I-methylene blue yokucindezeleka nokukhathazeka: izivivinyo, imikhawulo, nobungozi bokusebenzisana kwemithi

I-methylene blue ibinikezwa iziguli ezinokuphazamiseka kwengqondo kusukela ngeminyaka yawo-1890, ihlolwa ezivivinyweni ezilawulwayo kusukela ngeminyaka yawo-1980, futhi icwaningwa ezilwaneni ezisetshenziswa njengemifanekiso yokuhlola eziveza amajika acace ngendlela engavamile obudlelwano phakathi komthamo nempendulo. Umfundi ofuna “i-methylene blue nokucindezeleka” uthola zonke lezi zinhlobo ezintathu zobufakazi zixutshwe ndawonye, ngaphandle kwezimpawu ezizihlukanisayo.

Lokhu kuhlukanisa kubalulekile. Bonke ubufakazi obulawulwayo obuvela kubantu mayelana nesimo semizwa buqukethe izivivinyo ezimbili nokuhlolwa okukodwa kwaselabhorethri kokubhekana nokwesabekayo, futhi zombili izivivinyo ezibhalisiwe zaphela eminyakeni engaphezu kweyishumi edlule. Lesi sihloko sichaza okwatholwa ngakunye. Asincomi i-methylene blue njengokwelashwa kokuphazamiseka kwesimo semizwa.

Kungani udayi wagcina usezincwadini zocwaningo lwesimo semizwa

I-methylene blue yayiyinhlanganisela yokuqala eyenziwe ngokuphelele ngokwenziwa eyasetshenziswa njengomuthi. I-monoamine oxidase A, efushaniswa ngokuthi MAO-A, idiliza i-serotonin, futhi imithi eyivimbayo iyimithi yokucindezeleka eyamukelekile. URamsay, uDunford, noGillman balinganisa umphumela ku-MAO-A yomuntu ehlanziwe futhi babika isilinganiso esingaguquki sokuvimbela esiseduze no-27 nanomolar, lapho ukuvinjelwa kungabuyiseleka khona. I-MAO-B yayidinga izinga lokugxila eliphindwe ngaphezu kwamashumi amahlanu. Yona le molekyuli iphinde ivimbele i-nitric oxide synthase ne-guanylate cyclase, yingakho ukubuyekezwa kwango-2017 okwenziwa uDelport nozakwabo kubheka isenzo sayo sokulwa nokucindezeleka njengesibhekiswe ezindaweni eziningi kunokuba kube umphumela wesamukeli esisodwa.

Lokho kuchaza ukuthi kungani ucwaningo lwezilwane luthembisa futhi lumangaza. Emagundaneni, i-methylene blue iveza ukuziphatha okufana nomphumela wemithi yokucindezeleka ekuhlolweni kokubhukuda okuphoqelelwe kuphela ngaphakathi kwebanga elithile lemithamo: uEroglu noCaglayan bathola imiphumela phakathi kuka-15 no-30 mg/kg kodwa ayibanga khona ku-60 mg/kg, futhi ukuziphatha okubonisa ukuncipha kokukhathazeka kwalandela lona leli jika lika-U obheke phansi. Ukujova inani elincane kakhulu endaweni empunga engemuva ezungeze umsele wobuchopho kwasebenza ku-30 nanomoles kodwa hhayi ngaphandle kwalelo banga. Lokhu yi-hormesis, futhi ijika elinjalo alikwazi ukusetshenziswa ukuqagela imiphumela yemithamo ephakeme.

Izivivinyo zeminyaka yawo-1980 nomthamo we-placebo okungenzeka wawungeyona i-placebo

UNaylor nozakwabo benza isivivinyo seminyaka emibili lapho iziguli zazishintshana phakathi kwemithamo futhi iziguli nabacwaningi bengazi ukuthi yimuphi onikezwayo ezigulini ezingu-31 ezinokuphazamiseka kwe-bipolar, beqhathanisa u-300 mg ngosuku no-15 mg ngosuku kuyilapho kuqhubeka i-lithium. Ezingu-17 zasiqeda, futhi ukucindezeleka kwakunciphe ngokuphawulekayo ngokwezibalo emthanjeni ophakeme.

Indlela isivivinyo esaklanywa ngayo inenkinga okufanele iqondwe, ngoba iyaphindaphindeka. Amamiligremu ayishumi nanhlanu ngosuku akhethwa engxenyeni ye-“placebo” kucatshangwa ukuthi ayengenamphumela. Ababhali babe sebebhala “ukungabaza kwabo ngokuthi ukwabiwa kokwelashwa kwakufihlekile yini, nokungaqiniseki ngokuthi u-15 mg we-methylene blue ngosuku ungabhekwa yini njenge-placebo.” I-methylene blue yenza umchamo ube luhlaza okwesibhakabhaka okuxubene nokuluhlaza, ngakho zonke iziguli esivivinyweni sokushintshana zazithatha udayi onomphumela obonakalayo kuzo zombili izikhathi. Uma umthamo ophansi wawunomphumela, isivivinyo sasiqhathanisa imithamo emibili esebenzayo.

Isivivinyo esifushane sahlola u-15 mg ngosuku siwuqhathanisa ne-placebo yangempela ekuguleni kokucindezeleka okukhulu emasontweni amathathu, ezigulini ezingu-35, futhi sathola ukuthuthuka okukhulu ngokuphawulekayo ngokwezibalo nge-methylene blue. Amasonto amathathu neziguli ezingamashumi amathathu nanhlanu kuwuphawu lwangempela, kodwa oluncane.

Isivivinyo sokushintshana ku-bipolar: ubufakazi obuqine kakhulu obuvela kubantu

Isivivinyo esinikeza ulwazi oluningi kakhulu ucwaningo lwango-2017 olwenziwa u-Alda nozakwabo, olubhaliswe ngokuthi NCT00214877. Kwakunabahlanganyeli abangamashumi amathathu nesikhombisa abanokuphazamiseka kwe-bipolar I noma II, bonke bethatha i-lamotrigine njengomuthi wabo oyinhloko wokuzinzisa isimo semizwa, iningi linezimpawu ezisele ezincane noma ezilinganiselayo. Kwakuyisivivinyo sokushintshana lapho iziguli nabacwaningi bengazi ukuthi yimuphi umthamo onikezwayo: u-15 mg ngosuku izinyanga ezintathu uma kuqhathaniswa no-195 mg ngosuku izinyanga ezintathu, ngokulandelana okwakhethwa ngokungahleliwe. Ababhali basisho ngokucacile isizathu sokuqhathanisa nomthamo ophansi: “Sakhetha le ndlela ngoba i-methylene blue ishintsha umbala womchamo, ngakho sasingakwazi ukusebenzisa i-placebo evamile.”

Ekuhlaziyweni kweziguli ezingu-27 ezaqeda isivivinyo:

• Ukucindezeleka kwathuthuka kakhulu emthanjeni ophakeme, ngobukhulu bomphumela obungu-0.71 Esikalini sikaHamilton Sokulinganisa Ukucindezeleka (95% CI 0.15 kuya ku-1.25, P = 0.034) nobungu-0.80 Esikalini seMontgomery-Asberg Sokulinganisa Ukucindezeleka (95% CI 0.27 kuya ku-1.30, P = 0.020).
• Ukukhathazeka kwathuthuka kakhulu emthanjeni ophakeme, ngobukhulu bomphumela obungu-0.79 Esikalini sikaHamilton Sokulinganisa Ukukhathazeka (95% CI 0.22 kuya ku-1.33, P = 0.028). Izingxenye ezilinganisa ukukhathazeka ngokwengqondo zaziyizona eziveza umphumela; ukukhathazeka okubonakala emzimbeni kwafinyelela ekubalulekeni ngokwezibalo kuphela ekuhlaziyweni kwabo bonke ababelwe ukwelashwa.
• Izimpawu ze-mania zahlala ziphansi futhi zizinzile, ngaphandle kokushintshela ku-hypomania noma ku-mania.
• Amakhono okuqonda awashintshanga kunoma yimuphi wemisebenzi eyisithupha, okuhlanganisa ukufunda ngamazwi, ikhono lokuhlela nokulawula ukwenza, kanye nenkumbulo yokukhumbula okwenzeka.

Abayishumi kwabangu-37 baphuma esivivinyweni, oyedwa ngenxa yomchamo oluhlaza okwesibhakabhaka, oyedwa ngenxa yokwanda kokukhathazeka, noyedwa ngemva kokuba isimo sakhe somtholampilo sibi kakhulu. Imiphumela engemihle yayidlula futhi imincane, ikakhulukazi ukushisa emgudwini womchamo, isifo sohudo, isicanucanu, nekhanda elibuhlungu. Abahlanganyeli abaphakathi kuka-20 no-27 babethatha umuthi wokucindezeleka noma umuthi wokuphazamiseka kwengqondo okubandakanya ukulahlekelwa ukuxhumana neqiniso kuso sonke isikhathi, futhi isivivinyo asibikanga ubuthi be-serotonin.

Iqembu elacwaningwa lalingacindezelekile kakhulu. Amaphuzu okuqala ayengu-12.7 esikalini seMontgomery-Asberg, esifinyelela ku-60, futhi engu-7.6 esikalini sikaHamilton esinezinto ezingu-17: kwakuyizimpawu ezisele ezigulini esezizinzisiwe, hhayi ukuphazamiseka kokucindezeleka okukhulu. Ukubuyekezwa okuhlelekile okuzimele kwango-2021 kokwelashwa kokukhathazeka kubantu abane-bipolar eseyidambile kubala lesi sivivinyo njengesinye sezifundo ezimbili kuphela zemithi ezaba nomphumela omuhle ekukhathazekeni phakathi kwezivivinyo eziyishumi zokwabiwa ngokungahleliwe ezahlolwa, futhi kuphawula ukuthi ukuphuma kwabahlanganyeli abaningi nemiphumela engemihle ebonakalayo kungenzeka kwaphazamisa ukufihlwa kokwabiwa kokwelashwa.

Ukuhlolwa okukodwa okulawulwayo kokukhathazeka kubantu

Ukuhlolwa kokuqala okulawulwayo kwe-methylene blue nokukhathazeka kubantu kwakungesona isivivinyo sokwelashwa kodwa kwakuwukuhlolwa kokuqiniswa kwenkumbulo. UTelch nozakwabo babhalisa abantu abadala ababenokwesaba okukhulu kwezindawo ezivalekile, ngamunye wabo waqeda izikhathi eziyisithupha zokubhekana nokwesabekayo zemizuzu emihlanu egunjini elivalekile. Ngokushesha ngemva kwalokho, futhi kuphela ngemva kwalokho, banikezwa u-260 mg we-methylene blue noma i-placebo, abahlanganyeli nabacwaningi bengazi ukuthi kunikezwe yiphi. Ukuhlolwa futhi ngemva kwenyanga egunjini elihlukile kwalinganisa ukuthi ukwesaba kubuyile yini.

Umphumela wahlukanisa iqembu. Abahlanganyeli abaqeda isikhathi sokubhekana nokwesabekayo besaba kancane bagcina leyo nzuzo kangcono kakhulu nge-methylene blue, kuyilapho labo abaqeda besesaba baba nemiphumela emibi kunalabo abathatha i-placebo. Kubonakala sengathi umuthi uqinisa noma yini efundiwe, ngakho isikhathi esasiqinise ukwesaba saveza ukwesaba okwengeziwe. Inkumbulo yomongo yathuthuka kungakhathaliseki lokho, okuqinisekisa ukuthi umuthi wafinyelela ebuchosheni. Umthamo ofanayo ngaphansi kwenqubo efanayo waveza imiphumela ephikisanayo kuye ngento eyodwa eyayihluka, okuyisihloko sokuthi kungani ikhwalithi yesikhathi sokubhekana nokwesabekayo inquma lo mphumela.

Isivivinyo se-PTSD nesinqumo esizimele

Ucwaningo olukhulu olwalandela kwakuyisivivinyo sikaZoellner nozakwabo sokwabiwa ngokungahleliwe kubantu abane-PTSD engapheli, esibhaliswe ngokuthi NCT01188694. Iziguli ezingamashumi amane nambili zanikezwa izikhathi ezinhlanu, ngosuku ngalunye, zokubhekana nokwesabekayo ngokukucabanga, zilandelwe ngu-260 mg we-methylene blue; uhlelo olufanayo lulandelwe yi-placebo; noma zafakwa ohlwini lokulinda olwabe seluthola ukwelashwa okuvamile kokubhekana nokwesabekayo isikhathi eside.

Emphumeleni oyinhloko, Isikali Sezimpawu Ze-PTSD esasilinganiswa ngumhloli ozimele, i-methylene blue ayizange ihluke ku-placebo. Imiphumela eshicilelwe ebhukwini lokubhalisa ibonisa amaphuzu ngemva kokwelashwa angu-17.10 nge-methylene blue uma kuqhathaniswa nangu-14.67 nge-placebo, womabili ethuthuke kusuka cishe ku-32 ekuqaleni. Umehluko wawuvuna i-placebo.

Imiphumela emibili yesibili yavuna olunye uhlangothi. Iziguli eziningi ezazithatha i-methylene blue zahlonzwa njengeziphendule ekwelashweni, nenani elidinga ukwelashwa ukuze kube nomuntu oyedwa owengeziwe ozuzayo lingu-7.5, futhi ikhwalithi yempilo yathuthuka ngobukhulu bomphumela obungu-0.58. Inzuzo yayincike ekhonweni lenkumbulo yokusebenza kunokuba incike ekushintsheni kwezinkolelo ezihlobene nesigameko esibuhlungu.

Ukubuyekezwa okuhlelekile kwango-2023 kokuguqulwa kwenkumbulo ngemithi ekwelashweni kwengqondo okugxile ezigamekweni ezibuhlungu kwabe sekubeka i-methylene blue eqenjini lemithi engazange ibonise umphumela obalulekile ngokwezibalo ekunciphiseni izimpawu ze-PTSD. Yilokho ukuhunyushwa kwamanje okuzimele kobufakazi: akufakazelwanga ukuthi ayisebenzi, akufakazelwanga ukuthi iyasebenza, futhi ubufakazi abuqinile ngokwanele ukuba isetshenziswe ngaphandle kwenqubo yocwaningo.

Yini ehlukanisa amaqembu acwaningiwe

Funda ikholomu yokugcina uyibhekise kweyesibili, hhayi esifinyezweni socwaningo.

Asikho kulezi zivivinyo esahlola i-methylene blue njengokwelashwa okuzimele kokuphazamiseka kokucindezeleka okukhulu, futhi i-ClinicalTrials.gov ayinalo ucwaningo olusha lokungenelela ekuphazamisekeni kokucindezeleka noma kokukhathazeka kunalezi ezimbili ezingenhla, ezabhaliswa ngo-2003 nango-2009. Noma ubani ochaza i-methylene blue njengomuthi wokucindezeleka ofakazelwe uchaza umbono onendlela yokusebenza enengqondo nesivivinyo esisodwa esincane esinomphumela omuhle esiwusekelayo. Asikho isivivinyo esibike ukushintshela ku-mania.

Ubungozi bokusebenzisana kwemithi yisizathu sokuqapha

I-methylene blue ivimbela i-MAO-A. Yilokho okwenza ibe nesithakazelo ekucwaningeni isimo semizwa, futhi yilokho futhi okwenza ibe yingozi uma ihambisana neminye imithi ethinta i-serotonin, okuhlanganisa imithi eminingi yokucindezeleka. Umuthi ovimbela i-MAO owengezwa emthini ovimbela ukuphinde kumuncwe i-serotonin ukhulisa ukusebenza kwe-serotonin ngezindlela ezimbili ezihlukene, futhi le nhlanganisela ingabangela ubuthi be-serotonin, ngezinye izikhathi obubulalayo.

Umkhiqizo ofakwa emthanjeni unesexwayiso esisebhokisini ngalokhu. I-FDA yaxwayisa ngokusebenzisana kwale mithi ngo-2011 futhi kamuva yagxilisa isexwayiso sayo ekufakweni emthanjeni nasemithini ethile yokucindezeleka. I-methylene blue iphinde ibe yisithako kweminye imikhiqizo yokudambisa ubuhlungu bomgudu womchamo, okuyindlela okwenzeka ngayo okungenani icala elilodwa lokuthathwa ngomlomo esigulini esasithatha imithi eminingana ethinta i-serotonin. Umhlahlandlela wokusebenzisana kwemithi uchaza ubungozi ngokwezigaba zemithi nangendlela enikezwa ngayo.

Asikho kulezi zivivinyo zesimo semizwa esiphikisa lokhu kukhathazeka, kodwa futhi asikho esikuxazululayo. Zombili zenziwa ezigulini eziningi zazo ezazithatha eminye imithi yezengqondo, futhi asikho esabika ubuthi be-serotonin. Lokho kuyaduduza ezivivinyweni ezincane, eziqashwe ngeso lokhozi, ezinemibandela yokukhipha abathile, kunokuba kube isiqinisekiso sokuphepha sokuzihlanganisela imithi. Ubuthi be-serotonin bubonakala ngokuyaluza noma ukudideka, imfiva noma ukujuluka kakhulu, ukushaya kwenhliziyo ngokushesha, ukuthuthumela, ukuqina kwemisipha, nokunyakaza ngokuzumayo okungalawuleki, futhi abusona isimo okufanele sihlolwe ekhaya.

Izinga lomkhiqizo lihlobene kanjani nalokhu

Amabhodlela amabili anelebula elifanayo angahluka ngezinto ezengeziwe eziqukethwe kuwo. Ukuhambisana nombhalo wezindinganiso we-USP yinto umthengi angayihlola, futhi umkhiqizo ongahambisani nawo cishe uyimpahla yezinga lokusetshenziswa ezindwangwini, engase ibe nokungcola kwezinto eziphilayo njenge-Azure B ne-Azure C, izinsalela zezincibilikisi, nezinsimbi ezisindayo emazingeni abekelwa imikhawulo yizindinganiso zemithi.

Abathengisi abaningi abasebenzisa amazwi athi “ihlolwe umuntu wesithathu” bahlola izinsimbi ezisindayo kuphela, bese bethula lelo qoqo elilodwa lokuhlolwa njengokungathi lihlangabezana nazo zonke izindinganiso. I-Blupreme ihlola zonke izindinganiso ze-USP: ukuhlonza into, ubumsulwa, ukungcola kwezinto eziphilayo, izinsalela zezincibilikisi, ukungcola kwezakhi, izinsalela ngemva kokushiswa, imikhawulo yamagciwane, nama-endotoxin ebhaktheriya, futhi ishicilela isitifiketi sokuhlaziywa seqoqo ngalinye. Ukusifunda ngendlela efanele kusho ukuhlola inombolo yeqoqo, ilabhorethri, izindlela zokuhlola, nemikhawulo kunokuba ubheke uphawu lokuphumelela.

Isiphetho esithembekile

Isivivinyo se-bipolar siwubufakazi obuqine kakhulu obuvela kubantu, futhi sibonisa umphumela olinganiselayo womuthi owengeziwe ezimpawini ezisele eqenjini elizinzisiwe elinezimpawu ezincane. Isivivinyo sokucindezeleka okukhulu sathatha amasonto amathathu futhi sahlanganisa iziguli ezingamashumi amathathu nanhlanu. Ukuhlolwa kokwesaba izindawo ezivalekile kubonisa umphumela wangempela ekuqinisweni kwenkumbulo ongase usebenze kunoma yiluphi uhlangothi. Isivivinyo se-PTSD asizange siwuphinde umphumela omuhle esilinganisweni saso esiyinhloko. Akukho okuhloliwe kusukela lapho.

Yilokho indlela yokusebenza ethembisayo ebukeka ngayo ngaphambi kokuba ibe ukwelashwa, futhi yilokho futhi okubukeka ngakho lapho inhlanganisela ithengiswa ngamandla endlela esebenza ngayo kunemiphumela yayo. Uma uthatha umuthi wokucindezeleka owunikezwe udokotela, umuthi ovimbela i-MAO, i-opioid, noma yimuphi omunye umuthi othinta i-serotonin, lolo hlu kufanele luqale ingxoxo, ngaphambi kwanoma yimuphi umbuzo ngomthamo. Umtapo ogcwele wocwaningo ukhomba izivivinyo nocwaningo lokuhlola olusekela lezi zimangalo. Qala ngesifinyezo semiphumela engemihle nezimo ezingavumeli ukusetshenziswa kanye nokubuyekezwa kwalokho okusekelwa ucwaningo kubantu, bese ufunda ubufakazi obuqondene nokuphazamiseka kwe-bipolar uma kuyilokho okuxilongwe kuwe. Ungayeki umuthi owunikezwe udokotela ukuze uvule indawo yomuthi osahlolwa.