I-methylene blue yokuzivocavoca nokululama: yini ekalwe ngempela

NgoMashi 2022 umgijimi wemarathoni wezinga eliphezulu washicilela isincomo esixhasiwe sephilisi le-methylene blue elimuncwayo, ethi “lingasiza ukuthuthukisa ukugxila, ukukhuthazela nokulala” nokuthi wayelisebenzisa ngaphambi kokuzivocavoca kanzima. Kulelo sonto, odokotela abacashunwe emaphephandabeni kazwelonke bachaza lo mkhuba osabalele ngokuthi abagqugquzeli ezinkundleni zokuxhumana bagwinya isihlanzi samathangi ezinhlanzi. Awukho kule mibono ophendula umbuzo umgijimi anawo ngempela.

Ukhona yini owake wanikeza abantu i-methylene blue walinganisa ukuthi bahambe ibanga elingakanani, ngesivinini esingakanani, noma ukuthi balulame kahle kangakanani? Ukusesha okwenzelwe le ndatshana akutholanga ngisho ucwaningo olulodwa olulawulwayo lwabantu olunomphumela wokusebenza ekuzivocavoceni noma wokululama. Uchungechunge lwezikhombo luqukethe izinhlobo ezintathu zezilwane, amalungiselelo amaningana aselabhorethri, kanye nengxube eyodwa engeyona nhlobo i-methylene blue.

Ukukhuthazela, ukululama, nendlela yokusebenza kuyizimangalo ezihlukene

Inkomba ingashintsha iye kolunye uhlangothi uma iqhathaniswa nokusebenza, noma ishintshe ngaphandle kokuba ukusebenza kushintshe nhlobo. Lokhu akuyona imininingwane emincane yezobuchwepheshe: yilokho kanye okwenzeka ocwaningweni lwe-methylene blue nokuzivocavoca olucashunwa kakhulu.

Ucwaningo lwezinja lwasebenzisa udayi ohlukile

Iphepha elicashunwa kakhulu nge-methylene blue nokuzivocavoca ucwaningo luka-Imai nozakwabo lwango-1986 lokusebenzisa umshini wokugijima ezinjeni eziphapheme. Lwahlola ukuthi ukwanda kwegazi elimpontshwa yinhliziyo ngesikhathi sokuzivocavoca kuncike yini esimweni sezicubu sokwamukela nokudedela ama-electron, lisebenzisa lokho izindlela zocwaningo ezikuchaza ngokuthi “4 mg/kg we-new methylene blue 3,7-bis(ethylamino)-2,8-dimethylphenazothonium chloride, Eastman Kodak Company”. I-new methylene blue ingudayi ohlukile wohlobo lwe-thiazine, onamaqembu amabili e-ethylamino lapho i-methylene blue inamaqembu amabili e-dimethylamino, futhi yaziwa kakhulu ngokuba udayi wokugqamisa ama-reticulocyte. Umphumela otholwe ngayo awuwona umphumela otholwe nge-methylene blue.

Lolu cwaningo lusabalulekile, ngoba luyisibonelo esicace kakhulu sokuthi inkomba nokusebenza komzimba kungashintsha ngokwehlukana. Izinja zagijima izigaba ezimbili zemizuzu engu-20 ngesivinini esingu-2.5 bese kuba ngu-5.0 mph endaweni ekhuphuka ngamaphesenti angu-6. Ukuzivocavoca kwaphindaphinda kabili igazi elimpontshwa yinhliziyo futhi kwandisa ukusetshenziswa komoya-mpilo ngumzimba wonke ngokuphindwe kathathu kuya kane kuwo womabili amaqembu. Eqenjini elathola isixazululo sikasawoti, isilinganiso se-lactate ne-pyruvate egazini lemithambo ethwala igazi lisuka enhliziyweni sakhuphuka sisuka ku-6.0 saya ku-9.97. Eqenjini elathola udayi asikhuphukanga.

Zonke izilinganiso zokusebenza azishintshanga. Izinga lokushaya kwenhliziyo, umfutho wegazi emithanjeni ethwala igazi lisuka enhliziyweni, amandla okufinyela kwe-ventricle yangakwesobunxele, nama-catecholamine ku-plasma kwakhuphuka ngendlela efanayo kuwo womabili amaqembu, futhi ubudlelwano phakathi kwegazi elimpontshwa yinhliziyo nokusetshenziswa komoya-mpilo ngumzimba wonke babungahlukani ngokwezibalo. Ababhali baphetha ngokuthi izinguquko zesilinganiso “azihlobene njengembangela nokukhuthazwa kokujikeleza kwegazi okwenzeka ngesikhathi sokuzivocavoca okuncane kuya kokuphakathi.”

Lesi silinganiso asinamandla njengoba sibonakala. Sehla ngoba i-pyruvate yakhuphuka, isuka ku-0.14 yaya ku-0.38 mmol ilitha ngalinye, kuyilapho i-lactate nayo yakhuphuka, isuka ku-1.05 yaya ku-2.85 mmol ilitha ngalinye. Ezinjeni ezanikwa udayi ziphumule, ukusetshenziswa komoya-mpilo kwakhuphuka kancane, i-pH yegazi lemithambo ethwala igazi lisuka enhliziyweni yakhuphuka, kanti i-carbon dioxide yehla. Ababhali babiza lezi zinguquko ngokuthi “ziyafana” nalezo ze-2,4-dinitrophenol, into ehlukanisa izinqubo ezixhumene kuma-mitochondria. Isivinini sasibekwe yinqubo yocwaningo, ngakho ayikho inja eyake yagijinyiswa yaze yaphelelwa amandla.

Ucwaningo lokubhukuda lwamagundane amakhulu, nomthamo walo

Umphumela onamandla kakhulu wokusebenza kwezilwane uvela ocwaningweni luka-Peng nozakwabo lwango-2025 ku-Frontiers in Behavioral Neuroscience. Amagundane amakhulu abhukuda ubusuku obuyishumi obulandelanayo, anezisindo ezilingana namaphesenti angu-3 esisindo somzimba eziboshelwe emisileni, okungenani amahora amabili ubusuku ngabunye, aze afinyelela esigabeni sokuphelelwa amandla esihlolwe ngamaphuzu. Ngemva kweseshini ngayinye, iqembu elilodwa lathola i-methylene blue ngamakhala kanti elinye lathola isixazululo sikasawoti ngendlela efanayo. Amagundane athola i-methylene blue abhukuda isikhathi eside ngaphambi kokuhlangabezana nemibandela yokuphelelwa amandla, anyakaza kakhulu endaweni evulekile ngosuku olulandelayo, abonisa ukuziphatha okufana nokukhathazeka okuncane, futhi aba nokulahleka okuncane kwama-neuron, ukuphazamiseka okuncane kwe-myelin, nokuhlukana okuncane kwama-mitochondria abe yizicucu ku-hippocampus naku-striatum.

Umthamo uvame ukushiywa ngaphandle lapho lolu cwaningo lulandiswa kabusha. Isixazululo samaphesenti angu-1 singu-10 mg/mL; kwafakwa ama-microlitre ayishumi embotsheni ngayinye yekhala, ngakho ingqikithi yayicishe ibe ama-microlitre angu-20, noma u-0.2 mg ngegundane ngalinye ngeseshini ngayinye. Ukufaka ngamakhala kukhethwa ukuze kufinyelelwe ebuchosheni ngemizila yezinzwa zokuhogela ne-trigeminal, futhi ababhali bathi ucwaningo lwabo “aluzange lukale ukusabela kokufakwa kwe-oksijini, ukuvuvukala, noma amazinga amahomoni ebuchosheni naku-plasma.” Isinyathelo esilandelayo abasincomayo siwukucwaninga “imiphumela ebanzi yokwengeza i-MB ngaphambi kokuzivocavoca.”

Yilokho umgijimi angathanda ukuba kuhlolwe. Le nqubo yanikeza le ngxube ngemva komsebenzi, ukuze kuncishiswe ukulimala. Ukubhukuda isikhathi eside ngosuku olulandelayo kumodeli yamagundane akhathele kungumphumela ophathelene nokululama, hhayi umphumela ophathelene nomuntu oqeqeshiwe othatha umthamo ngaphambi kweseshini.

Lapho kwavela khona igama elithi “ukukhuthazela”

Ucwaningo lwamagundane amancane oluvame ukuchazwa njengolubonisa ukukhuthazela okuthuthukile umsebenzi ka-Gureev nozakwabo wango-2016 ku-Neuroscience Research. Amagundane aphuza amanzi ane-methylene blue engu-15 mg/kg ngosuku izinsuku ezingu-60. “Ukukhuthazela komzimba” kwakuwukuhlolwa ngentambo, noma ngezinsimbi ezivundlile, okunikeza amaphuzu ahlanganisa amandla okubamba, ukuhambisana kokunyakaza, nokulinganisela. Amagundane aphakathi nendawo ngokweminyaka angayitholanga athola amaphuzu angu-1.17; ayitholile athola angu-2.23, okusondele ezingeni lamagundane amadala asekhulile. Amagundane amadala asekhulile awazange athuthuke kunoma yini.

Ukusetshenziswa komoya-mpilo ngesikhathi sokuphumula kwakhuphuka cishe ngamaphesenti angu-15. Ukukhiqizwa kwe-hydrogen peroxide kuma-mitochondria obuchopho kwakhuphuka kusuka ku-94.9 kuya ku-176.7 pmol ngomzuzu nge-milligram ngayinye yephrotheni. I-DNA yama-mitochondria yanda ngokuphindwe ka-2.3. Lokho kusho ukwanda kokushintshwa nokuvuselelwa kwama-mitochondria ezilwaneni ezigugayo, kanye nokuthunyelwa kwezimpawu ngokusabela kokufakwa kwe-oksijini okukushukumisayo. Akukona ukubonisa ukuthi umsubathi ophile kahle angashesha.

Ukuhlolwa kwamaseli, nokuthi kugcina kuphi

U-Louters nozakwabo babika ngo-2005 ukuthi i-methylene blue ivuselela ukuthuthwa kwe-glucose nge-GLUT1 kumaseli e-fibroblast e-L929, kuze kufike emaphesentini angu-800 ku-50 micromolar. Ucwaningo olulandelayo lwango-2008 lwabonisa ukuthi i-methyl-beta-cyclodextrin ibopha i-methylene blue ngokuqondile futhi ivimbe lowo mphumela. Lokhu kuwumphumela ophathelene nomugqa wamaseli, ongakaze uboniswe emisipheni ehambisa amathambo.

Indlela yokusebenza ngokwayo iyaphikiswa

Ocwaningweni luka-Tretter nozakwabo lwango-2014 lwama-mitochondria ahlukaniswe nobuchopho bama-guinea pig, i-methylene blue engu-100 nanomolar kuya ku-1 micromolar yandisa ukusetshenziswa komoya-mpilo ngesikhathi sokuphumula, yabuyisela umehluko wamandla kagesi olwelwesini nokukhiqizwa kwe-ATP lapho i-Complex I noma i-Complex III ivinjelwe, futhi yandisa ukukhiqizwa kwe-hydrogen peroxide. Okubalulekile, “ukuphefumula okukhuthazwa yi-ADP akuzange kuthintwe yi-MB nganoma yiziphi izinto ezisetshenziswa kulokhu kusabela” ezahlolwa. Ukuphefumula okuphezulu okuxhumene nokukhiqizwa kwamandla, okuyikho isimangalo sokuzivocavoca esisekelwe kukho, akuzange kwande.

Ocwaningweni olulandelayo luka-Gureev nozakwabo lwango-2019, ilabhorethri efanayo eyakhiqiza umphumela wamagundane amancane yathola ukuthi i-methylene blue “iyehluleka ukubuyisela umehluko wamandla kagesi olwelwesini nokuphefumula okuvinjelwe yi-antimycin” kuma-mitochondria obuchopho bamagundane amancane, futhi yaphetha ngokuthi indawo eyamukela ama-electron yindawo ye-Qo ye-Complex III, hhayi noma iyiphi indawo esesigabeni esilandelayo. Umbono olula wokuthi udayi uthutha ama-electron adlule uchungechunge lokuphefumula oluvinjiwe awusebenzi kuwo wonke amalungiselelo okuhlolwa.

Akukho kulokhu okuphikisa ukuthi kungase kube nomphumela kubantu. Kodwa kusho ukuthi impikiswano esekelwe kuphela endleleni yokusebenza, lapho amakhemikhali ama-mitochondria abonakala engase asebenze ethathwa njengomphumela, inezinkinga ngaphakathi kwendlela yokusebenza uqobo.

Izinkinga ezimbili zokwakhiwa kocwaningo lwabantu okufanele zixazululwe

Kunzima ukufihla ukuthi ubani othola i-methylene blue ocwaningweni. Yenza umchamo ube luhlaza okwesibhakabhaka nokotshani, futhi abantu bayakubona. Ucwaningo lwango-2017 lokushintshanisa ukwelashwa kubantu abanenkinga yokushintshashintsha kwesimo sengqondo phakathi kokuphakama nokudangala lwakusho ngokuqondile: “Sakhetha lolu hlobo locwaningo ngoba i-methylene blue ishintsha umbala womchamo, ngakho asikwazanga ukusebenzisa i-placebo evamile.” Lolo cwaningo lwaqhathanisa umthamo omncane nomkhulu kunokuwuqhathanisa nephilisi elingenasithako esisebenzayo.

Le nkinga inkulu kakhulu ocwaningweni lokuzivocavoca kunasezindaweni eziningi, ngoba umzamo umuntu awuzwayo nokusebenza ekuhlolweni kwesikhathi kuthonywa kakhulu yilokho akulindele. Ucwaningo olungakwazi ukufihlela ababambiqhaza lokho abakutholayo lulinganise inkolelo ngendlela efanayo nokulinganisa umuthi.

Sikhona isixazululo esibhalwe phansi. Ucwaningo lwango-2016 lokuthwebula izithombe zomzimba olwahlukanisa ngokungahleliwe abantu abadala abaphile kahle abangu-26 lwabanikeza u-280 mg we-methylene blue yezinga le-USP, cishe u-4 mg/kg, noma i-placebo eyenziwe ngombala wokudla i-FD&C blue no. 2, emaphilisini afanayo angabonakali ngaphakathi. Lwacela ababambiqhaza ukuba bachame ngaphambi kokuthatha umthamo kodwa bangaphinde bachame, “ukuze kugwenywe ukuphazamiseka kokufihlwa kolwazi ngenxa yanoma yimuphi umbala womchamo.”

Inkinga yesibili ngumthamo nendlela yokuwufaka emzimbeni. I-methylene blue ethathwa ngomlomo ikhishwa ngokwengxenye emchameni, futhi inani elifinyelela ebuchosheni ngemva kokuthathwa ngomlomo licishe libe yingxenye yalelo elifinyelela ngemva kokufakwa emthanjeni, njengoba iqembu lika-Gureev liphawula lapho licaphuna umsebenzi ka-Peter nozakwabo omayelana nokuhamba komuthi emzimbeni. Ukufakwa ngamakhala egundaneni elikhulu akuhunyusheki kube yiphilisi, futhi uhla lwemithamo yabantu emisebenzini eshicilelwe lungu-0.5 kuya ku-4 mg/kg, kanti ucwaningo lokuthwebula izithombe lwango-2016 luphawula umphumela ophambene ngaphezu kuka-10 mg/kg.

Ucwaningo lwabantu lukala okunye

Ukuhlolwa okubili okulawulwayo kwabantu kuvela lapho lesi sihloko silandiswa kabusha, futhi akukho kokubili okwakala ukuzivocavoca. Ocwaningweni lokuthwebula izithombe lwango-2016, isikhathi sokusabela lapho kuhlolwa ukuphaphama asibonisanga ukuhlangana okubalulekile ngokwezibalo phakathi komuthi nesikhathi: nge-placebo kwakungu-230 kwase kuba ngu-220 milliseconds, kanti nge-methylene blue kwakungu-230 kwase kuba ngu-230 milliseconds, P = .43. Ocwaningweni lwango-2023 lokufakwa emthanjeni kwabesifazane abayisishiyagalombili abaphile kahle, ukugeleza kwegazi ebuchosheni nezinga lokusetshenziswa komoya-mpilo ebuchosheni kokubili kwehla kunokukhuphuka. Umhlahlandlela wobufakazi bamandla nokukhathala uchaza kokubili.

Uma unquma ukuyizama noma kunjalo

Ukuzihlola ngokwakho ngeke kufakazele ukusebenza kwayo, kodwa kungaqoshwa kahle ngokwanele ukuze ugweme ukuzikhohlisa. Bhala umkhiqizo nenombolo yeqoqo, indlela yokuwufaka emzimbeni, isikhathi ngaphambi kokuqeqesha, iseshini eqondile enebanga noma umthwalo, umzamo owuzwayo esikalini esinezinombolo, ukulala, i-caffeine nanoma yimuphi umuthi, kanye nobuhlungu bemisipha ngosuku olulandelayo nokusebenza ngemva kwamahora angu-48 ohlotsheni olufanayo lweseshini. Bese uphinda izikhathi ezifanayo ngaphandle kwayo.

Umuntu oyedwa olandelela into eyodwa eshintshayo akakwazi ukuhlukanisa umphumela womuthi nokuqina komzimba, ugqozi, isimo sezulu, kanye nokushintshashintsha okuvamile kokuqeqesha. Ingxenye ephathelene nalokho umuntu akuzwayo iyona engase idukise kakhulu.

I-methylene blue iphinde ibe nezingozi ezingahlobene nokusebenza. Ivimbela i-monoamine oxidase A, okuyenza ibe nenkinga uma ihlanganiswa nemithi kadokotela yokudangala neminye imithi ethinta i-serotonin, futhi ayifanele ukusetshenziswa kubantu abantula i-G6PD ngenxa yengozi ye-anemia ebangelwa ukubhujiswa kwamangqamuzana abomvu egazi. Umhlahlandlela wokuphepha uchaza kokubili, kanti umhlahlandlela wokusebenzisana nemithi uhlela imibuzo yemithi ngokwezigaba. Uma uncintisana ngaphansi kwemithetho evimbela ukusetshenziswa kwezinto zokuthuthukisa ukusebenza, hlola imithetho kunokuthembela esimangalweni somthengisi.

Into esetshenziswayo iyisici esishintshayo kulo lonke ucwaningo olungenhla

Wonke umthamo ochazwe lapha wawuyinani elilinganisiwe lengxube ecacisiwe. Ibhodlela elivela kumthengisi ongaqinisekisiwe alinjalo. Ukuhambisana ne-monograph ye-USP kuyindinganiso umthengi angayihlola, futhi into engahambisani nayo kungenzeka ibe yesezingeni lokusetshenziswa ezindwangwini, engase iqukathe ukungcola kwamakhemikhali anekhabhoni njenge-Azure B, izincibilikisi ezisele, nezinsimbi ezisindayo emazingeni imfuneko yemikhiqizo yemithi ewabekela umkhawulo. Lokho ukuchazwa njenge-USP okukufakazelayo nokungakufakazeli kuchaza izinga, kanti izindlela zokuhlola ukungcola zichaza lokho ilabhorethri ekufunayo.

Abathengisi abaningi abachaza umkhiqizo ngokuthi uhlolwe umuntu ozimele bahlola izinsimbi ezisindayo kuphela, bese bethula lelo qoqo elilodwa lokuhlolwa sengathi lihlangabezana nazo zonke izimfuneko. I-Blupreme ihlola zonke izimfuneko ze-USP: ubuwena bento, ukuhlanzeka, ukungcola kwamakhemikhali anekhabhoni, izincibilikisi ezisele, ukungcola kwezakhi zamakhemikhali, insalela ngemva kokushiswa, imikhawulo yamagciwane, nama-endotoxin amagciwane. Lonke iqoqo lithunyelwa nesitifiketi sokuhlaziywa, futhi ukusifunda ngendlela efanele kusho ukuqondanisa inombolo yeqoqo nelabhorethri nebhodlela oliphethe.

Isiphetho

Alukho ucwaningo olulawulwayo lwabantu olukale i-methylene blue mayelana nokukhuthazela, isivinini, amandla, noma ukululama. Ucwaningo lwezinja olucashunwa ngomphumela we-lactate lwasebenzisa udayi ohlukile futhi alutholanga mehluko ekusebenzeni. Ucwaningo lokubhukuda lwamagundane amakhulu lwafaka u-0.2 mg ngamakhala ngemva komsebenzi. Ucwaningo lwamagundane amancane olusemuva kwegama elithi “ukukhuthazela” lwasebenzisa ukuhlolwa kokubamba nokuhambisana kokunyakaza ezilwaneni ezigugayo, futhi indlela yokusebenza iyaphikiswa ezincwadini zocwaningo lwama-mitochondria.

Lokho kushiya indlela yokusebenza engase ibe nengqondo, iqoqo lemiphumela yezifundo ezincane zezilwane, inkinga eyodwa yokwakhiwa kocwaningo enesixazululo esibhalwe phansi, kodwa kungekho datha yokusebenza kwabantu. Ukubuyekezwa kobufakazi bezinzuzo kubantu kubeka izimangalo zokuzivocavoca eceleni kolunye ucwaningo lwabantu, kanti umtapo wocwaningo uhlela izifundo ezisekela isimangalo ngasinye.

Uma uziqeqeshela okuthile, isici esishintshayo esinobufakazi obuqine kakhulu bokusisekela ukuqeqesha uqobo.