Ingabe i-methylene blue iyazilapha izimuncagazi?

Umbuzo uzwakala sengathi ungumbuzo owodwa. Empeleni uyimibuzo eyishumi nambili egqoke izingubo ezifanayo. Isimuncagazi sikamalaleveva esingaphakathi kwamangqamuzana egazi abomvu, isikelemu esisemathunjini, kanye nesidalwa esibangela i-cutaneous leishmaniasis cishe akukho okunye okufanayo phakathi kwazo ngaphandle kwegama elithi isimuncagazi. Umuthi olimaza esisodwa awuphoqelekile ukulimaza ezinye. Bambelela kulowo mqondo kukho konke lokhu kubuyekezwa: ukuba yi-antiparasitic akusona isici se-molecule iyodwa. Kuyisici se-molecule kanye nesidalwa esithile, esigabeni esithile sempilo, endaweni ethile yomzimba.

Uma usuzihlukanisile izidalwa, umlando we-methylene blue mayelana nezimuncagazi uhlukana ngokucacile. Kukhona umalaleveva, lapho kukhona khona izivivinyo kubantu. Bese kuba khona konke okunye: izitsha zaselebhu, amagundane, ukwelashwa kwesikhumba okwenziwa kusebenze ukukhanya, nezindaba ezineminyaka engaphezu kwekhulu. Akukho protocol eyodwa yezimuncagazi esebenza kubo bonke ephuma kunoma yikuphi kwalokhu.

Impendulo emfushane

I-methylene blue iyi-antimalarial yokuhlola yangempela. Ukubuyekezwa okuhlelekile kwezifundo zabantu ezingu-21 ezihlanganisa iziguli zikamalaleveva ezingu-1,504 kwathola umsebenzi wangempela esigabeni segazi kanye nemiphumela enamandla ikakhulukazi esigabeni se-gametocyte esidlulisela ukutheleleka komiyane. Ngaphandle kukamalaleveva, ubufakazi obushicilelwe abusekeli ukuphatha i-methylene blue njenge-antiparasitic ebanzi noma njengendlela yokuhlanza izimuncagazi zamathumbu. Cishe konke okutholakele okungahlobene nomalaleveva kusezingeni eliphansi kakhulu lesitebhisi sobufakazi: kuyasebenza esitsheni saselebhu, kwesinye isikhathi kuyasebenza egundaneni, futhi cishe akukaze kuhlolwe kubantu abathelelekile.

Umalaleveva: isimuncagazi esisodwa esinezivivinyo kubantu

Ngo-1891, uGuttmann no-Ehrlich babika ukwelapha iziguli zikamalaleveva nge-methylene blue, okungenzeka kube umuthi wokuqala wokwenziwa owake wasetshenziswa ukulwa nesifo kubantu. Umlando ukusuka kudayi kuya ekubeni yinhlanganisela ehamba phambili ye-antimalarial uqhubeka uze ufike ku-chloroquine, eyazuza ifa lekhemistri elaqale lahlolwa ngalo dayi.

Ucwaningo lwesimanje lwayivuselela ngoba izimuncagazi ezimelana nemithi zakha isidingo. Emasikweni aselebhu, i-methylene blue ivimbela i-Plasmodium falciparum ezwela ku-chloroquine kanye nemelana nayo ngama-concentration aphansi e-nanomolar, futhi kubikwe ukusebenzisana okuqinisanayo nama-artemisinin derivatives. Njenge-monotherapy kubantu yabonakala isebenza kancane: isivivinyo esilawulwayo kubantu abadala abane-semi-immunity eBurkina Faso sathola izinga lokwehluleka kusenesikhathi elingu-16 percent, futhi ababhali banquma ukuthi ayifanele njengomuthi owodwa wesikhathi esifushane. Izinhlanganisela zasebenza kangcono. Esivivinyweni esenziwe ngokungahleliwe ezinganeni ezingu-180, i-methylene blue ne-amodiaquine yafinyelela ekuphenduleni okulungisiwe okungu-95 percent ngosuku 28, futhi womabili amaqembu e-methylene blue anciphisa kakhulu ukuthwalwa kwama-gametocyte ekuhlaziyweni okuhambisanayo kokudluliselwa. Isivivinyo senhlanganisela yezidakamizwa ezintathu ezinganeni ezingu-221 kamuva saqinisekisa umphumela kuma-gametocyte nge-microscopy nangokutholwa kwamangqamuzana. Umphumela ogqame kakhulu wasebenzisa omiyane njengendawo yokugcina yokulinganisa: esivivinyweni se-phase 2 eMali, ukwengeza izinsuku ezintathu ze-methylene blue kwaveza ukuncipha kwe-median okungu-100 percent ekuthelelekeni komiyane ngosuku lwesibili.

Kuxoxwa ngezindlela ezintathu ezingaba khona futhi akufanele zihlanganiswe kube yinto eyodwa. Udayi uvimbela i-enzyme yesimuncagazi i-glutathione reductase eshubhuni lokuhlola (Ki near 6.4 micromolar) futhi wenza i-redox cycling njenge-substrate edonsa ama-reducing equivalents (kuboniswe kuma-reductase abantu nawezimuncagazi). Kodwa izimuncagazi eziguqulwe ngokofuzo ezingenayo leyo enzyme zigcina ukuzwela okufanayo, ngakho lokho akukwazi ukuba yindaba yonke, futhi umbono omdala wokuphazamiseka kokususwa kwe-heme (owahlotshaniswa namandla e-nanomolar) awukakafakazelwa ezigulini. Isifinyezo esiqondile: ukusebenza kwangempela kubantu, akukho target eyodwa esivunyelwene ngayo ngokuphelele, futhi ayinayo indima ku-regimen evamile. Ama-regimen nedatha yokudluliselwa kutholakala ekubuyekezweni kwethu kwe-methylene blue yomalaleveva, okungaphindwa yileli khasi.

Babesia ne-Toxoplasma: zinamandla emasikweni aselebhu, azikho emtholampilo

I-Babesia, isihlobo sikamalaleveva esihlala kumangqamuzana egazi abomvu, nayo yabulawa ezitsheni zaselebhu ngama-concentration angaphansi kwe-micromolar, futhi izimuncagazi ezazichayekile zahluleka ukukhula kabusha (Journal of Protozoology Research) kanti ukuhlolwa kwakamuva kwabeka udayi njengomenzeli onamandla kakhulu owahlolwa, cishe ku-0.2 micromolar (Carvalho nozakwabo, 2020). Emagundaneni, ngisho no-50 mg/kg wanikeza ukuvinjelwa okubuthakathaka kuphela, futhi akukho sifundo se-babesiosis kubantu esikhona.

I-Toxoplasma ikhombisa iphethini efanayo. Izifundo ezimbili zamasiko aselebhu ezahlukene ngamashumi eminyaka zathola ukucindezelwa okungaphansi kwe-micromolar kwama-tachyzoite azalanayo: 0.45 micromolar kuma-macrophage ngo-1989 kanye cishe no-0.30 micromolar ekuhlolweni kwe-antimalarial ngo-2018. Akukho kokubili okwathinta i-latent bradyzoite tissue cyst, okuyisigaba esinzima ngokomtholampilo, futhi asikho isifundo sokwelashwa ezilwaneni noma kubantu esatholakala. Inombolo ye-tachyzoite esitsheni saselebhu ayibona ubufakazi nganoma yikuphi ukutheleleka kumuntu.

Leishmania nama-trypanosome: qaphela ukukhanya, qaphela igundane

Ingxenye enkulu yezincwadi ze-Leishmania empeleni imayelana ne-photodynamic therapy, okuwumqondo ohlukile ngokuphelele nokugwinya udayi. I-photoactivation yehlisa i-concentration yokuvimbela i-Leishmania amazonensis ukusuka cishe ku-100 kuya ku-20 micromolar, futhi bonke ubufakazi kubantu buphelela esigulini esisodwa izilonda zaso ezathola i-antimony kuyilapho esisodwa sazo sathola futhi udayi owenziwe wasebenza ukukhanya. Ucwaningo kuma-hamster lwathola ukuthi ukwelashwa kwendawo okwenziwa kusebenze ukukhanya kwasiza, kuyilapho udayi ofakwe ngaphakathi kwesikhumba ungazange usize (Sbeghen nozakwabo, 2015). Udayi wendawo kanye nokukhanya okubomvu esikhumbeni akusikho ukwelashwa kwe-systemic.

Umlando wama-trypanosome unomphumela omubi owusizo kakhulu kulokhu kubuyekezwa: i-methylene blue yabulala i-Trypanosoma brucei in vitro kodwa yehluleka ukwelapha amagundane athelelekile ngo-300 mg/kg ngomlomo noma ngo-200 mg/kg ngomjovo. Mayelana nesifo i-Chagas, ubufakazi bungokwe-biochemistry, nge-enzyme eqondene nesimuncagazi i-trypanothione reductase (Buchholz nozakwabo, 2008), kanye nokubulala okuthuthukiswa ukukhanya in vitro (Barbosa nozakwabo, 2020). Ukubulala amagciwane e-plasma efakwe isimuncagazi ngamabomu ebhange legazi (Gironés nozakwabo, 2006) kuthinta imikhiqizo yegazi, hhayi iziguli. Abafundi abafika lapha ngenxa yezifo ezithwalwa imikhaza kufanele baqaphele ukuthi isifo i-Lyme sibangelwa amagciwane kunokuba sibe yisifo sezimuncagazi; ubufakazi baso buhlolwa ekubuyekezweni kwethu kwe-methylene blue yesifo i-Lyme.

Izikelemu, ama-fluke, kanye nesimangalo sokuhlanza amathumbu

I-Schistosoma mansoni iyisibonelo esihle kakhulu sezikelemu kodwa nayo ayifinyeleli ezingeni elanele: udayi wabulala ama-schistosomula ngaphansi kuka-10 micromolar kanye nezindala ku-10 kuya ku-30 micromolar, kodwa amagundane athelelekile abonisa cishe u-60 percent wokuncishiswa komthwalo futhi akukho ukwelapheka okuphelele. I-pilot encane yabantu kulelo phepha yayiphathelene nenhlanganisela ehlukile yemithi, ngakho ayikwazi ukubizwa ngesivivinyo sikadayi kubantu. Ngokumelene nezibungu nezindala ze-Strongyloides, ama-concentration okuvimbela aseduze kuka-4 kuya ku-6 micromolar ahambisana nokungena kukadayi esikelemwini, kodwa amagundane anikezwe ngomlomo abonisa ukungabikho kokulawulwa okubalulekile kokutheleleka. Mayelana ne-scabies nezintwala, abukho ubufakazi bokwelapha kubantu obatholakala.

Asikho isivivinyo sesimanje, uchungechunge, noma umbiko wecala okholisayo obonisa ukuthi i-methylene blue yomlomo iqeda i-Giardia, i-Entamoeba, i-Strongyloides, noma ama-helminth amathumbu kubantu. Into eseduze kakhulu efakwe ohlwini umbiko wango-1956 nge-giardiasis yenyongo ongenayo i-dose etholakalayo noma ukwelapheka okuqinisekisekayo. Amaphepha amabili esimanje e-Giardia kulula ukuwahumusha kabi: kwelinye, udayi ongu-1 percent wawuyistain eyayiveza ama-trophozoite, kanti kwelinye, udayi ohlanjululwe wawuyistain yokufunda umphumela ngemva kwemithi evamile. I-stain efaka umbala esimuncagazini ngaphansi kwe-microscope akuwona umuthi osibulala emathunjini. Mayelana ne-Trichomonas, isifundo esisodwa sezilwane futhi siyi-photodynamic: udayi wesitho sangasese sowesifazane kanye nokukhanya kumagundane athelelekile (Fonseca nozakwabo, 2019), hhayi ukuhlanza ngomlomo.

Ukuqhathanisa

Yini engashintsha le mpendulo

Izikhala zicacile ngokwanele ukuthi zingabizwa ngamagama. Akukho sivivinyo esibhalisiwe sokungenelela kubantu sikadayi nganoma yisiphi isimuncagazi esingewona umalaleveva esatholakala kuze kube uSeptember 2026, ngakho into yokuqala engekho yinoma yiluphi ucwaningo olulawulwayo kubantu ngaphandle kwe-Plasmodium. Okwesibili, ama-concentration ezitsheni agcinwa izinsuku amaningi aphinde ehluleka ezilwaneni ngenxa yokususwa ngokushesha noma ukufinyelela ezindaweni ezingalungile zomzimba, njengoba kuboniswa ukwehluleka kuma-trypanosome nase-Strongyloides emagundaneni. Okwesithathu, imiphumela ye-photodynamic kufanele iyeke ukucashunwa njengobufakazi be-systemic; udayi kanye ne-dose yokukhanya elinganisiwe kuyindlela yokubulala amagciwane endaweni ethile enenkinga yayo yokulethwa. Okwesine, izimangalo zamathumbu zidinga ama-endpoint e-parasitology, okusho ukuqedwa esitulweni noma ezicutshini kumaqembu alawulwayo, hhayi imibono yezimpawu ngesikhathi sama-protocol okuhlanza aqukethe izithako eziningi.

Amaqiniso amabili okuphepha abeka imingcele ekuhloleni umuntu azenzela khona. Udayi awuvunyelwe kubantu abanokuntuleka kwe-glucose-6-phosphate dehydrogenase ngenxa yengozi ye-hemolysis, futhi ukuhlaziywa okuhlanganisiwe kwezivivinyo ezine zikamalaleveva ezinganeni kwathola ukwehla okukhulu kwe-hemoglobin ezinganeni ezinentuleka ephelele kuma-dose e-antiparasitic aseduze kuka-15 mg/kg per day. Futhi iyi-monoamine oxidase A inhibitor enamandla futhi ebuyisekayo (indlela eholela ku-serotonin toxicity), efakwe ekulebheni kwamanje njenge-boxed warning, futhi umchamo oluhlaza okwesibhakabhaka ungakwazi ukuphazamisa ukuhlolwa komchamo okuzenzakalelayo. Imibuzo nge-dosing, ubumsulwa, nokusebenzisana neminye imithi itholakala kumhlahlandlela wethu osebenzayo wokusebenzisa i-methylene blue.

I-methylene blue yazuza idumela layo njenge-antiparasitic ngendlela efanele, ngokumelene nomalaleveva, ezivivinyweni ezenziwe ngokungahleliwe ezazine-endpoint yomiyane. Konke okungaphezu kwalokho kusebenzisa igunya elibolekiwe. Kuze kube yilapho ucwaningo olulawulwayo kubantu lubonisa okuhlukile ngesidalwa esithile esiqanjwe ngegama, isikhundla esingavikelwa sihlala sincane: i-antimalarial yangempela evimba ukudluliselwa esaphenywa, futhi kuyo yonke enye indawo kuwumphumela waselebhu osalinde ubufakazi bokuthi uyasinda lapho uhlangana nomzimba ophilayo.