Isihloko
I-methylene blue nomalaleveva: ukusetshenziswa emlandweni nezinhlolo zanamuhla
Ngo-1891 iziguli ezimbili ezazinomalaleveva zelashwa ngodayi oluhlaza okwesibhakabhaka wokudaya izindwangu. UPaul Guttmann noPaul Ehrlich babeqaphele ukuthi i-methylene blue yayidaya ngokukhetha izimuncagazi zikamalaleveva, base becabanga ukuthi udayi okwazi ukukhetha isimuncagazi ukuze asiveze angase akwazi nokusilimaza ngokukhetha okufanayo. Zombili iziguli zalulama. Lokho kuhlola kwenza i-methylene blue yaba umuthi wokuqala wokulwa nomalaleveva owenziwe ngokwenziwa, kusasele amashumi eminyaka ngaphambi kokuba kube khona i-chloroquine.
Lo dayi wabe usuchitha ingxenye enkulu yekhulu lamashumi amabili ulahlekelwa yindawo yawo. Imithi eyenziwe ngokwenziwa eyayibekezeleleka kangcono yathatha indawo yawo, futhi enkathini yanamuhla wawusasetshenziswa kakhulu njengento esetshenziswa elabhorethri ekuhloleni, njengodayi wokusiza ukuxilonga, nanjengomuthi wezimo eziphuthumayo wesinye isifo segazi. Ngakho ukubuyela kwawo ocwaningweni lukamalaleveva eBurkina Faso naseMali kwakungekona ukulangazelela okwakudala. Abacwaningi babenombono othile ababefuna ukuwuhlola: yona le nqubo yamakhemikhali ye-redox eyenza udayi ukwazi ukudaya ingase iphazamise izivikelo ze-redox zesimuncagazi uqobo, futhi umthelela wawo esigabeni sesimuncagazi esikwazi ukudluliselwa ungase wenze okuthile imithi ejwayelekile engakwenzi kahle. Ukuhlola lowo mbono kwakudinga ukuba njalo kucaciswe inhlanganisela, uhlobo lwesimuncagazi, nomphumela olinganiswayo, ngoba ukushintsha noma yikuphi kwalokhu kushintsha isiphetho.
Umehluko obanzi phakathi kwemithi egunyaziwe nokusetshenziswa okusacwaningwa uchazwe esihlokweni esithi i-methylene blue kwezokwelapha. Umalaleveva usohlangothini lokusetshenziswa okusacwaningwa: lo muthi uyasebenza ngokwebhayoloji, futhi uhlolwe ezinhlolweni uhlanganiswe neminye imithi, kodwa awuyona indlela ejwayelekile yokwelapha ngokweziqondiso.
Kungani udayi ka-Ehrlich wasebenza nokuthi kungani wayekwa
Umbhalo wakudala uyisibonelo sendlela yokufunda ubufakazi bangaphambi kwezindlela zanamuhla. Ukubuyekezwa kwango-1904 kwamacala abikiwe angu-425 kwalinganisela ukuthi cishe amaphesenti angu-85 asabela ekwelashweni, kodwa lawo macala andulela ukwabiwa kweziguli ngokungahleliwe, ukusetshenziswa kwemiphumela yokuhlola elinganiswa ngendlela efanayo, ukuqinisekiswa kwezinhlobo zezimuncagazi, nokuqashwa kokumelana nemithi. Afakazela ukuthi le nhlanganisela yamakhemikhali yayinamandla okulwa nomalaleveva ayefanele ukuqhubeka ecwaningwa, hhayi izinga lokwelapheka elingaqhathaniswa nelenhlolo yanamuhla.
Ukuyekwa kwawo kwakubangelwa ubunzima bokuwusebenzisa kunokuphikiswa kokusebenza kwawo. I-methylene blue yenza umchamo ube luhlaza okwesibhakabhaka noma ube luhlaza, idaya izicubu, futhi ibangela izinkinga zesisu namathumbu nezokuchama, okuhlanganisa ukuhlanza nokuchama okubuhlungu ngemithamo eyayisetshenziswa ngaleso sikhathi. Imithi emisha yayisusa izimuncagazi ngaphandle kokudaya isiguli. Ukubuyekezwa komlando okulandelela ukusuka ku-methylene blue kuya ku-chloroquine kuchaza indaba yokuthathelwa kwayo indawo, kanti ukubuyekezwa kwemithi ye-phenothiazinium yokulwa nomalaleveva kuqoqa imibono mayelana nezindlela zokusebenza eyagcina abacwaningi benentshisekelo ngemva kokuba ukusetshenziswa kwayo emtholampilo sekunciphile.
Ngokwendlela osebenza ngayo, lo dayi uchazwa kangcono njengosebenza nge-redox kunokuba uqondiswe entweni eyodwa kuphela. Uvimbela i-glutathione reductase yesimuncagazi ekuhlolweni kweshubhu, ngesikhathi esifanayo ujikeleza ama-electron ngezindlela ezisebenzisa amandla okunciphisa amakhemikhali adingwa isimuncagazi futhi zibangele ingcindezi ye-oxidative; kuphinde kwaphakanyiswa ukuthi uphazamisa ukususwa kobuthi be-heme. Akukacaci ukuthi iyiphi yalezi zindlela ebusa ngaphakathi kwesiguli. Umphumela obalulekile akuyona into ethile eqondiswe kuyo, kodwa ukukhetha isigaba esithile: i-methylene blue isebenza ngamandla angavamile ngokumelene nama-gametocyte, okuyisigaba socansi isimuncagazi esikuso okufanele umiyane usigwinye ukuze ukudluliselwa kuqhubeke. Izinhlanganisela ezijwayelekile ze-artemisinin zisusa izimuncagazi ezingekho esigabeni socansi ezigulisa isiguli, kodwa zingashiya ama-gametocyte asekhulile. Umuthi onciphisa isikhathi sokuba nama-gametocyte noma owenza ama-gametocyte angakwazi ukuthelelana uhlaselela ukudluliselwa uqobo.
Lokho izinhlolo zanamuhla ezakuhlola
Yonke imiphumela yanamuhla engezansi ivela ekuhlanganisweni kwemithi. Umthamo, umuthi ohambisana nawo, uhlobo lwesimuncagazi, nomphumela olinganiswayo kuyingxenye yokutholakele.
| Inhlolo neqembu labahlanganyeli | Uhlelo lokwelapha | Umphumela olinganiswayo nokutholakele | Umkhawulo |
|---|---|---|---|
| Burkina Faso 2005, izingane ezingu-226 ezinezinyanga ezingu-6 kuya ku-59, umalaleveva we-falciparum | I-chloroquine kanye ne-methylene blue engu-4 mg/kg/day izinsuku ezingu-3 kuqhathaniswa ne-chloroquine yodwa | Ukusabela okwanele ekwelashweni ngosuku 14 cishe amaphesenti angu-56 kuqhathaniswa nangu-46; akukho nzuzo ecacile | Umthamo ophansi kadayi lapho isimuncagazi simelana ne-chloroquine; ukuhlola okungafanele kahle kohlelo lokwelapha lwanamuhla |
| Zoungrana 2008, isigaba 2, izingane ezingu-180 ezineminyaka engu-6 kuya ku-10, umalaleveva we-falciparum | I-methylene blue kanye ne-artesunate, kanye ne-amodiaquine, noma i-artesunate-amodiaquine ejwayelekile; udayi ongu-20 mg/kg/day izinsuku ezingu-3 | Izinga lokwelapheka elilungisiwe ngosuku 28 lalingamaphesenti angu-62, 95, no-82 ngokulandelana; ukususwa kwezimuncagazi kwakushesha kakhulu ngenhlanganisela ye-artesunate; womabili amaqembu athola udayi anciphisa ukuba nama-gametocyte ngezinsuku 3, 7, no-14 | Abahlanganyeli nabacwaningi babazi ukuthi yimiphi imithi eyayinikezwa, futhi amaqembu ayemancane; izinga eliphansi lokwelapheka ngenhlanganisela ye-artesunate libonisa ukuthi umuthi ohambisana nawo unquma umphumela |
| Coulibaly 2015, isigaba IIb, izingane ezingu-193 eqenjini lokuhlolwa kokusebenza, umalaleveva we-falciparum | I-artesunate-amodiaquine kanye nodayi ongu-15 mg/kg/day izinsuku ezingu-3 kuqhathaniswa naleyo nhlanganisela yodwa | Ama-gametocyte atholakala ngesibonakhulu ngosuku 7 ayengamaphesenti angu-1.2 kuqhathaniswa nangu-8.9; ukususwa kwezimuncagazi ezingekho esigabeni socansi kwakushesha kancane; izinga lokwelapheka elilungisiwe lalifana, cishe amaphesenti angu-80 kuqhathaniswa nangu-85 | Ukuncipha kokutholakala kwama-gametocyte, hhayi ukwelapheka, kwakuyinzuzo eyinhloko; kwakukhona ukuhlanza okuningi nokwehla kwe-hemoglobin okwesikhashana ngokusetshenziswa kukadayi |
| Mali 2018, isigaba 2, abesilisa abangu-80 abane-G6PD ejwayelekile, abanokutheleleka kwe-falciparum okunama-gametocyte kodwa okungenazimpawu | I-dihydroartemisinin-piperaquine kanye nodayi ongu-15 mg/kg/day izinsuku ezingu-3 kuqhathaniswa nomuthi wokulwa nomalaleveva wodwa | Phakathi kwabahlanganyeli ababekwazi ukuthelela ekuqaleni, ukwehla okumaphakathi kokukwazi ukuthelela omiyane kwakungamaphesenti angu-100 ngodayi, kuqhathaniswa nokucishe kungabi khona ukwehla ngaphandle kwawo ngosuku 2, futhi lokhu kwaqhubeka ngosuku 7 | Abamukeli bakadayi abangu-11 kuphela ababekwazi ukuthelela ekuqhathanisweni okuyinhloko; abesilisa kuphela, abane-G6PD ejwayelekile kuphela, abathwali abangenazimpawu; umphumela wokudluliselwa, hhayi inhlolo yokwelapheka |
| Burkina Faso 2019, izingane ezingu-100, umalaleveva we-falciparum | I-artesunate-amodiaquine kanye nodayi kuqhathaniswa nale nhlanganisela kanye nomthamo owodwa we-primaquine | Izinga lokwelapheka elilungisiwe lalingamaphesenti acishe abe ngu-96 kuwo womabili amaqembu; ukususwa kwezimuncagazi ngosuku 1 kwakushesha ngodayi; ama-gametocyte ngosuku 2 ayengamaphesenti angu-4 kuqhathaniswa nangu-31, nakuba i-primaquine ingazange inikezwe kwaze kwaba usuku 2 | Inhlolo yayincane futhi abahlanganyeli nabacwaningi babazi ukuthi yimiphi imithi eyayinikezwa; isikhathi sokunikezwa kwemithi senza ukuqhathaniswa kwangaphambili kwama-gametocyte kungalingani; okwakugxilwe kukho kakhulu kwakuwukuphepha okuphathelene negazi |
Kunezinto ezimbili ezihlala zibonakala kuzo zonke lezi zifundo. Okokuqala, udayi usebenza ngempela ngokumelene ne-Plasmodium falciparum, kodwa uwodwa ususa izimuncagazi kancane kakhulu futhi uvumela ukuthi ukutheleleka kuphinde kuqubuke; ucwaningo oluncane lwabantu abadala lwaphetha ngokuthi kufanele uhlanganiswe nomuthi osebenza ngokushesha. Okwesibili, inzuzo yawo eyengeziwe ephindeka ngokwethembeka kakhulu ngaphezu kwenhlanganisela yanamuhla ekhethwe kahle isemiphumeleni ephathelene nama-gametocyte nokudluliselwa, kunokuba ibe ukukhuphuka okukhulu kokwelapheka okujwayelekile. Ucwaningo lokuphakelwa komiyane ngegazi ngokuqondile ngolwelwesi eMali luyisibonakaliso esicace kakhulu salokho kwesibili, ngoba omiyane abaphakelwa igazi labahlanganyeli baba namathuba aphansi kakhulu okutheleleka.
Imikhawulo phakathi kwezinhlobo ibaluleke njengemikhawulo phakathi kwezinhlanganisela. Cishe bonke ubufakazi bomtholampilo banamuhla obuqinisekisayo buphathelene nomalaleveva we-falciparum. Ngomalaleveva we-vivax, ubufakazi bomtholampilo buhlanganisa ukubonwa kwangokomlando kanye nomsebenzi wanamuhla waseshubhini nelabhorethri wokuphakela omiyane, okuhlanganisa ukuzwela kudayi emazingeni aphansi e-nanomolar kwezimuncagazi ezahlukaniswa endaweni yaseThailand-Myanmar kanye nokuvinjwa okunamandla kokudluliselwa ocwaningweni lokuphakela lwango-2024. Akukho kulokhu okufakazela ukwelapheka emtholampilo kwezigaba ze-vivax ezisegazini, futhi akukho okubhekana nama-hypnozoite asesibindini abangela ukubuya kwe-vivax, adinga izinqumo zawo zokwelapha eziqondene nalolo hlobo. Ukwenza umphumela wokudluliselwa kwe-falciparum ube isimangalo ngazo zonke izimuncagazi kuphinda iphutha elidala kunawo wonke kule mibhalo yocwaningo. Umtapo wocwaningo ugcina okutholwe ezinhlolweni zabantu nokutholwe ekuhloleni kwaselebhu kumakholomu ahlukene ngenxa yalesi sizathu.
Ukuphepha kuhambisana nohlelo lokwelapha
Izingozi ezintathu kudingeka kubhekwane nazo ngokucacile ngoba zinquma ukuthi obani okungafanele bazame ukuzihlola ngalo muthi.
Ukushoda kwe-glucose-6-phosphate dehydrogenase kudala ingozi yokubhidlika kwamangqamuzana abomvu egazi, noma i-hemolysis. Ukuhlaziywa okuhlanganisiwe kwezifundo ezine zezingane zaseBurkina Faso, ezazihlanganisa izingane ezingu-1,005, kwathola ukwehla kwe-hemoglobin okwakuthe xaxa ngokusetshenziswa kukadayi kubahlanganyeli ababenokushoda okuphelele, kanye nezigameko ezimbili ze-hemolysis ezinganeni ezelashwa ngodayi ezazinokushoda noma ezaziyi-heterozygous. Ilebula yase-United States ye-methylene blue ejovwayo iyakwenqabela ukusetshenziswa kubantu abanokushoda kwe-G6PD ngoba kungenzeka i-hemolysis enzima. Izinhlelo zikamalaleveva zomuthi ophuzwa ngomlomo zihlukile kumthamo wezimo eziphuthumayo ofakwa emthanjeni, ngakho izinombolo ezikulebula azikwazi ukuguqulwa zibe umkhawulo womthamo wokwelapha umalaleveva, kodwa umthelela webhayoloji uya ohlangothini olufanayo. Ukuhlolelwa lokhu kushoda nokuqashwa kufanele kube yingxenye yanoma yikuphi ukusetshenziswa okwenziwa ngokucophelela.
Ukusebenzisana nemithi ethinta i-serotonin kufanele kubhekwe kanye nalokhu. I-methylene blue esebenza emzimbeni wonke ivimbela i-monoamine oxidase futhi ingabangela i-serotonin syndrome uma ihlanganiswe nemithi evimbela ngokukhetha ukumuncwa kabusha kwe-serotonin, imithi evimbela ukumuncwa kabusha kwe-serotonin ne-norepinephrine, imithi evimbela i-monoamine oxidase, kanye namanye ama-opioid nemithi yokukhwehlela; kuye kwabikwa nezigameko zokufa. Lokhu kusebenzisana, izimo ezinqabela ukusetshenziswa, nokuqashwa kuchazwe kabanzi esihlokweni esithi imiphumela engemihle, izimo ezinqabela ukusetshenziswa, nokuphepha.
Ukubekezeleleka komuthi kuyisithiyo esingabonakali kakhulu. Umchamo oluhlaza okwesibhakabhaka oxubene noluhlaza ulindelekile futhi awunabungozi, kodwa ubonakala ngokwanele ukuba uphazamise ukwamukelwa komuthi kusukela ngeminyaka yawo-1890s. Ukuhlanza kuncike emthamo nasendleleni umuthi owakhiwe ngayo, futhi kwabangela ukuhoxa ezinhlolweni zezingane, kwafinyelela kumaphesenti angu-40 abamukeli bakadayi uma kuqhathaniswa nangu-14 nge-primaquine kokunye ukuqhathanisa kwakamuva. Umuthi izingane eziwuhlanzayo ungumuthi ukusebenza kwawo okukhona ephepheni kuphela kulezo zingane.
Kungani lobu bufakazi bungakusekeli ukuzelapha
Iziqondiso zamanje zikamalaleveva zidinga ukuqinisekiswa kwesimuncagazi futhi zikhetha ukwelashwa ngokohlobo lwaso, ubunzima besifo, indawo nokumelana nemithi kuyo, iminyaka nesisindo, ukukhulelwa, nesimo se-G6PD, kanti izinhlanganisela ze-artemisinin ziyindlela ejwayelekile yokwelapha isifo se-falciparum. Akukho emibhalweni yocwaningo ngodayi okuthatha indawo yalolo hlelo lokwenza izinqumo. Ukusebenzisa umuthi wodwa kuhamba kancane kakhulu, ukukhetha umuthi ohambisana nawo kunquma ukwelapheka, ama-hypnozoite e-vivax adinga ukwelashwa okuhlukile, isimo se-G6PD sibeka imikhawulo ekusetshenzisweni, futhi imithi ethinta i-serotonin esetshenziswa ngesikhathi esifanayo idala ukusebenzisana okuyingozi. Ukwelashwa okungalungile kungashiya ukutheleleka kwe-falciparum okuphinde kuqubuke, kwehluleke ukubhekana nokubuya kwe-vivax, kubangele i-hemolysis, futhi kuveze izimuncagazi emandleni abuthakathaka omuthi avuna ukumelana nawo.
Isifinyezo esithembekile sinomkhawulo omncane kunalowo othandwa yilabo abawusekela ngokushisekela noma yilabo abawuchithayo. Udayi wekhulu leshumi nesishiyagalolunye unomsebenzi wangempela wemithi wekhulu lamashumi amabili nanye, kanti umnikelo wawo wanamuhla ocace kakhulu usekuvimbeni ukudluliselwa kwe-falciparum lapho wengezwa enhlanganiselweni efanele ngaphansi kokuqashwa kwenhlolo. Lokho kuwukutholakele ngokuphathelene nokunqamula ukusabalala emaqenjini acwaningiwe, hhayi umyalo wokuzelapha.