Iigrutamatergicyeza unyango lwezilwanyana nezilingo zokuziphatha (2013)

Pharmacol Biochem Behav. I-2012 ngoFebruwari; 100(4): 801-810. Ishicilelwe kwi-intanethi 2011 April 22. ikhonkco: 10.1016 / j.pbb.2011.04.015

M. Ukunyusa umnquma,^1,^* URichard M. Cleva,¹ UPeter W. Kalivas,² kwaye URobert J. Malcolm³

Ulwazi loMbhali ► Ulwazi lobunikazi kunye neLayisenisi ►

Inguqulelo yokugqibela yomhleli yeli nqaku iyafumaneka apha Pharmacol Biochem Behav

Bona amanye amanqaku ku-PMC Wisdom nqaku epapashwe.

Abstract

Ngokwembali, uninzi lweendlela zeyeza ezisebenzisa unyango kunyango lweziphazamiso zisebenzise zonke iindlela ezisekelezwe (okt, ukutshintshwa kwe-nicotine okanye ukugcinwa kwe-opioid) okanye zijolise kwinkqubo ye-monoaminergic okanye ye-endo native opioidergic neurotransmitter. Nangona kunjalo, ubungqina obuninzi buqokelelene obubonisa ukuba i-ligands isebenzisa ukuhanjiswa kwe-glutamatergic ikwaluncedo lwezinto ezinokubakho kunyango lweziyobisi, kunye nokuziphatha okwahlukileyo okunje ngokungcakaza. Injongo yolu phononongo kukushwankathela iindlela ze-pharmacological of action kunye nokusebenza ngokubanzi kweklinikhi amayeza e-glutamatergic avunyiweyo njengangoku okanye aphandwayo ngenjongo yokuvunywa kunyango lweengxaki zokuphazamiseka. Amayeza aneempembelelo ekuhanjisweni kweglutamatergic eza kuxoxwa kubandakanya i-acamprosate, N-acetylcysteine, D-cycloserine, gabapentin, lamotrigine, memantine, modafinil, kunye ne-topiramate. Sigqiba kwelokuba ukuxhaphaza i-glutamatergic neurotransuction kuncinci kodwa kuthembisa indlela yokuphuhliswa kweearhente zonyango eziphuculiweyo kunyango lweziyobisi kunye nokuziphatha.

Internet: iziyobisi, iziyobisi, iziyobisi, indlela yokungcakaza, unyango ngamachiza, glutamate

1. intshayelelo

Iziyobisi, ezichazwe yiAmerican Psychiatric Association njenge ukuxhomekeka kwento (Umbutho we-Psychiatric Association, i-2002), inezimpawu ezininzi ezingalunganga zengqondo kunye nokuziphatha okubandakanya: ukuphulukana nolawulo lokusebenzisa iziyobisi, ukuthatha iziyobisi ngesixa esikhulu kunokuba bekucwangcisiwe, ukuzama okuphindaphindiweyo ukungayeki okanye ukunciphisa ukusetyenziswa kweziyobisi, ukuqhubeka nokusetyenziswa kweziyobisi ngaphandle kwemiphumo emibi, kunye nokuvela kokuchazwa ngqo kwesiyobisi. iimpawu zonyamezelo kunye / okanye ukurhoxa. Ukongeza kwimiba emininzi engabonakaliyo yobuntu efana nokuphazamiseka kwiintsapho kunye nobudlelwane phakathi kwabantu, ukungasebenzi kakuhle ekuhlaleni, kunye nokulahleka kobomi, umthwalo wentlalo ozobeka iziyobisi kuluntu mkhulu kakhulu (Cartwight, 2008; UGilson noKreis, 2009; I-Malliarakis kunye neLuky, 2007; Rehm okqhubekayo., 2009; I-Spanagel, 2009; I-Thavorncharoensap okqhubekayo., 2009). Kwiminyaka yakutshanje kuye kwabonakala ukuba i-neural substrates isiyobisi esisebenzisa kakubi iziyobisi sisebenzisa kakhulu abo bangenanto iziyobisi "ngokuziphatha" (okt. Ukugembula komzimba, iphonografi / umlutha we-intanethi, njl njl.) (Grant okqhubekayo., 2010a).

Ukuza kuthi ga ngoku, amayeza aqulunqelwe ukunceda kunyango lweengxaki zokungalungisi abonakalise impumelelo elungileyo kuphela. Izithintelo ezaziwayo ezithi zenze umqobo ekusebenzeni kweendlela ezisebenzisa amayeza kunyango ukuya kuphazamiso zibandakanya ukungahambelani amayeza, iziphumo ezichaseneyo, imiba yezokhuseleko, iimpendulo zamayeza eziguquguqukayo kumaqela onyango, ukudityaniswa okungalunganga kolawulo lwamayeza kunyango lwengqondo nakwezengqondo. amayeza okanye ukhathalelo lwempilo olwaneleyo, kwaye uphinde ubuye emva kokuyekiswa kwonyangoKoob okqhubekayo., 2009; IMontoya kunye neVocci, 2008; I-O'Brien, 2008; I-Ross kunye ne-Peselow, i-2009; I-Zahm, 2010). Ngelixa amayeza amaninzi eeklasi ezahlukeneyo ezamkelweyo ngenxa yezinye iimeko zonyango ngoku aphandwayo njengoncedo olunokubakho kunyango lweengxaki zokuphazamiseka, amayeza ekuphela kwawo amkelweyo kunyango ukuza kuthi ga ngoku eUnited States yi-varenicline, ibuproprion, ne-nicotine Unyango lokuphelisa ukutshaya, ukusebenzela i-opioids ende (okt, methadone okanye ibuprenorphrine) yokuxhomekeka kwe-opiate, kunye ne-disulfiram, i-naltrexone, kunye ne-acamprosate yokuxhomekeka kotywala. Akukho mayeza okuncedisa kunyango lwe-cocaine, i-methamphetamine, okanye i-marijuana ngoku evunyiweyo, kwaye akuvunyelwanga kunyango lokuziphatha kakubi.

Injongo yoqwalaselo lwangoku kukubonelela ngesishwankathelo sendlela yokusebenza kwecandelo lezonyango kunye nokusebenza ngokubanzi kweklinikhi kwamayeza abandakanyeka ekuhanjisweni kwe-glutamatergic kunyango lweengxaki eziphazamisayo. La mayeza abandakanya i-acamprosate, i-N-acetylcysteine, i-D-cycloserine, i-gabapentin, i-lamotrigine, i-memantine, i-modafinil kunye ne-topiramate. Kufuneka kuqatshelwe ukuba uninzi lala mayeza baneendlela zokusebenza ezibandakanya iinkqubo ze-neurotransmitter ezininzi, kwaye mhlawumbi ngaphandle kwe-D-cycloserine, akukho mntu waziwa ngokukhethekileyo ekujolise ekusasazeni i-glutamatergic okanye ii-receptors ezithile ze-glutamate. Nangona kunjalo, kukho umzimba oqinileyo wobungqina bokuqala obuvela ngaphezu kweminyaka engamashumi amabini yezifundo zezilwanyana ezibonisa indima ebalulekileyo yokuhanjiswa kwe-glutamate kunye ne-glutamate receptors kumvuzo wamachiza, ukuqiniswa, kunye nokuphinda ubuye (Intaka kunye neLawrence, 2009; Bowers okqhubekayo., 2010; IGass kunye neOlive, 2008; Kalivas okqhubekayo., 2009; IMoussawi kunye neKalivas, 2010; Olive, 2009, 2010; I-Reissner kunye neKalivas, 2010; I-Tzschentke kunye neSchmidt, 2003; I-Uys kunye neLaLumiere, i-2008). Ukufumana ukujongwa kwakhona kokuhanjiswa kwegutamatergic kunye neeplatamate receptors, umfundi ugqithiselwe ekuhlolweni yiSanacora kumcimbi okhoyo ngoku (Umshicileli-nceda ufake inombolo zamaphepha apha). Ukongeza, imizimba encinci kodwa ekhulayo yoncwadi ngokusetyenziselwa la mayeza ukunyanga imikhwa yokuziphatha efana nokungcakaza okunyanzelekileyo, kwaye nezifundo kwesi sihloko ziya kuqwalaselwa kwakhona.

2. Amayeza e-Glutamatergic kunyango lokuphazamiseka kokusetyenziswa kweziyobisi

2.1. I-Acamprosate

2.1.1. Indlela yokuSebenza

I-Acamprosate (i-calcium acetylhomotaurine) ithathwe kwi-homotaurine, i-agonist ye-ons-aminobutyric acid (GABA) engacacanga. Imolekyuli yi-N-acetylated ukuququzelela ukungena ngaphakathi kuthintelo lobuchopho-begazi, kwaye yenziwa njengeetyuwa yecalcium yokunyusa ukufunxwa kwekhompawundi ukusuka kwithumbu lesisu. Ngaphandle kolu hlengahlengiso lweekhemikhali, ukungafumaneki kwayo ngokubanzi kuhlala kuhlwempuzekile (okt, <20%) kwaye kufuna idosi kuluhlu lwe-2-3 yeegram ngosuku ukubonisa ukusebenza. Zininzi iindlela zokwenza amayeza e-acamprosate ezicetywayo, kodwa izifundo zokuqala ezibonisa ukuba i-acamprosate inezenzo zayo ngokusebenzisa iindlela ze-glutamatergic ezichazwe nguZeise kunye noogxa (Zeise okqhubekayo., 1990, 1993). Aba baphengululi babonisa ukuba i-acamprosate iyinciphisile into yokukhutshelwa kwe-neuronal ekhutshwe yi-iontophoretic yesicelo se-L-glutamate kwi-cortical neurons kwi-vivo, kunye ne-inhibited poscostic posentials (EPSPs) evuswe yi-glutamate kunye ne-N-methyl-D-aspartate (NMDA). Ubungqina obengezelelweyo bendlela ye-NMDA yomchasi ofana nesenzo se-acamprosate buvela kwizifundo ezibonisa ukuba le ndawo icekeceke I-NMDA-ikhuphe uvuthondaba lwesondo (ii-EPSC) kwii-hippocampal neurons (Iimpawu okqhubekayo., 2001) kunye nokulawula ukubonakaliswa kwesiqwengana seNMDA ngendlela efanayo naleyo yalandelwa unyango kunye nomchasi we-NMDA ongenakhuphiswano uMK-801 (Putzke okqhubekayo., 1996; Iimpawu okqhubekayo., 2001). Nangona kunjalo, abanye abaphandi abafumananga siphumo se-acamprosate kwi-NMDA-mediated transaptic transaptise kwingingqi ye-CA1 ye-hippocampus (I-Popp kunye neLovinger, 2000), ngelixa abanye bafumanise ukuba i-acamprosate eneneni inokubangela ukuba i-NMDA receptor isebenze kwingingqi ye-CA1 ye-hippocampus (UMadamba okqhubekayo., 1996) kwi-nucleus accumbens (Berton okqhubekayo., 1998). Ngaphandle kwezi ziphumo ezingahambelaniyo ze-elektriksiyuli, izifundo ezibophayo ziqinisekisile ukusebenzisana kwe-acamprosate kunye ne-spermidine-, glutamate- kunye / okanye i-MK-801-indawo yokubopha ye-NMDA receptor (al Qatari okqhubekayo., 1998; Harris okqhubekayo., 2002; UNaassila okqhubekayo., 1998), kwaye ngaloo ndlela i-acamprosate ihlala ibizwa ngokuba yi "NMDA module" (Umzobo 1). Nangona iithagethi ezichanekileyo ze (ii) ze-acamprosate azikaqinisekiswa (Umcuphi kunye neMann, 2010; Reil okqhubekayo., 2008), Uninzi lweengcinga zangoku lubonisa ukuba i-acamprosate ibuyisela ukungalingani phakathi kokuvuyisa kunye ne-inhibitory amino acid neurotransmission ebangelwa kukusela kakhulu (De Witte okqhubekayo., 2005; Umcuphi kunye neMann, 2010; Spanagel okqhubekayo., 2005; Umhau okqhubekayo., 2010).

Inkqubo ye-Putative glutamatergic yeendlela zesenzo se-8 amayeza okulwa neziyobisi. I-Acamprosate -Iinjongo zeemolekyuli ze-acamprosate aziqinisekanga, kodwa izifundo ezininzi zibonise ukuba zihlengahlengisa umsebenzi wee-NMDA receptors kwaye zibuyise umlinganiso phakathi ...

2.1.2. Ukusebenza kweeklinikhi

Umboniso wokuqala wokusebenza kakuhle kweklinikhi ye-acamprosate ekwehliseni imeko yokuphinda ubuye kwiziselo ezinxilisayo wapapashwa phakathi kwe-1980's (I-Lhuintre okqhubekayo., 1985). Kwiminyaka edlulileyo, i-acamprosate ibonakalise ubungakanani besiphumo esusela kumncinci ukuya kokumiselweyo ekunciphiseni ukusetyenziswa kotywala ngokupheleleyo, amanyathelo afanelekileyo okukhanuka utywala, kunye nokukhuthaza ukungabinakho, njengoko kuhlaziywa kuhlalutyo meta-lwakutsha nje (Kennedy okqhubekayo., 2010; Umcuphi kunye neMann, 2010; I-Kranzler kunye neGage, 2008; indoda okqhubekayo., 2008; Ixesha kunye neHyser, 2010a, b; IRosner okqhubekayo., 2010; I-Snyder kunye ne-Bowers, 2008). Ngenxa yokungaxakekisi komlomo okukhohlakeleyo, kuthathwa iidosi ezinkulu ze-acamprosate (ngokuthe gabalala kwi2-3 g ngemini yosuku) ukuze kubekhona ukusebenza kakuhle. Nangona kunjalo, uphononongo olukhulu lwamva nje lweziko elingaphezulu kwizigulana ezixhomekeka kakhulu kwi-1200 (eyaziwa ngokuba yi-Combined Medication and Behavioural Intervention, okanye u- "COMBINE") ifumanise ukuba i-acamprosate yayingasasebenzi kakhulu kune-placebo ekunciphiseni imeko yokuphinda iphinde iphinde ibuyele kwimo yezonyango. useto lolawulo (Anton okqhubekayo., 2006). Olunye uphononongo lwakutshanje lubonakalise ukunqongophala kokusebenza kwe-acamprosate ekunciphiseni ukusela utywala okanye ukunqwenela, okanye ukukhuthaza ukungafuni (Donovan okqhubekayo., 2008; Laaksonen okqhubekayo., 2008; Morley okqhubekayo., 2006; Richardson okqhubekayo., 2008). Izizathu zezi ziphumo zingalunganga, ngakumbi xa kufunyaniswa iziphumo ezibi zangaphambili (zishwankathelwe kwimeta-kuvavanyo olukhankanywe apha ngasentla), kusaxoxwa ngazo. Abanye abaphandi bacebise ukuba "iziphumo ze-placebo" ebalulekileyo kwisifundo se-COMBINE zinokuba zisithuse nayiphi na impembelelo ye-acamprosate (Weiss okqhubekayo., 2008), kwaye ukuphucuka kokungazithathi iziphumo zokunxibelelana neendlela zokuphila ezinje ngomgangatho wobomi zaziphezulu kwizigulana ezanyangwa i-acamprosate- ngokuchasene ne-placebo kunyango lwe-COMBINE (LoCastro okqhubekayo., 2009). Abanye bacebise ukuba ukuqalwa kunyango lwe-acamprosate emva kokukhupha isisu kusenza sinciphise isiselo esinxilisayo kunokuba kunikwe xa kusenziwa utywala.Kampman okqhubekayo., 2009), njengoko kwenziwe kwisifundo seBONO. Imfuno yeedosi ezintathu ngosuku kunokuba sisithintelo sokuthotyelwa kwezinye izigulana. Ukwehla kwesibambiso esivakalayo sokuqalisa unyango phakathi koxinzelelo njengoko kuthelekiswa nonxinzelelo olunxilisayo kuchaphazela kakhulu ukuthotyelwa kwezigulana kunyango lwe-acamprosate.I-Lejoyeux kunye neLehert, 2011). Okokugqibela, ezinye izinto ezishukumisayo ezinje ngokuba nenjongo yokunyanga ukungaseli ngokupheleleyo ngokuchaseneyo nokusela ngokulinganiselweyo kubonakala kuneziphumo ezizizo kwizigulana eziphathwa nge-acamprosate xa kuthelekiswa ne-placebo (Mason okqhubekayo., 2006; Imason kunye neLehert, 2010). Kungenzeka ukuba, njengalo naluphi na unyango lwe-psychotropic, ii-subsets ezithile zezigulana zingaphendula ngcono kwi-acamprosate kunabanye. Uphando olongezelelekileyo luyafuneka ngokucacileyo ukufumanisa ngqo ukuba zeziphi izinto ezizizo ezinokukunceda, indlela yokusebenza, umlinganiso wesiphumo, okanye izizathu zofuzo ukuze kuchongwe iziselo ezinxilisayo ezinokuthi zibonakalise impendulo efanelekileyo kwi-acamprosate.

Ngokumalunga nokusetyenziswa kwe-acamprosate ekunyangeni umlutha kwezinye iziyobisi zokuphathwa gadalala okanye indlela yokuziphatha enje ngokugembula, izifo ezinkulu azikho, kwaye izifundo ezimbalwa ezipapashiweyo ziye zaxela iziphumo ezixubeneyo. Umzekelo, ingxelo yamatyala yakutshanje ixhase into enokusetyenziswa ye-acamprosate ekunyangeni ukungcakaza kwe-pathological (URaj, 2010). Kwelinye icala, u-Kampman kunye noogxa bakhe baxela ukuba kuvavanyo olulawulwa kabini nge-placebo elawulwa zi-60 i-cocaine, i-acamprosate ayibonisanga ziphumo ziluncedo ekusebenziseni i-cocaine, ukuthanda, okanye ukurhoxa iimpawu xa kuthelekiswa nezigulana ezifumana i-placebo (Kampman okqhubekayo., 2011). Ezi zinto zifunyanisiweyo kamva ziyadanisa kuba izifundo ezininzi zepententi zibonise ukuba i-acamprosate ifumana iziphumo ezinembuyekezo zecocaine kunye nokusetyenziswa kwakhona kweziyobisi nakwi-cue-primedBowers okqhubekayo., 2007; UMcgeehan kunye no-Olive, 2003, 2006). Nangona kunjalo, xa unikwe isampulu encinci yesayizi kunye nenqanaba lokuyeka lokufunda okwenziwe nguKampman noogxa bakhe, kunokwenzeka ukuba i-acamprosate inokuba luncedo kunyango lwekhoboka le-cocaine kwimeko engekacaciswa yabantu abaxhomekeke kwi-cocaine.

2.2. I-N-acetylcysteine (NAC)

2.2.1. Indlela yokuSebenza

I-NAC sisiphumo esivela kwi-Nino-acetylated ye-amino acid cysteine yendalo. Nje ukuba amalungu angaphakathi abandakanyeke kwingqondo, ibandakanyeke kwi-cysteine yasimahla, kunye nokuphuculwa kwekhaya leemolekyuli ezimbini ze-cysteine nge-discride bond ziphumela ekusekweni kwe-cystine. Ke, i-NAC ithathwa njenge-cystine pro-drug ebopha i-cystine-glutamate exchanger (idla ngokubizwa ngokuba yinkqubo xc-) kwaye ikhuthaza ukumiliselwa kwe-glutathione (Baker okqhubekayo., 2002; McBean, 2002). Ngale ndlela i-NAC ibonakalise ubuchwephesha bonyango njenge-arhente ye-mucolytic nakwonyango lwe-acetaminophen overdose. Nangona kunjalo, ukongeza ekukhuthazeni ubume be-glutathione, inkqubo ye-xc- yiproteni ye-antiporter ehambisa i-cystine ye-extracellular kwiiseli ze-glial kunye ne-glutamate ye-intracellular ukusuka ngaphakathi kwe-glia ukuya kwindawo engaphandle kwecala. Isiphumo esisiphumo se-NAC kukuphakama kwamanqanaba e-glutamate ye-extracellular, encitshiswa ngexesha lokurhoxiswa kwe-cocaine (Baker okqhubekayo., 2002, 2003; Kau okqhubekayo., 2008; UMadayag okqhubekayo., 2007; Melendez okqhubekayo., 2005; Moran okqhubekayo., 2005). Oku "kuqhelekileyo" kwamanqanaba e-glutamate ye-extracellular ibuyisela ithoni ye-glutamatergic kwiqela lokulawula ukukhululwa kwe-II metabotropic glutamate receptors (mGluR2 / 3, Moran okqhubekayo., 2005; yabona Umzobo 1) kunye nokuthintela amandla omngeni olandelayo wecocaine wokwandisa amanqanaba e-glutamate angaphandle kwi-nucleus accumbens. Isiphumo sesiphelo kukungakwazi ukubonakalisa ukubonakaliswa kwe-cocaine eyingozi kakhulu ekubuyiseleni kwindlela yokuziphatha efuna i-cocaine (Amen okqhubekayo., 2011; Baker okqhubekayo., 2003; Kau okqhubekayo., 2008; UMadayag okqhubekayo., 2007; Moran okqhubekayo., 2005; Moussawi okqhubekayo., 2009).

2.2.2. Ukusebenza kweeklinikhi

Ngokusekwe koku kufunyanisiweyo kwizifundo zezilwanyana, izifundo ezininzi malunga nokusebenza kwe-NAC ukunciphisa ukusetyenziswa kwecocaine, ukuthanda, iimpawu zokurhoxa, kunye nokuphinda kubuyele kwizidakamizwa zabantu abasebenzisa icocaine. Kwisifundo esincinci sokhuseleko kunye nonyamezelo (n = izifundo ze-13), kwaboniswa ukuba i-NAC (1200 mg / usuku lweentsuku ezimbini) yanyamezelwa ngokufanelekileyo ngamakhoboka e-cocaine kwaye yavelisa ukuthambekela okuncinci ekunciphiseni kweengxelo zokuzisebenzisa ze-cocaine, kunye neempawu zokurhoxa (LaRowe okqhubekayo., 2006). Izifundo ezilandelayo zokulandela (n = izifundo ze-15-23) ziqinisekisile ukuba iidosi ezifanayo ze-NAC ziyanyamezelwa ngokuchanekileyo yimilutha ye-cocaine kwaye ngenene zivelisa ukuncipha ekusebenziseni i-cocaine kwaye zinqwenele ukunyangwa ngabantu abafuna ukuxhomekeka kwi-cocaine.Amen okqhubekayo., 2011; LaRowe okqhubekayo., 2007; IsiMardikian okqhubekayo., 2007). Okubalulekileyo, nangona kunjalo, uphononongo lwamva nje lomvavanyi lubonise ukuba i-NAC ayinciphisi imvakalelo yokusebenzisa icocaine "ephezulu" okanye "ukungxama" kulandela ukuboniswa kwevidiyo ye-cocaine ehambelana necocaine, kodwa ikwenza oko ngokufuna ukubhencwa kukuvezwa kwe-cocaine ye-acute (Amen okqhubekayo., 2011). Ngelixa ezi ziphumo zokugqibela zinokubonakala ngathi azingqinelani nezo zeLaRowe, iMardikian, kunye nabalingane, abafumene iziphumo ezinciphisayo ze-NAC kumnqweno we-cue-evoked cocaine craine, ubukhulu obuncinci kakhulu isampulu yesifundo ngu-Ameni kunye noogxa bakhe (n = izifundo ze4 ) inokuwunqanda umda ukutolikwa kwayo. Ngaphandle koko, ezi ziphumo zokuqala zibonelela ngedatha ekhuthazayo yokuba i-NAC isenokusetyenziselwa unyango kunyango lwe-cocaine, kunye nezilingo ezongeziweyo zeziko leeklinikhi ezifunekayo ukuqinisekisa ezi ziphumo kwinqanaba elikhulu.

Ngokuphathelele kwamanye amachiza okuphathwa gadalala, uvavanyo oluncinci lwekliniki (n = izifundo ze-29) liphande ngokusebenza kwe-NAC ngokuncedisa ekupheliseni ukutshaya (Knackstedt okqhubekayo., 2009). Iziphumo zolu phononongo zibonise ukuba unyango lwe-NAC (i-2400 mg / ngosuku) luyanciphisa inani lecuba elitshayiweyo kwinani lecuba elitshayiswe zizifundo ezifumana i-placebo, kodwa unyango lwe-NAC aluzange linciphise amanqanaba e-carbon monoxide, iimpawu zokurhoxisa i-nicotine, okanye i-nicotine ukunqwenela. Olunye uphononongo oluncinci lokuqhuba (n = izifundo ze-24) lubonise ukuba i-NAC iyaphungula ukusetyenziswa kwentsangu kunye nokunqwenela abantu abadala abancinci abaxhomekeka kwi-18-21 xa kuthelekiswa ne-placebo (Ngwevu okqhubekayo., 2010). Ngokubhekisele kwizyobisi ezingekho iziyobisi, ulingo oluncinci lweklinikhi (n = izifundo ze-23) lubonise ukuba i-NAC (kuthetha ukuba idosi eyi-1477 mg / ngosuku) iye yehlisa amanqaku kwi-Yale Brown Obsessive Compulsive Scale Modified for Pathological Ginji [PG-YBOCS] (Grant okqhubekayo., 2007), kwaye ibonakalisiwe iyasebenza ekunciphiseni ukunyanzelwa kwezipikili ezinxulumene nokuphazamiseka kwengqondo kwizifo ezithathu ((Berk okqhubekayo., 2009). Okokugqibela, i-NAC yaphinda yaboniswa ukuba icinezele ukutsalwa kweenwele kwisifundo esingaboni kabini kwizigulana ze-50 ezine-trichotillomania (Grant okqhubekayo., 2009).

Nangona zonke ezi zifundo zeklinikhi zikhankanyiweyo ngaphambili kwaye zisebenzisa isampulu ezincinci zesampulu, izinto ezibonakala ngathi ziyahambelana ezichasene ne-NAC zibonelela ngobungqina obuqinisekileyo bokuba eli liyeza, kunye nezinye iikhompawundi ezibuyisela i-glutamate homeostasis (Knackstedt okqhubekayo., 2010; Sari okqhubekayo., 2009), inokubonakalisa ukuba inokunceda ekuncediseni amachiza kunyango lweziyobisi nakwindlela yokuziphatha.

2.3. I-D-cycloserine (DCS)

2.3.1. Indlela yokuSebenza

I-DCS (D-4-amino-3-isoxazolidone) sisiphumo esivela ngokwendalo i-amino acid serine. Isebenza njenge-agonist ngokubambisana kwindawo ebopha i-glycine kwi-NR1 subunit ye-NMDA receptor, ekhoyo kuzo zonke ii-receptors ze-NMDA kwinkqubo ye-nervous central. I-DCS ayonelanga ekusebenziseni ii-NMDA receptors ngokwayo, kwaye ifuna ubukho be-glutamate ibophelele kwi-receptor ukuze ikhuphe iziphumo zayo. Ukusebenza kwendawo yokubopha ye-glycine yiDCS kuphucula ukusebenza kwe-NMDA ngokwandisa i-calcium protx kwezi zixhobo ezilandelwayo ngaphandle kokubangela i-neurotoxicity (Sheinin okqhubekayo., 2001; yabona Umzobo 1).

2.3.2. Ukusebenza kweeklinikhi

Ngenxa yesakhono saso sokuphucula umsebenzi we-NMDA receptor, iDCS kukholelwa ukuba incedisa ubumbano lweplastiki kunye neendlela ezithile zokufunda, kubandakanywa ukufundwa okunxulumene nokufunda kunye nokufunda okungapheliyo, kwaye ngenxa yoko kuye kwanikelwa ingxelo yokuba kuphumelele ukuphelisa iimpendulo zoloyiko kuxinzelelo. Izigulana ezingalunganga ngexesha lonyango lokuvezwa kwengqondo kwizifundo zeklinikhi ezininzi (eziphononongiweyo kwi Davis okqhubekayo., 2006; Myers okqhubekayo., 2011; I-Myers kunye noDavis, 2007). Ngokumalunga nokulutha, izifundo zesilwanyana zibonise ukuba iDCS inceda ukupheliswa kukhetho (cPP) lweCocaine.Botreau okqhubekayo., 2006; Thanos okqhubekayo., 2009), kunciphisa ukuzilawula kwakhona kwe-cocaine-self-management ngokwandisa imfundo yokupheliswa (UNic Dhonnchadha okqhubekayo., 2010), kwaye ikwaphindise ukubuyiselwa kokufuna i-cocaine ngendlela-ezimeleyo (I-Torregrossa okqhubekayo., 2010). Nangona kunjalo, zimbalwa nje kuphela izifundo zekliniki kwiziphumo ze-DCS kwiindlela zokuziphatha eziqhubekekileyo okwangoku.

USanta Ana kunye noogxa bakhe (Santa Ana okqhubekayo., 2009) Kutsha nje kuxelwe ukuba kwi-12 i-nicotine e-cuba etshaya icuba ebonakalayo, ulawulo lwe-DCS (50 mg) iimpendulo ezibonakalayo (okokuziphatha, ulusu) kunye nokulinganisa ukutshaya komsi wokuphendula ukutshaya. Iimpawu ezinxulumene nazo ngokuthelekiswa nezifundo eziphathwe nge-placebo (n = 13). Izifundo eziphathwe yiDCS zikwabonisa ukunciphisa amanqanaba e-carbon monoxide aphelelwe lixesha kuvavanyo olulandelayo kwiveki kamva, nangona kungekho miphumo kwizenzo zokutshaya jikelele ezifunyenweyo. Ezi ziphumo zakwangoko zibonisa ukuba iDCS inokuba luncedo ekunyusweni kweziphumo zonyango lokuchwayita xa uzama ukuyeka ukutshaya. Ngokuchasene noko, olunye uvavanyo lwakutsha nje lubonise ukuba idosi enye ye-DCS iye yavelisa indlela yokunyusa kwiingxelo zekhomishini yokufuna i-cocaine kwi-5 yabantu abaxhomekeke kwicocaine (Price okqhubekayo., 2009). Ixesha lolawulo lweDCS kwizigulana ezifuna unyango zingangqinelana nezi ziphumo zibonakalayo zingafaniyo. Ngokwale migca, kufanelekile ukuba uqaphele ukuba uphononongo lwezilwanyana lwakutsha nje lubonise ukuba ukufakwa kwe-DCS kwi-amygdala ye-basolater ngokwenene kunefuthe lokudityaniswa kwakhona kweenkumbulo ezinxulumene ne-cocaine kwimigudu yokuzilawula ye-cocaine (Lee okqhubekayo., 2009). Ngokucacileyo ngakumbi izifundo ziyafuneka ukuvavanya ukuba iDCS inokuthi inyuse, kunokuba iqhubele phambili ukupheliswa, ukunyanzela ukunganyanzelekanga kwezinto ezinxulumene necocaine. Ukongeza, izifundo kufuneka zenziwe ukufumanisa ukuba ngaba iDCS yonyusa ukuchaneka kokunyangwa ngokubonakalayo kubantu abakhoboka iziyobisi gwenxa ngaphandle kwecocaine okanye i-nicotine, njengoko kunjalo kwizifundo ngeziphumo zeDCS kwinto engeyiyo iziyobisi.

2.4. UGabapentin

2.4.1. Indlela yokuSebenza

IGabapentin iyeza elichasene nesifo esinesithintelo ngokubanzi sokuhanjiswa kwe-neuronal ngokuthintela i-presynaptic voltage-gated Na⁺ kunye Ca²⁺ iziteshi (UDickenson kunye noGhandehari, 2007; Indawo yomhlaba, i-2007; I-Rogawski kunye neLoscher, 2004). Ngenxa yoko, i-gabapentin inqanda ukukhutshwa kwee-neurotransmitters ezahlukeneyo, kubandakanya i-glutamate, njengoko kubonisiwe kwi Umzobo 1 (Ikhowudi okqhubekayo., 2007; Cunningham okqhubekayo., 2004; Dooley okqhubekayo., 2000; Fink okqhubekayo., 2000; Maneuf okqhubekayo., 2004; UManeuf noMcK Night, 2001; UShimoyama okqhubekayo., 2000).

2.4.2. Ukusebenza kweeklinikhi

Izifundo ezininzi zibonakalise ukuba i-gabapentin iyasebenza ekunciphiseni iimpawu ezizodwa zokurhoxisa utywala (cap okqhubekayo., 1999; I-Bozikas okqhubekayo., 2002; UMariani okqhubekayo., 2006; UMartinez-Raga okqhubekayo., 2004; Myrick okqhubekayo., 1998; I-Rustembegovic okqhubekayo., 2004; Voris okqhubekayo., 2003), edla ngokubonisa ngokuphakathi ukuya kwi-CNS hyperexcitability enzulu kunye nokukhuseleka. UGabapentin ikwabonakalisiwe ukuba ingaphezulu kwe-benzodiazepine yelazepam ekunciphiseni ukuphazamiseka kokulala okunxulunyaniswa nokushenxiswa kotywala (Malcolm okqhubekayo., 2007). Okwangoku ukuza kuthi ga ngoku, izifundo zeklinikhi ngokusebenza kakuhle kwonyango lwe-gabapentin ekunciphiseni ukusetyenziswa kweziyobisi, ukuthanda, okanye ukuphinda ubenemiphumo emibi. Izifundo ezininzi zibonakalise ukuba i-gabapentin (enamaqondo e-600-1200 mg / ngosuku) ayikuthothisi ukusetyenziswa kwe-cocaine kubantu abakhobileyo (Bisaga okqhubekayo., 2006; Gonzalez okqhubekayo., 2007), ngelixa ezinye izifundo zibonise ukuba i-gabapentin iyanciphisa ukusetyenziswa kwe-cocaine kunye nokulangazelela (Berger okqhubekayo., 2005; Myrick okqhubekayo., 2001; URaby, 2000; URaby kunye neCoomaraswamy, 2004), mhlawumbi ngokufumana ucalucalulo lweempawu ezikwenza ukuba ube necocaine (Haney okqhubekayo., 2005). Izifundo zamva nje zibonise ukuba i-gabapentin (600-1500 mg / day) iyanciphisa inkanuko kunye nokusetyenziswa kotywala (I-Furieri kunye neNakamura-Palacios, 2007; Mason okqhubekayo., 2009; Myrick okqhubekayo., 2009), kunye nokwandisa ukungabuseli ekusebenziseni utywala kwizifundo ezixhomekeke kuotywala (Brower okqhubekayo., 2008). Nangona kunjalo, abanye abaphandi ababonisanga ziphumo zedosi efanayo ye-gabapentin kulangazelelo lotywala (I-Bisaga kunye no-Evans, 2006; Myrick okqhubekayo., 2007). Ukongeza, kuye kwanikelwa ingxelo yokuba i-gabapentin ayinciphisi ukusetyenziswa kwe-methamphetamine (Heinzerling okqhubekayo., 2006), ineziphumo ezinomda ekukhuthazeni ukuyeka ukutshaya (Mhlophe okqhubekayo., 2005), kwaye ayizibonakalisi iimpawu zokurhoxisa ezihambelana nezifundo kwizifundo ezixhomekeke ku-opiate (Kheirabadi okqhubekayo., 2008). Zidibene kunye, ezi datha zibonisa ukuba i-gabapentin iyasebenza kunyango lweempawu zokurhoxisa isiselo esinxilisayo kwaye inokuba nokusebenza okufanelekileyo kokunciphisa inkanuko yotywala okanye icocaine (nangona kungezizo zonke izifundo ezixhasa lo mbono), kodwa eli yeza alinakho ukubakho koku ukunciphisa umlutha wecuba, i-methamphetamine, okanye ukunciphisa iimpawu zokurhoxisa i-opiate. Ngolwazi lwethu, i-gabapentin ayikavavanywa ukusebenza kakuhle kunyango lweziyobisi zokuziphatha.

2.5. Lamotrigine

2.5.1. Indlela yokuSebenza

Ifana ne-gabapentin, i-lagotrimine sisibulala-ntsholongwane esenza ukuba amandla e-presynaptic voltage-gated Na⁺ kunye Ca²⁺ iziteshi (UDickenson kunye noGhandehari, 2007; Indawo yomhlaba, i-2007; I-Rogawski kunye neLoscher, 2004), ngokwenza oko kuthintele ukukhutshwa kwee-neurotransmitters ezahlukeneyo, kubandakanya i-glutamate (jonga Umzobo 1; Ahmad okqhubekayo., 2004; ICunningham kunye noJones, 2000; Leach okqhubekayo., 1986; Amabala kunye neLeach, 1993; I-Lingamaneni kunye neHemmings, 1999; Sitges okqhubekayo., 2007; Teoh okqhubekayo., 1995; Waldmeier okqhubekayo., 1995, 1996; wang okqhubekayo., 2001). I-Lamotrigine ithwala into engaqhelekanga kodwa inobungozi obukhulu bokubangelwa kukuqhaqha kolusu olunzima, olubizwa ngokuba yiStevens-Johnson Syndrome. Umngcipheko wokuvela kwale mpembelelo yeziphumo ezinokwehliswa ungathotyelwa ngokuthe chu ngokuhamba kancinci kwethamo lokudibanisa, uhlala uqala idosi ye-25 mg / ngosuku kwaye uphontshwe ngeveki ukuya kwiidosi kuluhlu lwe-200-300 mg / ngosuku.

2.5.2. Ukusebenza kweeklinikhi

Njenge-gabapentin, i-lamotrigine inhibit kwiimpawu ezithile zokurhoxisa utywala (I-Krupitsky okqhubekayo., 2007b). Izifundo zamva nje zeklinikhi zibonisa ukuba i-lamotrigine ikwabonakalisa ukusebenza ngokuchanekileyo ekunciphiseni umnqweno wokusebenzisa nokusebenzisa icocaine (Berger okqhubekayo., 2005; Ntsundu okqhubekayo., 2003, 2006; UMargolin okqhubekayo., 1998; I-Pavlovic, i-2011), nangona kubonakala ngathi kushiya iziphumo zecocaine engafakwanga (Ubusuku okqhubekayo., 2000). Iziphumo ezincitshisiweyo ezifanayo ze-lamotrigine ekunqweneleni utywala (Rubio okqhubekayo., 2006) kunye neziyobisi ezihlukumezayo (Shen, 2006) zixeliwe. Ezi ziphumo zibonisa ukuba i-lamotrigine isenokuba yenzuzo yeklinikhi kunyango lokulutha i-cocaine, utywala okanye inhalants. Izifundo malunga nokusebenza okunokwenzeka kwe-lamotrigine kunyango lokuziphatha okanye iziyobisi kwi-opiates, i-nicotine, okanye i-psychostimulants efana ne-methamphetamine iyasilela.

2.6. Imemorine

2.6.1. Indlela yokuSebenza

IMemantine sisichasi esingangqinelaniyo kwi-receptor ye-NMDA (Umzobo 1) kwaye isetyenziswa ikakhulu kunyango lokwehla kwengqondo kwisifo se-Alzheimer's. Ukongeza kwizenzo zayo ezichasayo kwii-receptors ze-NMDA, i-memantine ikwathintela uhlobo lwe-serotonin i-3 receptor (5-HT₃) kunye ne-nicotinic acetylcholine receptors. Nangona ezinye izinto ezixhaphaza izinto ezinjenge phencyclidine, ketamine, dextromethorphan okanye utywala zinezinto ezichasayo kwi-receptor ye-NMDA, imemantine yenye yeembono ezimbalwa zeNMDA receptor ezichaphazeleka kakuhle ngabantu kwaye azibonakali ngathi ziphethe amandla okuxhaphaza (Vosburg okqhubekayo., 2005).

2.6.2. Ukusebenza kweeklinikhi

Ukongeza kokusebenza ngempumelelo ekunciphiseni iimpawu zokurhoxa ekukhuseleni isiselo esinxilisayo (I-Krupitsky okqhubekayo., 2007b) kunye neziyobisi ze-opiate (Bisaga okqhubekayo., 2001), i-memantine (iidosi eziqhelekileyo kuluhlu lwe-30-60 mg / usuku) kuye kwaxelwa ukuba ungaphezulu kwe-placebo ekufumaneni ukusela okuqhubekayo kunye / okanye nokunqwenela utywala kwizifundo ezinotywala (Arias okqhubekayo., 2007; I-Bisaga kunye no-Evans, 2004; I-Krupitsky okqhubekayo., 2007a). Oku kuthandiswa kokunxanelwa isiselo esinxilisayo kunokuba sisiphumo sotywala-njengempembelelo yememantine (I-Bisaga kunye no-Evans, 2004; I-Krupitsky okqhubekayo., 2007a). Nangona kunjalo, uphononongo olukhulu olulawulwa yi-placebo lubonise ukuba i-memantine ayinciphisi indlela yokuziphatha ephucukileyo kwizigulana ezixhomekeke kwiziselo ezinxilisayo (Evans okqhubekayo., 2007). Imemorine ixeliwe ukuba iyanciphisa iziphumo zecuba (ukutshaya)Jackson okqhubekayo., 2009) kunye ne-heroin ye-intravenous (UComer noSullivan, 2007); Nangona kunjalo, ngakumbi kwiidosi eziphezulu, i-memantine inokunyusa ukungqinelana kunye neziphumo zeentliziyo kunye necocaine (Collins okqhubekayo., 1998, 2007). Ngokudibeneyo, ezi datha zibonisa ukuba i-memantine inokuba yinto enokusetyenziswa ekukhutshweni kwabaguli- okanye abaguli abaxhomekeke ku-opoate, kwaye mhlawumbi njenge-adjunct ye-pharmacological kunyango lotywala. Nangona kunjalo, ukusebenza kwayo okunokubakho kokunyanga umlutha kwezinye iziyobisi zokuxhatshazwa kuhlala kungaziwa, kwaye kubonakala ngathi kungangqinwa ukuba kunganyangwa i-cocaine. Nangona kunjalo, uphononongo oluvulekileyo lweleyibheli oluvulekileyo lubonise ukuba i-memantine inciphise amanqaku e-PG-YBOCS kunye nexesha elichithwe ukungcakaza kwi-29 ye-pathological gamblers (Grant okqhubekayo., 2010b), ephakamisa ukuba i-memantine inokuba yeyokusetyenziswa kwonyango lweziyobisi ezinjengokugembula kwengqondo.

2.7. Imodafinil

2.7.1. Indlela yokuSebenza

I-Modafinil yinto ekhuthazayo ye-CNS kwasekuqaleni eyenzelwe ukomeleza ukuphaphama nokunyanga kunyango lwe-narcolepsy kunye nokulala kakhulu ngexesha lokulala okubangelwa yi-apnea yokulala okanye ukufuduka. I-Modafinil ngamanye amaxesha imiselwa njengonyango lwe-off-ilebula yokujongwa kwengxaki / ukuphazamiseka kwengqondo. Nangona iinkqubo zayo zentshukumo ye-neuropharmacological yesenzo ingekaqondwa ngokupheleleyo, imodafinil ayibonakali isebenza njengento evuselelayo ye-monoamine njengoko kunjalo kwiimvuseleli-ezinjengee-amphetamine. Endaweni yoko, i-modafinil inokuthi isebenze ngokuvuselela i-α-adrenoceptors, ngokunyanzela ukukhutshwa kwe-GABA, ukuthintela ukuhanjiswa kwe-dopamine, okanye ukuvuselela i-neurothalamic orexin-equkethe i-neurons (I-Ballon kunye ne-Feifel, i-2006; UMartinez-Raga okqhubekayo., 2008). Ezinye iindlela zokwenza isenzo ezixeliweyo zibandakanya ukunciphisa ukujikeleza kweeradicals zasimahla kunye ne-cytotoxicity ebangelwa kukupheliswa kokulala (UGerrard noMalcolm, 2007). Ngelixa uninzi lwezifundo licebisa isiseko sedopaminergic yeziphumo zayo ezibi (Andersen okqhubekayo., 2010; Volkow okqhubekayo., 2009; Ubulumko kunye no-Eriksson, 2005), i-modafinil ibonakalisiwe ukuba iphakamise amanqanaba angaphezulu kwe-glutamate kwimimandla emininzi yobuchopho kubandakanya i-dorsal striatum, hippocampus kunye ne-diencephalon (bona Umzobo 1) (UFerraro okqhubekayo., 1997, 1998, 1999) ngaphandle kokuchaphazela ukwakheka kwe glutamate (UPerez de la Mora okqhubekayo., 1999). I-Modafinil ithathwa njengenganamandla okuxhatshazwa okuphantsi (UMartinez-Raga okqhubekayo., 2008), nangona iingxelo zokuxhatshazwa zinokubakho kumthamo omkhulu (Andersen okqhubekayo., 2010) kunye nosetyenziso olungalunganga lonyango luyanda (I-Ballon kunye ne-Feifel, i-2006). Ngenxa yoko i-modafinil okwangoku ihlelwa njengesihedyuli IV elawulwa yinto eyiDrug Enforuction Administration. Iidosi ezisebenzayo zeklinik zemodafinil ziqhelekileyo kuluhlu lwe-200-400 mg / ngosuku.

2.7.2. Ukusebenza kweeklinikhi

Iingxelo ezininzi zekliniki zibonise ukuba imodafinil ibonakalisa ukusebenza kakuhle kunyango lwecocaine.UMartinez-Raga okqhubekayo., 2008). Kwisifundo esincinci esilawulwa yi-placebo esilawulwa ngokusetyenziswa kweziyobisi nguDackis kunye nabalingane, kwaxelwa ukuba i-modafinil (200 mg / ngosuku) igxeka iimpembelelo ze-euphorigenic ye-intravenous cocaine kwikhobokisa i-cocaine (Dackis okqhubekayo., 2003), kwaye ezi zinto zifunyanisiweyo kamva zaphindwa ngokuzimeleyo (Malcolm okqhubekayo., 2006). Uphononongo olugwetywe kabini olawulwa ngamehlo ngendlela engacacanga kunyango oluxhomekeke ngaphandle kwecocaine lubonisa ukuba imodafinil (400 mg / usuku) iyanciphisa kakhulu ukusetyenziswa kwecocaine yemihla ngemihla kunye nokuyekisa ixesha elide (Dackis okqhubekayo., 2005). Uvavanyo lweklinikhi lwamaziko amaninzi olutsha lufumanise ukuba imodafinil iyanciphisa ukusetyenziswa kwe-cocaine kunye nokulangazelela kwizifundo ezixhomekeke kwi-cocaine ngaphandle kokuxhomekeka kwi-co-morbid.Anderson okqhubekayo., 2009). Nangona ezi datha zibonisa ukuba i-modafinil inokuba isetyenziswa kunyango lwe-cocaine, kunokwenzeka ukuba ezinye zeziphumo ezinokubakho ngenxa yokuncipha kwe-plasma ye-cocaine ye-cocaine ebukho bemodafinil (Donovan okqhubekayo., 2005). I-Modafinil ivelise neendlela ezingancumisiyo zokunciphisa ekusetyenzisweni kwe-methamphetamine esebenzayo phakathi kwabasebenzisa kakubi eli chiza (Shearer okqhubekayo., 2009), kunye nokwehliswa kweendlela zokuziphatha ngokungcakaza ekungcakazeni okungenabungozi.I-Zack kunye nePoulos, 2009). Ngaphandle kwezi ziphumo ezilungileyo ezibonakalisa amandla e-modafinil ekunyangeni amakhoboka e-psychostimulant kunye nokugembula, uphononongo lwakutsha nje lubonise ukuba imodafinil ayisebenzi ekunciphiseni ukutshaya kwaye ichaza kakhulu ukurhoxa kunye nefuthe elibi kunakwabaphethi be-placebo.Schnoll okqhubekayo., 2008). Ke, imodafinil ibonakala ngathi ayikulungelanga ukusetyenziswa kunyango lokuyeka ukutshaya.

Ukusuka kwimbono ye-neurochemical, kuyadida ukuba kutheni ichiza elifana ne-modafinil, elonyusa amanqanaba e-glutamate angaphandle, kukhokelela ekunciphiseni ekutyeni i-cocaine, ngenxa yezifundo ezininzi zezilwanyana zibonise ukuba ukuvalwa kwe-glutamatergic neurotransmission (okt ngolawulo lwe-ionotropic I-glutamate receptor antagonists, postynaptic mGluR antagonists, or presynaptic mGluR2 / 3 agonists that suppress ukukhutshwa kwe glutamate) kunciphisa ukuqiniswa kwe-cocaine kunye / okanye ukubuyiselwa kwakhona kwendlela yokuziphatha efuna i-cocaine (IGass kunye neOlive, 2008; Kalivas okqhubekayo., 2009; I-Knackstedt kunye neKalivas, 2009; Olive, 2009; I-Tzschentke kunye neSchmidt, 2003). Enye yeengcinga ezinokubakho zendlela yokusebenza kwe-modafinil ekunciphiseni umnqweno wecocaine kukumisela ukunciphisa ukuncipha kwe-glutamate engaphandle eqatshelwe kwi-nucleus accumbens ngexesha lokurhoxiswa kwecocaine, kunye nokunciphisa amandla e-cocaine okanye iindlela ezinxulumene necocaine zokuvuselela umnqweno (ofana indlela yokusebenza ye-NAC - Umzobo 1). Izifundo ezongezelelweyo ziyafuneka ukuvavanya le hypothesis.

2.8. I-Topiramate

2.8.1. Indlela yokuSebenza

I-Topiramate, njengazo ezinye ii-anticonvulsants kubandakanya i-gabapentin kunye ne-lamotrigine, ineendlela ezahlukeneyo zesenzo, kubandakanya ukuthintela amandla e-presynaptic voltage-gated Na⁺ kunye Ca²⁺ Iindlela (ezithi zithintele ukukhutshwa kwee-neurotransmitters kubandakanywa i-glutamate) kunye nokusebenza kohlobo lwe-A GABA (GABA)_A) ii-receptors (UDickenson kunye noGhandehari, 2007; Indawo yomhlaba, i-2007; I-Rogawski kunye neLoscher, 2004). Ukongeza, kutshanje kuboniswe ukuba i-topiramate ikwangumchasi kwi-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors equlathe i-GluR5 subunit (Umzobo 1) (I-Gryder kunye neRogawski, 2003; Kaminski okqhubekayo., 2004). La manyathelo kwimisebenzi ye-receptor ye-AMPA anomdla ngokukodwa kuba le glutamate receptor subtype ibonakaliswe kakhulu kwiinguqu ezinomtsalane eziveliswa ngamachiza okuphatha gadalala kunye nokulamla ukuzilawula kwamachiza kunye nokuziphatha okufana nokuziphatha.Bowers okqhubekayo., 2010; IGass kunye neOlive, 2008; Niehaus okqhubekayo., 2009; I-Xi kunye noGardner, 2008). Iidosi eziqhelekileyo ezisebenzayo zodidi oluphezulu ukusuka kwi75-350 mg / ngosuku.

2.8.2. Ukusebenza kweeklinikhi

Ukongeza kwi-attenuation yeempawu zokurhoxisa utywala ezifanayo nezo zibonwa nge-gabapentin kunye ne-lamotrigine (I-Krupitsky okqhubekayo., 2007b), i-topiramate isenokuncedisa ekuzonwabiseni kweempawu zokurhoxiswa kwe-benzodiazepine (IMichopoulos okqhubekayo., 2006). Izifundo ezininzi zipapashiwe kule minyaka ilishumi idlulileyo zibonisa ukusebenza ngokugqibeleleyo kwe-topiramate ekunikezeleni iziphumo zotywala, inkanuko yotywala, kunye nokusela kakhulu kwizigulana ezinotywala (UAnderson no-Oliver, 2003; Johnson okqhubekayo., 2004; Kenna okqhubekayo., 2009; Komanduri, 2003; Ma okqhubekayo., 2006; Miranda okqhubekayo., 2008; Rubio okqhubekayo., 2004). Amandla e-topiramate yokunciphisa ukusela okunyanzelisayo kunokuba ngenxa yesakhono sako sokuguqula ukungathandeki kunye nokuphucula ukuthintelwa kokuziphatha (Rubio okqhubekayo., 2009). Olunye uphononongo luye lwafumanisa ukuba i-topiramate ingaphezulu kune "mgangatho wegolide" amachiza alwa notywala kwi-aktrexone ekwandiseni ukuzikhupha emzimbeni nasekunciphiseni ukusela nokubuyela umva (Ibhaltieri okqhubekayo., 2008). Ke, i-topiramate ibonakala iyeza elithembisayo lonyango olusetyenziswayo kunyango lotywala.

Ngokumalunga nezinye iziyobisi zokuxhatshazwa, i-topiramate ibonakalisiwe ukunciphisa ukusetyenziswa kwe-cocaine kunye nokulangazelela abantu abaxhomekeke kwi-cocaine (Kampman okqhubekayo., 2004; Reis okqhubekayo., 2008), nangona kunjalo isayizi encinci yesampulu yezi zifundo zibini zeklinikhi iyathintela (Minozzi okqhubekayo., 2008). Ingxelo yetyala ichaze ukuba i-topiramate inciphisa ukusetyenziswa kwe-methylenedioxymethamphetaine (MDMA, "Ecstasy") (Akhondzadeh kunye neHampa, 2005). Kwabantu abatshayayo, abanye abafundileyo baye babonisa iziphumo ezincumisayo zesiraphu enokukhuthaza ukungabhemi ukutshaya okanye ukunciphisa imeko yokutshaya (I-Arbaizar okqhubekayo., 2008; Johnson okqhubekayo., 2005; Khazaal okqhubekayo., 2006). Amandla topiramate yokwandisa ixesha lokungatshayi inokubhekiswa ngqo kwisini, kunye neempendulo ezinkulu emadodeni (UAnthenelli okqhubekayo., 2008). Nangona kunjalo, olunye uphando lwafumanisa ukuba, ngokufana ne-lamotrigine, i-topiramate yonyusa imiphumo ye-subjential yokuyeka ukutshaya kunye neziphumo ezinomvuzo zecuba elitshayiweyo kwaye azichaphazelanga umnqweno we-cue-indased (Reid okqhubekayo., 2007), ukubuza malunga nokusetyenziswa kwe-topiramate njengoncedo lokuyeka ukutshaya. Ngokunjalo, i-topiramate iboniswe ukuba iphucula iimvakalelo ezintle ezenziwa yi-methamphetamine (Johnson okqhubekayo., 2007). Ke ngoko, i-topiramate inokubamba isithembiso sokunceda kunyango lwe-alcohol alcohol kunye ne-cocaine kunye ne-nicotine, kodwa izifundo ezininzi ziyafuneka ukuvavanya amandla ayo njengezonyango zokunyanga umlutha kwamanye amachiza okuphatha gadalala.

Ngokumalunga nokuziphatha gwenxa, iqela lezifundo ezincinci kunye neengxelo zamatyala ziye zapapashwa kwiminyaka yakutshanje zibonisa ukuba i-topiramate ingaluncedo kakhulu kunyango lwezi ziphazamiso. Ukuza kuthi ga ngoku, iziphumo ezilungileyo ze-topiramate ziqaphelekile ekunciphiseni ukubuyela ekungcwabeni kwengxaki (Dannon okqhubekayo., 2007) kunye nokunciphisa ukutya okunyanzelayo kunye nokuziphatha ngokwesondo (Fong okqhubekayo., 2005; I-Khazaal kunye neZullino, i-2006; Utata kunye noKockler, 2006). Ngokucacileyo le ndlela yokunyanga iziyobisi ezingekho iziyobisi ifuna ukuphononongwa ngakumbi.

3. Isishwankathelo kunye neziphetho

Ngokumalunga namayeza asibhozo aqwalaselweyo apha anendlela yokusebenza ye-glutamatergic yesenzo (i-acamprosate, NAC, DCS, gabapentin, lamotrigine, memantine, modafinil, kunye ne-topiramate), sigqiba kwelokuba i-NAC, modafinil, kunye ne-topiramate zezona zibhalwe kakuhle kwaye eyona nto inokusetyenziswa ekunyangeni iziyobisi nasekuziphatheni. Ngokuqinisekileyo naluphi na amayeza aqwalaselweyo apha ayisiyi kuba luphawu lazo zonke iziyobisi, kodwa kunokwenzeka ukuba luncedo olusebenzayo lwezechiza kunyango oluqhelekileyo lomntu ngamnye okanye iindlela zonyango lokunyanga ngeendlela zokunyanga umlutha kumachiza athile okuhlukumeza (ngakumbi ikotywala kunye notywala) kunye iziyobisi ezingezizo iziyobisi (ngakumbi ukugembula komzimba). Idityaniswe kunye nomgangatho wokufumana kwakhona okanye umvavanyo osekwe kwimilinganiselo yokuchonga amaqobelo ezinto ezizezinye ezinokuthi zisabele ngokuncomekayo kunyango olunye okanye kolunye, zimbalwa iziphumo ebezingalindelekanga ezimbi, ixesha le-post-genomic lanamhlanje ngethemba lokuvumela abaphandi kunye noochwephesha basebenzise amayeza iindlela zokuchonga ezinokuthi ziphendule kunye nabantu abangaphenduliyo kula mayeza ngaphambi kokuqalisa unyango. Inani elilinganiselweyo ledatha elikhoyo kwezinye zezi komatshini, ezinjenge-DCS kunye ne-lamotrigine, iziqinisekiso ezikhulu zokwenza izifundo zamaziko amaninzi. Ukongeza, uphando olwandayo kunye neemodeli ezifanelekileyo zezilwanyana kwiindlela ezichanekileyo ze-glutamatergic ezichaphazela iindlela ezahlukeneyo zomjikelezo weziyobisi (okt, ukusebenzisa iziyobisi ngokunyanzelekileyo, ukurhoxa, ukuthanda, ukujonga iziyobisi, kunye nokubuyela umva kwakhona) kuya kukhokelela kwiindlela ezisebenzayo zekhemistiki. ingasetyenziselwa ukungenelela kumanqanaba athile okulutha.

Imibulelo

Ababhali bangathanda ukubulela uKatie Ris-Vicari ngoncedo lobugcisa. Lo msebenzi uxhaswe zi-NIH izibonelelo ze-DA024355, DA025606, kunye ne-AA013852 (MFO).

Imihlathi

Iphepha elichazayo ukuba awusenanto oyifunayo: Le fayili yeFayile yombhalo wesandla ongabhalwanga owamkelwe ukushicilelwa. Njengenkonzo kumakhasimende ethu sinika le ngcaciso yokuqala kwincwadi yesandla. Umbhalo wesandla uza kufumana ukukopishwa, ukufakela, nokuphonononga ubungqina obunokubakho ngaphambi kokuba kukhutshwe kwifomu yayo yokugqibela. Nceda uqaphele ukuba ngexesha lokuveliswa kweeprogram ezinokuthi zifumaneke ezinokuthi ziphazamise umxholo, kunye nazo zonke izisemthethweni ezichasayo ezisetyenziswa kwiphephancwadi.

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