Imethylene blue kudakumba nakwixhala: izilingo, imida, nomngcipheko wokusebenzisana kwamayeza

Imethylene blue ibinikwa izigulana zengqondo ukususela kwiminyaka yoo-1890, ivavanywa kwizilingo ezilawulwayo ukususela kwiminyaka yoo-1980, yaye iphandwa kwiimodeli zezilwanyana ezivelisa iigophe ezicace ngokungaqhelekanga zobudlelwane phakathi kwedosi nesiphumo. Umfundi okhangela “imethylene blue nodakumba” ufumana zontathu ezi ntlobo zobungqina zixutywe, kungekho mibhalo izahlulayo.

Kubalulekile ukuzahlula. Bonke ubungqina obulawulwayo ebantwini obuphathelele imo yeemvakalelo buvela kwizilingo ezimbini nakumfuniselo omnye wokuvezwa koko koyikwayo elebhu, yaye zombini izilingo ezibhalisiweyo zagqitywa ngaphezu kweminyaka elishumi eyadlulayo. Eli nqaku lichaza oko kwafunyanwa sisilingo ngasinye. Alicebisi imethylene blue njengonyango lwengxaki yemo yeemvakalelo.

Isizathu sokuba idayi ingene kuncwadi lwemo yeemvakalelo

Imethylene blue yaba yikhompawundi yokuqala eyenziwe ngokupheleleyo ngokwenziwa eyasetyenziswa njengeyeza. IMonoamine oxidase A, efinyezwa ngokuthi MAO-A, iqhekeza iserotonin, yaye amayeza ayithintelayo ngamayeza avunyiweyo okunyanga udakumba. URamsay, uDunford, noGillman balinganisa isiphumo kwiMAO-A yomntu ecocekisiweyo baza baxela ixabiso elingaguqukiyo lokuthintela elikufutshane ne-27 nanomolar, ngokuthintela okubuyisekayo. IMAO-B yayifuna uxinaniso olungaphezu kwamashumi amahlanu olwalufunwa yiMAO-A. Kwaloo molekyuli ikwathintela initric oxide synthase neguanylate cyclase, nto leyo eyenza ukuba uphononongo luka-2017 lukaDelport noogxa bakhe luchaze isenzo sokulwa udakumba njengesenziwa kwiindawo ekujoliswe kuzo ezininzi, kungekhona njengesiphumo somamkeli omnye.

Oku kucacisa isizathu sokuba uncwadi lwezilwanyana luthembise kodwa lube nokungaqheleki. Kwiimpuku, imethylene blue ivelisa indlela yokuziphatha efana naleyo ibangelwa ngamayeza okulwa udakumba kuvavanyo lokuqubha okunyanzelekileyo kuphela ngaphakathi koluhlu oluthile lweedosi: uEroglu noCaglayan bafumana iziphumo phakathi kwe-15 ne-30 mg/kg, kodwa kungekho nasinye kwi-60 mg/kg, yaye indlela yokuziphatha yokuncipha kwexhala nayo yabonisa igophe elifanayo lika-U ojikisiweyo. Ukufaka ngenaliti inani elincinane kwindawo engwevu engasemva ejikeleze umjelo wengqondo kwasebenza kwi-30 nanomoles kodwa akuzange kusebenze ngaphandle kolo luhlu. Le yihormesis, yaye igophe elinjalo alinakwandiselwa kwiidosi eziphezulu ngokuthelekelela.

Izilingo zeminyaka yoo-1980 nedosi yeplacebo ekusenokwenzeka ukuba yayingeyiyo iplacebo

UNaylor noogxa bakhe baqhuba isilingo seminyaka emibini sokutshintshiselana ngonyango, esifihliwe macala omabini kwizigulana ezingama-31 ezinengxaki yebipolar, bethelekisa i-300 mg ngosuku ne-15 mg ngosuku ngoxa ilithium yayiqhubeka. Ezilishumi elinesixhenxe zasigqiba, yaye udakumba lwalungaphantsi kakhulu kwidosi ephezulu.

Uyilo lunengxaki ekufanele iqondwe, kuba iphinda ivele. Kwakhethwa i-15 milligrams ngosuku njengeqela le-“placebo” kucingelwa ukuba ayinampembelelo. Emva koko ababhali babhala “amathandabuzo abo malunga nokufihlwa konyango, nokungaqiniseki malunga nokuba i-15 mg yemethylene blue ngosuku inokuthathwa njengeplacebo kusini na.” Imethylene blue itshintsha umbala womchamo ube luhlaza okwesibhakabhaka oluxutywe noluhlaza, ngoko sonke isigulana esasikwisilingo sokutshintshiselana ngonyango sasithatha idayi ebonakalisa ukusebenza ngawo omabini amaxesha. Ukuba idosi ephantsi yayingenzi nto kwakungeyonyaniso, isilingo sasithelekisa iidosi ezimbini ezisebenzayo.

Isilingo esifutshane savavanya i-15 mg ngosuku xa ithelekiswa neplacebo yokwenene kwizigulana ezinodakumba olunzima kangangeeveki ezintathu, kwizigulana ezingama-35, saza safumana ukuphucuka okukhulu ngakumbi kwimethylene blue. Iiveki ezintathu nezigulana ezingamashumi amathathu anesihlanu zinika umqondiso wokwenene, kodwa omncinane.

Isilingo sebipolar sokutshintshiselana ngonyango: obona bungqina bunamandla ebantwini

Esona silingo sinika ulwazi oluninzi luphando luka-2017 lukaAlda noogxa bakhe, olubhaliswe njengeNCT00214877. Kwakukho abathathi-nxaxheba abangamashumi amathathu anesixhenxe abanengxaki yebipolar I okanye II, bonke bethatha ilamotrigine njengeyeza labo eliphambili lokuzinzisa imo yeemvakalelo, uninzi luneempawu ezishiyekileyo ezingephi okanye eziphakathi. Uyilo lwalukukutshintshiselana ngonyango okufihliwe macala omabini: i-15 mg ngosuku kangangeenyanga ezintathu xa ithelekiswa ne-195 mg ngosuku kangangeenyanga ezintathu, ngokulandelelana okukhethwe ngokungakhethiyo. Ababhali bachaza ngokucacileyo isizathu sokusebenzisa idosi ephantsi njengento yokuthelekisa: “Sakhetha olu yilo kuba imethylene blue itshintsha umbala womchamo, ngoko sasingenakusebenzisa iplacebo yesiqhelo.”

Kuhlalutyo lwezigulana ezingama-27 ezasigqibayo:

• Udakumba lwaphucuka ngakumbi kwidosi ephezulu, ngobungakanani besiphumo obuyi-0.71 kwiSikali sikaHamilton sokuLinganisela Udakumba (95% CI 0.15 ukuya ku-1.25, P = 0.034) nobuyi-0.80 kwiSikali sikaMontgomery-Asberg sokuLinganisela Udakumba (95% CI 0.27 ukuya ku-1.30, P = 0.020).
• Ixhala laphucuka ngakumbi kwidosi ephezulu, ngobungakanani besiphumo obuyi-0.79 kwiSikali sikaHamilton sokuLinganisela Ixhala (95% CI 0.22 ukuya ku-1.33, P = 0.028). Imiba yexhala lengqondo yayiqhuba isiphumo; ixhala elibonakala emzimbeni lafikelela ekubalulekeni ngokweenkcukacha-manani kuphela kuhlalutyo olubandakanya bonke ababelungiselelwe unyango.
• Iimpawu zemania zahlala ziphantsi kwaye zizinzile, kungekho kutshintshela kwihypomania okanye kwimania.
• Ukuqonda akuzange kutshintshe nakuwuphi na wemisebenzi emithandathu, kuquka ukufunda amagama, ukusebenza kolawulo lwengqondo, nenkumbulo yokukhumbula.

Abalishumi kwabangama-37 barhoxa, omnye ngenxa yomchamo oluhlaza okwesibhakabhaka, omnye ngenxa yokwanda kwexhala, nomnye emva kokuba imeko yakhe yaba mandundu ngokwezonyango. Iziphumo ebezingalindelekanga zazizezexeshana kwaye zingephi, ubukhulu becala kukutshisa kwindlela yomchamo, urhudo, isicaphucaphu, nentloko ebuhlungu. Phakathi kwabathathi-nxaxheba abangama-20 nabangama-27 babethatha iyeza lokulwa udakumba okanye iyeza lokulwa ipsychosis ngalo lonke ixesha, yaye isilingo asizange sixele ubuthi beserotonin.

Eli qela lalingenalo udakumba olunzima. Amanqaku okuqala ayeyi-12.7 kwisikali sikaMontgomery-Asberg, esifikelela kuma-60, ne-7.6 kwisikali sikaHamilton esinemiba eli-17: ezi yayiziimpawu ezishiyekileyo kwizigulana ezizinzisiweyo, kungekhona ingxaki yodakumba olukhulu. Uphononongo olucwangcisiweyo oluzimeleyo luka-2021 lonyango lwexhala kwingxaki yebipolar eneempawu ezidambileyo lubala esi silingo njengolunye lwezifundo ezimbini kuphela zamayeza ezinesiphumo esilungileyo kwixhala, kwizilingo ezilishumi zokwabiwa ngokungakhethiyo eziphononongiweyo, yaye luphawula ukuba ukurhoxa okuninzi neziphumo ebezingalindelekanga eziphawulekayo kusenokuba kubeke esichengeni ukufihlwa konyango.

Umfuniselo omnye olawulwayo wexhala ebantwini

Umfuniselo wokuqala olawulwayo ebantwini wemethylene blue nexhala wawungesosilingo sonyango, kodwa wawungumfuniselo wokomelezwa kwenkumbulo. UTelch noogxa bakhe baqokelela abantu abadala abanoloyiko olukhulu lweendawo ezivaliweyo, ngamnye kubo wagqiba izilingo ezintandathu zemizuzu emihlanu zokuvezwa koko koyikwayo kwigumbi elivaliweyo. Kanye emva koko, kwaye kuphela emva koko, bafumana i-260 mg yemethylene blue okanye iplacebo, ngendlela efihliwe macala omabini. Ukuvavanywa kwakhona emva kwenyanga kwigumbi elahlukileyo kwalinganisa ukuba uloyiko lwalubuyile na.

Isiphumo salahlula iqela. Abathathi-nxaxheba abagqiba iseshoni yokuvezwa benoloyiko oluncinane bagcina loo mpumelelo ngcono kakhulu kwimethylene blue, ngoxa abo bayigqiba besoyika benza kakubi ngakumbi kunabo babekwiplacebo. Iyeza libonakala likhulisa nakuphi na ukufunda okwenzekileyo, ngoko iseshoni eyomeleza uloyiko yavelisa uloyiko olungakumbi. Inkumbulo yomxholo yaphucuka nokuba kwakunjani, nto leyo eqinisekisa ukuba iyeza lafikelela engqondweni. Idosi efanayo kwinkqubo efanayo yavelisa iziphumo ezichaseneyo ngokuxhomekeke kwinto enye, engumxholo wenqaku elithi isizathu sokuba umgangatho weseshoni yokuvezwa koko koyikwayo ugqibe esi siphumo.

Isilingo sePTSD nesigqibo esizimeleyo

Uphando olulandelayo olukhulu yayisisilingo sikaZoellner noogxa bakhe sokwabiwa ngokungakhethiyo kwiPTSD engapheliyo, esibhaliswe njengeNCT01188694. Izigulana ezingamashumi amane anesibini zafumana iiseshoni ezintlanu zemihla ngemihla zokuvezwa koko koyikwayo ngentelekelelo, zilandelwa yi-260 mg yemethylene blue; okanye ishedyuli efanayo ilandelwa yiplacebo; okanye zafakwa kuluhlu lokulinda olwathi kamva lwafumana unyango oluqhelekileyo lokuvezwa ixesha elide.

Kwisiphumo esiphambili, iSikali seeMpawu zePTSD esilinganiswe ngumvavanyi ozimeleyo, imethylene blue ayizange yahluke kwiplacebo. Iziphumo ezipapashwe kwirejista zibonisa amanqaku asemva konyango ayi-17.10 kwimethylene blue xa kuthelekiswa ne-14.67 kwiplacebo, omabini ephucukile ukusuka malunga nama-32 ekuqaleni. Umahluko wawuthanda iplacebo.

Iziphumo ezimbini zesibini zaya kwelinye icala. Izigulana ezininzi ngakumbi ezazik kwimethylene blue zalinganiswa njengabantu abaphendulayo kunyango, ngenani elifunekayo lokunyanga eliyi-7.5, yaye umgangatho wobomi waphucuka ngobungakanani besiphumo obuyi-0.58. Inzuzo yayixhomekeke kumthamo wenkumbulo esebenzayo kunokuba ixhomekeke kutshintsho kwiinkolelo eziphathelele ukwenzakala kwengqondo.

Emva koko uphononongo olucwangcisiweyo luka-2023 lokuguqulwa kwenkumbulo ngamayeza kunyango lwengqondo olujolise kukwenzakala kwengqondo lwabeka imethylene blue phakathi kwezinto ezingazange zibonise siphumo sibalulekileyo ekunciphiseni iimpawu zePTSD. Leyo yindlela yangoku ezimeleyo yokutolika ubungqina: ayiphikiswanga ngokupheleleyo, ayikaqinisekiswa, kwaye ayinamandla aneleyo okusetyenziswa ngaphandle kwenkqubo yophando.

Yintoni eyahlula amaqela afundiweyo

Funda ikholamu yokugqibela uyithelekisa neyesibini, kungekhona nesishwankathelo sophando.

Akukho nasinye kwezi zilingo esavavanya imethylene blue njengonyango oluzimeleyo lwengxaki yodakumba olukhulu, yaye iClinicalTrials.gov ayidwelisi phando longenelelo lutsha lwengxaki yodakumba okanye yexhala olwenziwa emva kwezi zimbini zingasentla, ezabhaliswa ngo-2003 nango-2009. Nabani na ochaza imethylene blue njengeyeza lokulwa udakumba eliqinisekisiweyo uchaza ingcamango enendlela yokusebenza esengqiqweni nesilingo esinye esincinane esinesiphumo esilungileyo esiyixhasayo. Akukho silingo sixele ukutshintshela kwimania.

Umngcipheko wokusebenzisana kwamayeza sisizathu sokulumka

Imethylene blue ithintela iMAO-A. Yiloo nto eyenza ibe nomdla kwimo yeemvakalelo, yaye ikwayiyo eyenza ibe yingozi xa isetyenziswa namanye amayeza achaphazela iserotonin, kuquka uninzi lwamayeza okulwa udakumba. Isithinteli seMAO esongezwa kwisithinteli sokufunxwa kwakhona sonyusa ukusebenza kweserotonin ngeendlela ezimbini ezahlukeneyo, yaye ukudityaniswa kwawo kunokubangela ubuthi beserotonin, obunokubulala ngamanye amaxesha.

Imveliso efakwa emthanjeni inesilumkiso esikwibhokisi ngale nto. I-FDA yalumkisa ngokusebenzisana kwamayeza ngo-2011 yaza kamva yagxininisa ngakumbi ekufakweni emthanjeni nakumayeza athile okulwa udakumba. Imethylene blue ikwasisithako kwezinye iimveliso zokunciphisa iintlungu zendlela yomchamo, nto leyo eyakhokelela ubuncinane kwisiganeko esinye sokuthathwa ngomlomo kwisigulana esasithatha amayeza aliqela achaphazela iserotonin. Isikhokelo sokusebenzisana kwamayeza sicazulula umngcipheko ngokodidi lwechiza nendlela elifakwa ngayo emzimbeni.

Akukho nasinye kwezi zilingo zemo yeemvakalelo esiphikisa le nkxalabo, kodwa akukho nasinye esiyigqibayo. Zombini zenziwa kwizigulana ezazithatha ubukhulu becala amanye amayeza engqondo, yaye akukho nasinye esixele ubuthi beserotonin. Oku kuyakhuthaza kwizilingo ezincinane, ezibekwe esweni, ezikhuphela ngaphandle abantu abathile, kodwa akubonisi mda wokhuseleko wokudibanisa amayeza ngokwakho. Ubuthi beserotonin bubonakala njengokuphazamiseka okanye ukudideka, umkhuhlane okanye ukubila kakhulu, ukubetha kwentliziyo ngokukhawuleza, ukungcangcazela, ukuqina kwezihlunu, nokuxhuzula okungalawulwayo, yaye asiyomeko yokuzivavanya ekhaya.

Umgangatho wemveliso ungena njani kule nto

Iibhotile ezimbini ezineleyibhile efanayo zinokwahluka ngokwezinye izinto ezikhoyo ngaphakathi. Ukuhambelana nemonografi yeUSP yinto anokuyijonga umthengi, yaye imveliso engahambelaniyo nayo kusenokwenzeka ukuba yimpahla yodidi lokusetyenziswa kumalaphu, enokuthwala ukungcola kwezinto eziphilayo ezifana neAzure B neAzure C, izinyibilikisi ezishiyekileyo, nezinyithi ezinzima kumanqanaba abekelwa imida yimigangatho yamayeza.

Uninzi lwabathengisi abasebenzisa ibinzana elithi “ivavanywe liqela lesithathu” bavavanya izinyithi ezinzima kuphela, baze babonise elo qela linye leemvavanyo ngokungathi lihlangabezana nayo yonke imigangatho. IBlupreme ivavanya zonke iimfuno zeUSP: ukuchongwa kwento, ukucoceka, ukungcola kwezinto eziphilayo, izinyibilikisi ezishiyekileyo, ukungcola kweziqalelo, intsalela emva kokutshiswa, imida yeentsholongwane, nee-endotoxin zebhaktheriya, yaye ipapasha isatifikethi sohlalutyo kwibhetshi nganye. Ukusifunda ngokuchanekileyo kuthetha ukujonga inombolo yebhetshi, ilebhu, iindlela, nemida, kunokukhangela nje uphawu lokuphumelela.

Isigqibo esinyanisekileyo

Isilingo sebipolar sinika obona bungqina bunamandla ebantwini, yaye sibonisa isiphumo esiphakathi sonyango olongezelelekileyo kwiimpawu ezishiyekileyo kwiqela elizinzisiweyo elineempawu ezingephi. Isilingo sodakumba olunzima sithathe iiveki ezintathu saza sabandakanya izigulana ezingamashumi amathathu anesihlanu. Umfuniselo woloyiko lweendawo ezivaliweyo ubonisa isiphumo sokwenene sokomelezwa kwenkumbulo esinokusebenza nakweliphi na icala. Isilingo sePTSD asizange siphinde sifumane isiphumo kwisiphumo saso esiphambili. Akukho nto ivavanyiweyo ukusukela ngoko.

Yiloo nto ibonakala ngayo indlela yokusebenza ethembisayo ngaphambi kokuba ibe lunyango, yaye ikwayiloo nto ibonakala ngayo xa ikhompawundi ithengiswa ngamandla endlela yayo yokusebenza endaweni yeziphumo zayo. Ukuba uthatha iyeza elimiselweyo lokulwa udakumba, isithinteli seMAO, iopioid, okanye naliphi na elinye iyeza elichaphazela iserotonin, olo luhlu kufuneka lube sekuqaleni kwengxoxo, ngaphambi kwawo nawuphi na umbuzo wedosi. Ithala elipheleleyo lophando lidwelisa izilingo nezifundo zemifuniselo ezixhasa la mabango. Qala ngesishwankathelo seziphumo ebezingalindelekanga neemeko ezingavumeli ukusetyenziswa kunye nophononongo lwento exhaswa luphando ebantwini, uze ufunde ubungqina obuphathelele ngokukodwa ingxaki yebipolar ukuba leyo yimeko efunyaniswe kuwe. Musa ukuyeka iyeza elimiselweyo ukuze wenze indawo yeliyeza lisalingwayo.