Imethylene blue yomthambo nokuchacha: yintoni elinganiswe ngokwenene

NgoMatshi 2022, imbaleki yomdyarho omde ekwinqanaba eliphezulu yapapasha inkxaso ehlawulelweyo yepilisi yemethylene blue enyibilikiswa emlonyeni, isithi “inokunceda ekuphuculeni ukugxila, ukunyamezela nokulala” yaye iyisebenzisa ngaphambi koqeqesho olunzima. Kwangaloo veki, oogqirha abacatshulwe kumaphephandaba esizwe bachaza lo mkhwa ubanzi njengabaphembeleli abasela isicoci setanki leentlanzi. Akukho nanye kwezi ngcamango ephendula umbuzo imbaleki enawo ngokwenene.

Ngaba ukho umntu onike abantu imethylene blue waza walinganisa umgama abawuhambileyo, isantya sabo, okanye indlela abachache ngayo? Uphando lokulungiselela eli nqaku alufumananga nasinye isifundo esilawulwayo kubantu esalinganisa isiphumo sokusebenza emthambweni okanye sokuchacha. Xa kulandelwa izifundo ezicatshulwayo, kufunyanwa iintlobo ezintathu zezilwanyana, amalungiselelo aliqela aselabhoratri, kunye nekhompawundi enye engeyiyo kwaphela imethylene blue.

Ukunyamezela, ukuchacha, nendlela yokusebenza ngamabango ahlukeneyo

Isalathisi sinokutshintsha siye kwicala elichasene nokusebenza, okanye sitshintshe ukusebenza kungatshintshanga kwaphela. Lo asingombandela nje wobugcisa: yile kanye indlela eyenzeka ngayo kwisifundo semethylene blue nomthambo esicatshulwa kakhulu.

Isifundo sezinja sasebenzisa idayi eyahlukileyo

Iphepha elicatshulwa rhoqo malunga nemethylene blue nomthambo sisifundo sikaImai noogxa bakhe sango-1986, esasisebenzisa umatshini wokubaleka kwizinja ezingalaliswanga. Savavanya ukuba ukwanda komthamo wegazi elimpontshwa yintliziyo ngexesha lomthambo kuxhomekeke na kwimeko yeredox yeethishu, kusetyenziswa oko kuchazwa ziindlela zesifundo ngokuthi “4 mg/kg ye-new methylene blue 3,7-bis(ethylamino)-2,8-dimethylphenazothonium chloride, Eastman Kodak Company”. I-new methylene blue yidayi yethiazine eyahlukileyo, enamaqela amabini e-ethylamino endaweni yamaqela amabini e-dimethylamino afumaneka kwimethylene blue, neyaziwa kakhulu njengedayi yokubonisa iireticulocyte. Isiphumo esifunyenwe ngayo asisosiphumo esifunyenwe ngemethylene blue.

Esi sifundo sisabalulekile, kuba sibonisa ngokucacileyo ukuba isalathisi kunye nokusebenza komzimba zinokutshintsha ngokwahlukeneyo. Izinja zabaleka izigaba ezibini zemizuzu engama-20 ngesantya se-2.5 saza saba yi-5.0 mph, kwithambeka le-6 pesenti. Umthambo wawuphinda kabini umthamo wegazi elimpontshwa yintliziyo waza wandisa ukusetyenziswa kweoksijini ngumzimba wonke ngokuphindwe kathathu ukuya kane kuwo omabini amaqela. Kwiqela elanikwa isisombululo setyuwa, umlinganiselo welactate nepyruvate egazini lemithambo ephuma entliziyweni wenyuka ukusuka ku-6.0 ukuya ku-9.97. Kwiqela elanikwa idayi awuzange unyuke.

Yonke imilinganiselo yokusebenza yahlala ingatshintshanga. Isantya sokubetha kwentliziyo, uxinzelelo lwegazi kwimithambo ephuma entliziyweni, amandla okuxhuzula kweventricle yasekhohlo, kunye neecatecholamine ezikwiplasma zenyuka ngokufanayo kuwo omabini amaqela. Ubudlelwane phakathi komthamo wegazi elimpontshwa yintliziyo kunye nokusetyenziswa kweoksijini ngumzimba wonke babungabonisi mahluko ngokweenkcukacha-manani. Ababhali bagqiba kwelokuba utshintsho kumlinganiselo “alunxulumananga ngokwesizathu nokuvuseleleka kokujikeleza kwegazi okwenzeka ngexesha lomthambo omncinane ukuya kophakathi.”

Lo mlinganiselo ubuthathaka kunokuba ubonakala. Wehla kuba ipyruvate yenyuka, ukusuka ku-0.14 ukuya ku-0.38 mmol ngelitha, ngoxa ilactate nayo yenyuka, ukusuka ku-1.05 ukuya ku-2.85 mmol ngelitha. Kwizinja ezanikwa idayi ziphumle, ukusetyenziswa kweoksijini kwenyuka kancinci, i-pH yegazi lemithambo ephuma entliziyweni yenyuka, yaza ikharbon dayokhsayidi yehla. Ababhali bathi olo tshintsho “lwalufana” nolo lwe-2,4-dinitrophenol, into eyahlula iinkqubo eziqhele ukudityaniswa kwiimitochondria. Isantya sasimiselwe yiprothokholi, ngoko akukho nja yabalekiswa de yaphelelwa ngamandla.

Isifundo sokuqubha kweempuku, kunye nedosi yaso

Esona siphumo sinamandla sokusebenza kwizilwanyana luvavanyo lukaPeng noogxa bakhe lwango-2025 kwiFrontiers in Behavioral Neuroscience. Iimpuku zaqubha ubusuku obulishumi obulandelelanayo, zibotshelelwe imithwalo elingana ne-3 pesenti yobunzima bomzimba emisileni, ubuncinane iiyure ezimbini ngobusuku, de zafikelela kwinqanaba elichaziweyo nelinikwa amanqaku lokuphelelwa ngamandla. Emva kweseshoni nganye, elinye iqela lanikwa imethylene blue ngeempumlo, elinye lanikwa isisombululo setyuwa ngendlela efanayo. Iimpuku ezanikwa imethylene blue zaqubha ixesha elide ngaphambi kokufikelela kwimigaqo yokuphelelwa ngamandla, zahamba-hamba ngakumbi kwindawo evulekileyo ngosuku olulandelayo, zabonisa ukuziphatha okumbalwa okufana nexhala, zaza zanokulahleka okuncinane kweeneuron, ukuphazamiseka okuncinane kwemyelin, kunye nokuqhekeka okuncinane kweemitochondria kwihippocampus nakwistriatum.

Idosi idla ngokushiywa xa esi sifundo siphinda sibaliswa. Isisombululo se-1 pesenti siyi-10 mg/mL; kwafakwa iimicrolitre ezilishumi kumngxuma ngamnye wempumlo, ngoko iyonke yayimalunga neemicrolitre ezingama-20, okanye i-0.2 mg kwimpuku nganye ngeseshoni. Ukunikezelwa ngeempumlo kukhethwa ukuze into ifikelele ebuchotsheni ngeendlela zemithambo-luvo yokunukisa ne-trigeminal, kwaye ababhali bathi isifundo sabo “asizange silinganise ukuphendula kweoxidation, ukudumba, okanye amanqanaba eehomoni ebuchotsheni nakwiplasma.” Inyathelo elilandelayo abalicebisayo kukufunda “iziphumo ezipheleleyo zokongezwa kwe-MB ngaphambi komthambo.”

Yiloo nto imbaleki engafuna ivavanywe. Le prothokholi yanika ikhompawundi emva komsebenzi, ukuze kuncitshiswe ukwenzakala. Ukuqubha ixesha elide ngosuku olulandelayo kwimodeli yempuku ephelelwe ngamandla sisiphumo esimalunga nokuchacha, hayi isiphumo esimalunga nomntu oqeqeshiweyo othatha idosi ngaphambi kweseshoni.

Livela phi igama elithi “ukunyamezela”

Isifundo seempukwana esidla ngokuchazwa njengesibonisa ukunyamezela okuphucukileyo ngumsebenzi kaGureev noogxa bakhe wango-2016 kwiNeuroscience Research. Iimpukwana zasela amanzi anemethylene blue kwi-15 mg/kg ngosuku kangangeentsuku ezingama-60. “Ukunyamezela komzimba” apha luvavanyo lomtya, okanye lweentsimbi ezithe tyaba, olunika amanqaku ngokudibanisa amandla okubambelela, ulungelelaniso lweentshukumo, kunye nokuzinza komzimba. Iimpukwana ezikwiminyaka ephakathi ezinganikwanga imethylene blue zafumana amanqaku ayi-1.17; ezinikiweyo zafumana ayi-2.23, kufuphi nenqanaba leempukwana ezikhulileyo. Iimpukwana ezikhulileyo azizange ziphucuke nakweyiphi na into.

Ukusetyenziswa kweoksijini xa ziphumle kwenyuka malunga ne-15 pesenti. Ukuveliswa kwehydrogen peroxide kwiimitochondria zobuchopho kwenyuka ukusuka ku-94.9 ukuya ku-176.7 pmol ngomzuzu ngemiligram yeprotheyini. I-DNA yeemitochondria yanda ngokuphindwe ka-2.3. Oko kukwanda komjikelo wokuhlaziywa kweemitochondria kwizilwanyana ezigugayo, kunye nemiqondiso yeoxidation eqhuba loo nkqubo. Akubobungqina bokuba imbaleki esempilweni ingahamba ngokukhawuleza ngakumbi.

Iimvavanyo zeeseli, nalapho ziphela khona

ULouters noogxa bakhe baxela ngo-2005 ukuba imethylene blue ivuselela ukuthuthwa kweglucose nge-GLUT1 kwiiseli zefibroblast ze-L929, ngokufikelela kwi-800 pesenti kwi-50 micromolar. Isifundo sokulandelela sango-2008 sabonisa ukuba imethyl-beta-cyclodextrin ibophelela ngqo kwimethylene blue ize ithintele esi siphumo. Esi sisiphumo esimalunga nomgca weeseli, esingazange siboniswe kwizihlunu zamathambo.

Indlela yokusebenza ngokwayo iyaphikiswa

Kwisifundo sikaTretter noogxa bakhe sango-2014 seemitochondria ezahlulwe ebuchotsheni beeguinea pig, imethylene blue kwi-100 nanomolar ukuya kwi-1 micromolar yandisa ukusetyenziswa kweoksijini xa ziphumle, yabuyisela umahluko wombane kwinwebu kunye nokuveliswa kwe-ATP xa i-Complex I okanye i-Complex III yayithintelwe, yaza yandisa ukuveliswa kwehydrogen peroxide. Okubalulekileyo kukuba, “ukuphefumla okuvuselelwe yi-ADP akuzange kuchatshazelwe yi-MB ngayo nayiphi na kwezi substrates” zavavanywayo. Ukuphefumla okudityanisiweyo okuphezulu, ekuxhomekeke kuko ibango elimalunga nomthambo, akuzange kwande.

Kwisifundo sokulandelela sikaGureev noogxa bakhe sango-2019, kwaloo labhoratri eyavelisa isiphumo seempukwana yafumanisa ukuba imethylene blue “iyasilela ukubuyisela umahluko wombane kwinwebu nokuphefumla okuthintelwe yi-antimycin” kwiimitochondria zobuchopho beempukwana. Yagqiba kwelokuba indawo eyamkela ii-electron yi-Qo site ye-Complex III, kungekhona nayiphi na indawo engaphaya kwayo kwikhonkco. Ingcamango elula yokuba idayi ithutha ii-electron zidlule kwindawo evalekileyo yekhonkco lokuphefumla ayisebenzi kuwo onke amalungiselelo ovavanyo.

Akukho nanye kwezi zinto ekhupha ukuba kunokubakho isiphumo ebantwini. Kodwa zithetha ukuba ingxoxo esekelwe kuphela kwindlela yokusebenza, apho imichiza yeemitochondria enengqiqo ithathwa njengesiphumo, ineengxaki ngaphakathi kwaloo ndlela yokusebenza ngokwayo.

Iingxaki ezimbini zoyilo ekufuneka lilinge labantu lizisombulule

Kunzima ukufihla ukuba umntu unikwe imethylene blue. Iguqula umchamo ube luhlaza okuxutywe noblowu, yaye abantu bayakuqaphela oko. Ulingo lwango-2017 olwalutshintshanisa unyango kubantu abanokuphazamiseka kweemvakalelo kwe-bipolar lwakutsho ngokucacileyo: “Sikhethe olu yilo kuba imethylene blue iguqula umbala womchamo, ngoko asikwazanga ukusebenzisa iplacebo eqhelekileyo.” Olo lingo lwathelekisa idosi encinane nedosi enkulu endaweni yokuyithelekisa nepilisi engenasithako sisebenzayo.

Le ngxaki inkulu ngakumbi kuphando lomthambo kunakweminye imimandla phantse yonke, kuba ubunzima bomthambo obuvakalayo kunye nokusebenza kuvavanyo olulinganiselwa ixesha ziphenjelelwa kakhulu koko kulindelweyo. Ulingo olungakwaziyo ukufihla kubathathi-nxaxheba ukuba bafumene ntoni lulinganisa inkolelo kanye njengokuba lulinganisa iyeza.

Sikhona isisombululo esibhaliweyo. Ulingo lwango-2016 lokufota imifanekiso yangaphakathi emzimbeni, olwalusebenzisa ulwabiwo olungacwangciswanga kubantu abadala abangama-26 abasempilweni, lwanika i-280 mg yemethylene blue yodidi lwe-USP, malunga ne-4 mg/kg, okanye iplacebo eyenziwe ngombala wokutya i-FD&C blue no. 2, kwiicapsule ezifanayo ezingabonisi okungaphakathi. Lwacela abathathi-nxaxheba ukuba bachame ngaphambi kokunikwa idosi kodwa bangaphindi emva koko, “ukuze kuthintelwe ukonakaliswa kokufihlwa kolwabiwo ngenxa yawo nawuphi na umbala womchamo.”

Ingxaki yesibini yidosi nendlela yokuyinika. Inxalenye yemethylene blue ethathwa ngomlomo ikhutshelwa emchameni, yaye ukufikelela kwayo ebuchotsheni emva kokuthathwa ngomlomo kumalunga nesiqingatha soko kwenzeka emva kokunikwa ngomthambo wegazi, njengoko iqela likaGureev liphawula xa licaphula umsebenzi kaPeter noogxa bakhe omalunga nendlela into efunxwa, isasazwa, iguqulwa, ize ikhutshwe ngayo emzimbeni. Ukunikezelwa ngeempumlo kwimpuku akunakuguqulelwa ngokuthe ngqo kwicapsule, kwaye uluhlu lweedosi zabantu kumsebenzi opapashiweyo luyi-0.5 ukuya kwi-4 mg/kg. Ulingo lokufota imifanekiso lwango-2016 lwaphawula isiphumo esichaseneyo ngaphezu kwe-10 mg/kg.

Izifundo zabantu zilinganisa enye into

Iimvavanyo ezimbini ezilawulwayo kubantu zivela xa esi sihloko siphinda sibaliswa, yaye akukho nanye eyalinganisa umthambo. Kulingo lokufota imifanekiso lwango-2016, ixesha lokuphendula kuvavanyo lokuphapha alizange libonise nxibelelwano lubalulekileyo ngokweenkcukacha-manani phakathi kweyeza nexesha. Ngeplacebo laliyi-230 laza laba yi-220 milliseconds, yaye ngemethylene blue laliyi-230 laza lahlala liyi-230 milliseconds, P = .43. Kwisifundo sango-2023 sokunikezelwa ngomthambo wegazi kubasetyhini abasibhozo abasempilweni, ukuhamba kwegazi ebuchotsheni kunye nezinga lokusetyenziswa kweoksijini kwiinkqubo zemetabolism zobuchopho zombini zehla endaweni yokunyuka. Isikhokelo sobungqina malunga namandla nokudinwa sixoxa ngazo zombini.

Ukuba ugqiba ekubeni uyizame noko

Ukuzivavanya ngokwakho akunakungqina ukusebenza kwayo, kodwa kunokurekhodwa kakuhle ngokwaneleyo ukuze uphephe ukuzikhohlisa. Bhala phantsi imveliso nenombolo yebhetshi, indlela oyithathe ngayo, ixesha oyithathe ngalo ngaphambi koqeqesho, iseshoni ethile kunye nomgama okanye umthwalo, ubunzima bomthambo obuvakalayo kwisikali samanani, ukulala, icaffeine nalo naliphi na iyeza, kunye nokuqaqamba ngosuku olulandelayo nokusebenza emva kweeyure ezingama-48 kuhlobo olufanayo lweseshoni. Emva koko phinda ezo seshoni ngaphandle kwayo.

Umntu omnye olandelela into enye etshintshayo akanako ukwahlula isiphumo seyeza ekomeleleni komzimba, ekukhuthazekeni, kwimozulu, nakuguquguquko oluqhelekileyo loqeqesho. Inxalenye esekelwe kwimvakalelo yeyona inokulahlekisa kakhulu.

Imethylene blue ikwanemingcipheko engenanto yakwenza nokusebenza emthambweni. Ithintela imonoamine oxidase A, nto leyo eyenza ibe nomba ekufuneka uqwalaselwe xa kukho amayeza amiselweyo okudakumba namanye amayeza achaphazela iserotonin. Ayifanele kusetyenziswa ngabantu abaswele i-G6PD ngenxa yomngcipheko we-anemia ebangelwa kukutshatyalaliswa kweeseli ezibomvu zegazi. Isikhokelo sokhuseleko sixoxa ngayo yomibini le miba, kwaye isikhokelo sokunxibelelana kwamayeza sihlela imibuzo ngamayeza ngokweendidi zawo. Ukuba ukhuphisana phantsi kwemithetho echasene nokusetyenziswa kwezinto ezithintelweyo kwezemidlalo, jonga imithetho endaweni yokuthembela kwibango lomthengisi.

Into esetyenzisiweyo yinto eguquguqukayo kwisifundo ngasinye esingasentla

Yonke idosi echazwe apha yayisisixa esilinganisiweyo sekhompawundi echaziweyo. Ibhotile evela kumthengisi ongakhange aqinisekiswe ayifani naloo nto. Ukuthobela imonograph ye-USP ngumgangatho umthengi anokuwujonga, yaye into engawuthobeliyo kusenokwenzeka ukuba yeyodidi lokusetyenziswa kumalaphu. Inokuba nokungcola kweekhompawundi ze-organic okufana ne-Azure B, iintsalela zezinyibilikisi, kunye neentsimbi ezinzima kumanqanaba abekelwa imida yimigangatho yamayeza. Oko ukuchazwa njenge-USP kungqinayo noko kungakungqiniyo kuchaza udidi, kwaye iindlela zokuvavanya ukungcola zichaza oko kukhangelwa yilabhoratri.

Uninzi lwabathengisi abachaza imveliso njengevavanywe ngumntu wesithathu luvavanya kuphela iintsimbi ezinzima, luze lubonise elo qela linye lovavanyo ngokungathi liyanelisa zonke iimfuno zomgangatho. IBlupreme ivavanya zonke iimfuno zomgangatho we-USP: uchongo, ubunyulu, ukungcola kweekhompawundi ze-organic, iintsalela zezinyibilikisi, ukungcola kweziqalelo, intsalela emva kokutshiswa, imida yeentsholongwane, kunye nee-endotoxin zebhaktheriya. Ibhetshi nganye ithunyelwa nesiqinisekiso sohlalutyo, yaye ukusifunda ngokuchanekileyo kuthetha ukuthelekisa inombolo yebhetshi kunye nelabhoratri nebhotile oyiphetheyo.

Isishwankathelo

Akukho sifundo silawulwayo kubantu esilinganise imethylene blue ngokunxulumene nokunyamezela, isantya, amandla, okanye ukuchacha. Isifundo sezinja esicatshulwa malunga nesiphumo kwilactate sasebenzisa idayi eyahlukileyo saza asafumana mahluko ekusebenzeni. Isifundo sokuqubha kweempuku sanika i-0.2 mg ngeempumlo emva komsebenzi. Isifundo seempukwana esingumthombo wegama elithi “ukunyamezela” sasebenzisa uvavanyo lokubambelela nokulungelelanisa iintshukumo kwizilwanyana ezigugayo, kwaye indlela yokusebenza iyaphikiswa kuncwadi lwezenzululwazi lweemitochondria.

Oko kushiya indlela yokusebenza enokwenzeka, iqela leziphumo zezifundo ezincinane zezilwanyana, ingxaki enye yoyilo lwesifundo enesisombululo esibhaliweyo, kwaye kungekho datha yokusebenza emthambweni kubantu. Uphononongo lobungqina beenzuzo kubantu lubeka amabango omthambo ecaleni kolunye uncwadi lwezifundo zabantu, kwaye ithala lophando lidwelisa izifundo ezixhasa ibango ngalinye.

Ukuba uziqeqeshela into ethile, eyona nto inobungqina obunamandla obuyixhasayo luqeqesho ngokwalo.