea kalafo litakatsong tse bakoang ke takatso e ka hlalosoang ke mathata a ts'ebetso ao karabelo e ikemiselitseng ea ho batla joala e seng matla ho feta lithethefatsi tse ling tsa tlhekefetso (Lingford-Hughes et al., 2006). Phokotseho e kholo ea litakatso tse kenelletseng tsa ho hlohlelletsoa joalo ka ha li hlahlojoa ke Short-DAQ e hlile ea bonoa kamora kalafo ea OSU6162 ha e bapisoa le placebo, hang hoba barupeluoa ba qete ho qeta ho noela joala. Leha ho le joalo, ho lokela ho hlokomeloa hore ha ho lakatsa ho batla ho sebelisoa VAS, ha ho na phello ea bohlokoa (leha e le mokhoa). Liphumano tseo OSU6162 li fositseng takatso ea nakoana ea takatso le ho rata joala li bonts'a hore matšoao a dopamine a tsitsitseng a moemeli enoa a bonahala ha joala bo tahiloe.

Mochine o tšehetsang bokhoni ba OSU6162 ba ho fumana mekhoa e kopaneng le joala literekeng (Steensland le al., 2012) le batho ba itšetlehileng ka joala joalo ka ha ho hlahisitsoe thutong ea hona joale, ha ba utloisisehe ka botlalo. Ho ka etsahala hore OSU6162 e bakile ho sithabela maikutlong ka kakaretso ka mokhoa o sa hlonepheng. Leha ho le joalo, sena ha se na monyetla kaha OSU6162 e ne e se na phello e kholo ho tšoenyeha kapa ho tsosa. Phuputso ea rona ea pejana ea Microbalal e bonts'itse hore OSU6162 e roala litheko tsa dopamine tse nooang ka har'a li-ligator tsa li-alcohol le naveve (Steensland le al., 2012), ho bonts'a hore OSU6162 e kanna ea ba le monyetla oa ho fumana thepa e tlisoang ke joala. Tlhahiso ena e tšehetsoa ke liphetho tsa rona tsa hona joale tseo OSU6162 e kentseng "ho rata" ha alcoho e chesitsoengl. Le ha ho le joalo, tlhahlobo ea rona ea morao-rao ea Microphiral ka litoebong tsa nako e telele tsa ho noa (Feltmann et al., Ka khatiso), e bonts'a hore OSU6162 e kanna ea ba le bokhoni ba ho hanyetsa boemo ba hypo-dopaminergic maemong a amanang le ts'ebeliso ea lino tse tahang (Narendran et al., 2014, Tupala et al., 2001, Volkow et al., 2007, Volkow et al., 1996). Litlamorao tse fapaneng tsa kalafo ea OSU6162 ho tlhahiso ea dopamine ho araba phephetso ea joala ho joala-naïve (Steensland le al., 2012) khahlanong le likhoto tsa nako e telele tsa ho noesa ka naha e nang le hypo-dopaminergic state (Feltmann et al., Ka khatiso), e totobatsa bokhoni ba OSU6162 ba ho hlohlelletsa kapa ho amohela dopamine ho latela molumo o teng. Bokhoni ba OSU6162 ba ho tsitsisa tšebetso ea dopamine bo tšehelitsoe hape ke thuto ea PET ho litšoene tsa Rhesus (Tedroff et al., 1998). Leha, bokhoni ba ho tiisa ba OSU6162 bo ntse bo bonts'oa ho batho, ho ho lekanya ho hakanya hore OSU6162 e kenyellelitsoeng boemong bo tloaelehileng ba bofokoli ba dopamine e ka khona ho hlalosa sephetho sa hona joale se bonts'ang hore OSU6162 e tlositse ts'ebetso ea joala e lakatsa batho ba its'epileng, joalo ka bofokoli ba dopamine bo na ho khothalelitsoe ho khanna takatso le ho kenya letsoho ho oeleng hape (Koob, 2013).

Thutong ea hona joale re fumane hore bokhoni ba OSU6162 ba ho lakatsa joala bo tlatselletsang bo tahiloeng bo fumanoe feela ho batho ba nang le maemo a phahameng a ho hlasimoloha. Ho se ho khothalelitsoe karohano pakeng tsa khatello ea maikutlo le tahi ea joala (Dick et al., 2010, Lejuez et al., 2010) le bofokoli ba cortical dopamine bo ka amanang le tšebeliso e mpe ea joala nako e telele, bo kenya letsoho taolong e sa tsitsang ea taolo ho batho ba its'ebeletsang joala.Goldstein le Volkow, 2011, Stavro et al., 2012). Ntle le moo, ho fumana hore tšusumetso ea bohloka le tšenyo e bakoang ke karabelo e sa lebelloang ho bolela esale pele takatso e kholo ea ba khothalletsang joala (Papachristou et al., 2013) e ts'ehelitsoe ke thuto e teng e bonts'ang hore barupeluoa ba nkang sebaka sa kalafo ba tšoaroang haholo ka sebaka sa placebo, ba ne ba e-na le litekanyetso tse phahameng tsa litakatso tsa bona tsa motheo (ke hore, pele ba betoa kapa ho hlalosoa pele). Ka hona, ha ho fanoa ka karolo ea dopamine ho laola boits'oaro bo sa tsitsang le boemo bo ikhethang ba pharmacological ea OSU6162 ho laola ts'ebetso ea dopamine ho latela molumo o teng oa dopaminergic (Carlson et al., 2004, SONerson et al., 1994, Tedroff et al., 1998), ho na le monyetla oa hore litlamorao tse ntle tsa OSU6162 tsa ho lakatsa ho ba le ts'oaetso e kholo ea batho ba lemaletseng joala li hlalosoa ke ts'ebetso ea boemo bo ka bang teng ba hypodopaminergic sehlopheng sena se ikhethileng ho batho ka bomong. Khopolo-taba ena e tšehetsoa hape ke litheolelo tsa hore barupeluoa ba OSU6162 ba tšoaroang haholo ba ne ba e-na le tekanyo e tlase haholo ea litakatso tse ikhethileng ho bapisoa le sebaka sa kalafo se tšoaroang le sebaka sa mantlha, ke hore, pele ho nako ea ho qala. Liphetho tse teng hona joale li fana ka maikutlo a hore batho ba itšetlehileng ka joala ba nang le litekanyetso tse tlase tsa dopamine ba ka ba le mathata a tebileng taolong ea tšusumetso mme ka hona ba na le monyetla oa ho rua molemo ho moemeli oa dopaminergic joalo ka OSU6162. Le ha ho le joalo, bokhoni ba OSU6162 ba ho ama mofere-fere ka bobeli e hloka ho hlahlojoa, lithuto tsa pejana li bonts'a hore modafinil e ntlafatsa ts'ebetso ea ts'ebetso ea neuropsychological ho kenyelletsa mosebetsi oa nako ea ho emisa ho etsa qeto ho baithaopi ba tsa bophelo bo botle (Turner et al., 2003) hammoho le thibelo ea karabo (Schmaal et al., 2013), le ho lelefatsa nako ea ho khutla (Joos et al., 2013) ho batho ba itšepisang joala ba nang le maemo a phahameng, empa eseng tlase, basement impulsivity (SSRT). Ka kopanelo, liphetho tsena li bonts'a melemo ea ho shebella sisteme ea dopamine kamanong le boitšoaro bo sa tsitsang 'me e bonts'a hore ho ts'oaroa ka matla ho emela phenotype ea bohlokoa ho ts'ebelisong ea joala, mme e hloka ho tsotelloa ha ho hlahlojoa li-dopaminergic agents ho bakuli bana.

Le ha ho le joalo, tlhahlobo ea hona joale ea tlhahlobo ea batho ea liteko le nako ea kalafo ea matsatsi a 14 e ne e sa etsetsoa ho bona phello ea OSU6162 ts'ebelisong ea joala, kalafo ea OSU6162 le kalafo ea placebo li kentse phokotso e fetang 50% matsatsing a ho nwa haholo. Ho haella ha liphapang tse kholo lipakeng tsa OSU6162 le lihlopha tsa placebo ho ka etsahala haholo ho bakoa ke ho nka karolo ho ithuteng lipatlisiso ka bobeli e na le litlamorao tse ntle ho tšebeliso ea joala (Weiss et al., 2008) le hore nako ea kalafo ea bonyane likhoeli tse tharo ho isa ho tse tšeletseng e hlokahala ho tiisa ts'ebetso le ho netefatsa ho hloka mamello hoa lithethefatsi bakeng sa meriana e ka bang teng (Setsi sa Litlhare tsa Europe, 2010). Ka 'nete liphumano tsa morao-rao ho bakuli ba nang le khatello ea kelello li bontša phello ea kalafo ea OSU6162 e kenngoa hanyane ka hanyane nakong ea libeke tsa pele tsa kalafo mme ha e fihlelle ka katleho ho fihlela kamora libeke tse' maloa tsa kalafo (liphetho tse sa phatlalatsoang ho tsoa ho mongoli Dr Carlsson). Le ha ho le joalo, e tsamaellana le lithuto tse fetileng ho lipalo tse ling tsa bakuli (Johansson et al., 2012, Kloberg et al., 2014, Tedroff et al., 1999) Phekolo ea OSU6162 ka kakaretso e ne e mamelletsoe hantle 'me ha ho le ea mong oa barupeluoa ea ileng a tlohela ho ithuta ka lebaka la litlamorao tse sa mamelleheng. Kahoo, liphumano tse fumanehang tsa polokeho le litlamorao ho ho lakatsa joala li fana ka ts'ehetso bakeng sa teko ea bongaka e matla e laoloang ke placebo ho lekola sephetho sa OSU6162 litlamorao tsa ho noa.

Ka bokhutšoanyane, tlhahlobo ena ea pele ea thuto ea motho ea mantlha ea batho ba ts'ehetsoeng joala e bonts'a hore monoamine stabilizer OSU6162 e ne e bolokehile e bile e mamelletsoe hantle mme e fumana ho ts'oaroa ha joala ho lakatsa joala le ho rata, tikolohong e laoloang ea laboratori. Litlamorao tsa OSU6162 li ne li tsamaisoa ke batho ba nang le maemo a phahameng a ho itlhahisa, ba totobatsang bohlokoa ba ho ts'oaroa ha basotho ha ba hlahloba li-dopaminergic agents ho batho ba itšebelisang joala. Teko e kholo ea taolo ea katleho ea placebo e laoloang ke placebo e hlokahala ho feta ho hlahloba bokhoni ba OSU6162 e le moriana o fumanehang oa ho itlopa joala.

Lichelete le ho senola

Dr. Carlsson ke mong'a A. Carlsson Research AB le moqapi oa patent e sebelisang (-) - OSU6162. Ngaka Carlsson ha e phatlalatse lithahasello tse ling tsa lichelete kapa likhohlano tsa phaello. Bangoli Khemiri, Steensland, Guterstam, Beck, Franck le Jayaram-Lindström ha ba phatlalatse lithahasello tsa lichelete kapa likhohlano tsa phaello.

phehisa

Lotfi Khemiri1, Pia Steensland1, Joar Guterstam1, Olof Beck2, Arvid Carlsson3, Johan Franck1*, Nitya Jayaram-Lindström1

1Lefapha la Neuroscience ea Clinical, Karolo ea Psychiki, Karolinska Institutet, Stockholm, Sweden

2 Lefapha la Bongaka, Kgaolo ya Clinical Pharmacology, Sepetlele sa Univesithi ea Karolinska, Stockholm, Sweden

3 Sahlgrenska Academy, Univesithi ea Gothenburg, Gothenburg, Sweden

Sengoli se tsamaellanang:

Lotfi Khemiri, MD

Pia Steensland, Ph.D.

Joar Guterstam, MD

Olof Beck, Ph.D

Arvid Carlsson, MD, Ph.D.

Johan Franck, MD, Ph.D.

Nitya Jayaram-Lindström, Ph.D.

Sengoli se lumellanang:

Johan Franck

Karolinska Institutet

Lefapha la Neuroscience ea Clinical

Karohano ea Psychiki

KS, Solna, R5: 01

EA-17176-Stockholm

Sweden

E-mail: [imeile e sirelelitsoe]

Fax: + 46-8-12349602

Mohloli oa lichelete

Boithuto bona bo tšehelitsoe ka lichelete ke lichelete tsa lipatlisiso tsa Karolinska Institutet, Lekhotla la Lipatlisiso la Sweden Alcohol Retailing Monopoly (FO2012-0053), Torsten Söderberg Foundation (M203 / 12) le Sweden Brain Foundation (FO2011-0106, FO2012-0083 le FO2013 -0042).

lumela hore baa fokola

Boithuto bona bo tšehelitsoe ka lichelete ke lichelete tsa lipatlisiso tsa Karolinska Institutet, Lekhotla la Lipatlisiso la Sweden Alcohol Retailing Monopoly (FO2012-0053), Torsten Söderberg Foundation (M203 / 12) le Sweden Brain Foundation (FO2011-0106, FO2012-0083 le FO2013 -0042) kaofela ho isa ho PS. Re leboha PhD Anders Hammarberg ka ho kenya letsoho ha hae moralo oa laboratori ea batho, baoki ba lipatlisiso Margareta Gard-Hedander le Else-Britt Hillner, setsebi sa kelello Angela Stünkel le seithuti sa undergraduate, Maria Östman ka thuso e ntle haholo ea ho bokella data le ho sebetsana le meriana ea ho ithuta.

Sehlomathiso A. Lintho tse tlatsetsang

Lintho tse ling tse eketsehileng

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