Ingabe i-methylene blue idala umdlavuza? Ubufakazi be-toxicology

I-methylene blue iveze izimpawu zezimila ekuhlolweni kwezilwane kwesikhathi eside kanye nemiphumela emihle ekuhlolweni okuningi kwaselabhorethri kokulimala kwezinto zofuzo. Leyo miphumela idinga ukunakwa. Ayinqumi amathuba okuthi umuntu athole umdlavuza ngemva kokuchayeka okuthile.

Ukuhlola kwe-IARC okushicilelwe ngo-2016 kwafaka i-methylene blue ku-Group 3, okusho ukuthi amandla ayo okubangela umdlavuza kubantu ayengakwazi ukuhlukaniswa. Iqembu elisebenzayo lalingenayo idatha yomdlavuza kubantu futhi labheka ubufakazi bezilwane njengobunomkhawulo. I-Group 3 ayisho ukuthi kutholakale ukuthi ayinabungozi. Ngokufanayo, umphumela otholwe ezilwaneni awusho ukuthi konke ukuchayeka kwabantu kufakazelwe njengembangela yomdlavuza.

Imibuzo emithathu edinga izimpendulo ezihlukene

Carcinogenicity iphathelene nokwakheka kwezimila. Ucwaningo lwezilwane lwesikhathi eside lungabona amaphethini ezimila ngemva kokuchayeka okuchaziwe. Genotoxicity iphathelene nokulimala kwezinto zofuzo noma izenzakalo zamaseli ezihlobene nalokho. Ukuhlolwa kwe-mutation okunomphumela omuhle kunikeza isignali yesixwayiso, kodwa akubali ngokuqondile imidlavuza kubantu. Ubungozi kubantu buphathelene namathuba okulimala ngaphansi kwezimo zangempela zokuchayeka.

Le mibuzo idinga izilinganiso ezihlukene. Ukubala ama-bacterial mutants, ukuhlola amaseli egazi lamagundane nokuxilonga izimila ngesikhathi se-necropsy akuzona izilinganiso ezingashintshaniswa. Futhi ukuhlolwa kokwelashwa okubonisa ukuthi into ethile ilimaza amaseli omdlavuza akusho ukuthi ukuchayeka okuphindaphindiwe kungaqalisa izimila ezicutshini ezinempilo. Ingxoxo ehlukile nge-methylene blue ocwaningweni lomdlavuza ibheka izimangalo zokwelashwa.

Ukuqhathanisa ucwaningo: ukuchayeka kwangempela kwesikhathi eside

Ukuhlolwa okuyinhloko kwasebenzisa i-methylene blue trihydrate, enikezwa ku-0.5% aqueous methylcellulose nge-oral gavage, okuwukunikezwa okulinganisiwe ngeshubhu elingena esiswini. Iqembu ngalinye lomthamo ocwaningweni lwesikhathi eside lalinabesilisa abangu-50 nabesifazane abangu-50 bohlobo ngalunye. Ukunikezwa kwenzeka izinsuku ezinhlanu ngesonto iminyaka emibili, ngokusho kombiko wocwaningo luka-Auerbach nozakwabo.

Ithebula ligcina iziphetho ze-NTP eziqondene nohlobo ngalunye. Amanani angama-milligram ezinto ezahlolwa ngekhilogremu yesisindo somzimba wesilwane ngezinsuku zokunikezwa, hhayi izincomo zabantu. Izilwane ezithole umthamo ongu-zero zathola i-vehicle.

Imodeli	Amaqembu omthamo, mg/kg	Indlela nesikhathi	Isiphetho se-NTP nomphumela ofanele
Amagundane esilisa e-F344/N	0, 5, 25, 50	Oral gavage; izinsuku ezinhlanu/ngesonto; iminyaka emibili	Ubufakazi obuthile: kwanda ama-pancreatic islet-cell adenomas kanye ne-adenoma/carcinoma ehlanganisiwe.
Amagundane esifazane e-F344/N	0, 5, 25, 50	Uhlelo olufanayo	Abukho ubufakazi bomsebenzi we-carcinogenic ngaphansi kwalezi zimo.
Amagundane esilisa e-B6C3F1	0, 2.5, 12.5, 25	Oral gavage; izinsuku ezinhlanu/ngesonto; iminyaka emibili	Ubufakazi obuthile: kwanda i-small-intestinal carcinoma kanye ne-adenoma/carcinoma ehlanganisiwe. I-malignant lymphoma kungenzeka nayo yayihlobene.
Amagundane esifazane e-B6C3F1	0, 2.5, 12.5, 25	Uhlelo olufanayo	Ubufakazi obungacacile: ukwanda okuncane kwe-malignant lymphoma.

“Ubufakazi obuthile” yisigaba se-NTP somphumela wokuhlola omuhle onamandla amancane kunokuthi “ubufakazi obucacile.” “Okungacacile” kuchaza umphumela ongaqinisekile. Lezi zigaba ziveza amandla obufakazi, hhayi iphesenti lobungozi noma ukulinganiswa kokuthi i-carcinogen inamandla kangakanani.

Umphumela wamagundane esilisa wawungewona ukukhuphuka okuqhubekayo ngokuhambisana nomthamo. I-pancreatic islet adenoma noma carcinoma yenzeka ku-4/50 yama-controls naku-9/50, 14/50 kanye no-8/50 wezilwane njengoba imithamo ikhuphuka. Iphepha elishicilelwe libika ukubaluleka kwezibalo kumthamo ophakathi kuphela. Lokhu kwenza incazelo elula yomugqa oqondile inganembi; akufakazeli ukuthi umthamo ophakeme kunayo yonke wawuvikela. I-adenoma iyisimila esingenamdlavuza, kuyilapho i-carcinoma iyisimila esiyingozi. I-endpoint ehlanganisiwe akufanele ichazwe sengathi sonke isimila esibaliwe sasiyisifo somdlavuza.

Kungani izifinyezo ezahlukene zizwakala ziphikisana

Imininingwane yamanje yokunikezwa kwe-PROVAYBLUE ibika imiphumela ye-pancreas kumagundane esilisa kodwa ithi akukho miphumela ye-neoplastic ehlobene nomuthi eyabonwa kumagundane. Iphepha locwaningo lithi ukwanda kwe-neoplastic kumagundane kwakungabalulekile ngokwezibalo, kuyilapho liphawula amathrendi amahle. Nokho, i-NTP yanikeza amagundane izigaba eziboniswe ngenhla.

Ukuhlaziywa kwe-IARC kocwaningo lwezilwane kucacisa umehluko obalulekile wezibalo: imiphumela yamathumbu kumagundane esilisa yayinamathrendi omthamo abalulekile, kodwa amaqembu ngamanye athole umthamo ayengabalulekile ekuqhathanisweni ngakubili nama-controls. Ukuhlola iphethini iyonke kuwo wonke amazinga omthamo kuhlukile ekuhloleni iqembu ngalinye ngokwehlukana. Abafundi kufanele bagcine umthombo namagama awo kunokucindezela yonke le miphumela ibe ukuthi “amagundane athola umdlavuza” noma “ucwaningo lwamagundane lwalunomphumela ongemuhle.” Akukho kulokhu okunikeza izinga lomdlavuza elilinganisiwe kubantu.

Ukuqhathanisa ucwaningo: izilinganiso zokulimala kwezinto zofuzo

Ingxenye ye-genetic toxicology ku-NTP Technical Report 540 ichaza uchungechunge oluhlukile lokuhlolwa. I-S9 iyingxube yaselabhorethri equkethe ama-enzyme esibindi esetshenziswa ukumodela i-metabolic activation. Ukuba khona kwayo akuguquli ukuhlolwa kwamaseli kube ucwaningo lokuchayeka komzimba wonke.

Uhlelo lokuhlola	Izimo zangempela zokuchayeka	I-endpoint elinganisiwe nomphumela
Ukuhlolwa kwe-bacterial mutation, i-lot yesibili ehloliwe	Salmonella: 0.25–150 µg/plate; E. coli: 0.25–1,500 µg/plate; nge-rat-liver S9 nangaphandle kwayo	Kwanda ama-mutations ezinhlotsheni ezahlolwa.
Amaseli e-Chinese hamster ovary akhuliselwe elabhorethri	Ukuhlolwa kwe-sister-chromatid exchange kwakuhlanganisa 0.17–2.5 µg/mL ngaphandle kwe-S9, kuze kufike ku-5 µg/mL nge-S9; ukuhlolwa kwe-chromosome-aberration kwasebenzisa 4.7–22 µg/mL	Imiphumela emihle ye-exchange ne-chromosome-aberration.
Amagundane esilisa, ukuhlolwa kwe-acute	Umjovo owodwa we-intraperitoneal: 25, 50 noma 150 mg/kg; amasampula ngemva kwamahora angu-48	Akukho kwanda kwama-micronucleated erythrocytes emnkantsheni noma egazini.
Amagundane esilisa nawabesifazane, ukuhlolwa okuphindaphindiwe	Oral gavage: 25, 50, 100 noma 200 mg/kg; izinsuku ezinhlanu/ngesonto izinyanga ezintathu	Akukho kwanda kwama-micronucleated erythrocytes egazini le-peripheral.

I-micronucleus iwumzimba omncane owengeziwe we-nucleus ongabonisa ukuphuka kwe-chromosome noma ukulahleka kwe-chromosome ngesikhathi sokuhlukana kwamaseli. Ukuhlolwa kwamangqamuzana egazi okunomphumela ongemuhle kuphendula lowo mbuzo othile kulawo maseli athathwe amasampula. Akukwazi ukukhipha amathuba azo zonke izinhlobo zokulimala kwe-DNA kuzo zonke izitho. Ngokuphambene, ukuhlolwa kwamaseli akhuliselwe elabhorethri okunomphumela omuhle akusitsheli ukuthi izicubu zomuntu zafinyelela kuliphi izinga lokugxila.

Imininingwane yokunikezwa nayo iqopha le phethini iyonke: ukuhlolwa kwamabhaktheriya namaseli akhuliselwe elabhorethri okunemiphumela emihle, nokuhlolwa kwe-micronucleus kumagundane okunemiphumela engemihle. Ukubiza i-methylene blue ngokuthi nje “genotoxic” noma “non-genotoxic” kususa ulwazi olubalulekile ekuchazeni imiphumela.

Lokhu kusho ukuthini ngokuchayeka komuntu

Lezi zifundo azinikezi umkhawulo wansuku zonke oqinisekisiwe wokuchayeka ongabhekwa njengophephile ngokomdlavuza kubantu. Ukuhlukanisa umthamo wegundane ngesici sesisindo somzimba ngeke kuxazulule umehluko ekumuncweni, metabolism, endleleni yokuchayeka, emvamisa yokuchayeka noma esikhathini sokuphila. Lokho kungakhiqiza inani eliguquliwe, hhayi ubufakazi bokuphepha.

Ukuhlolwa kwe-gavage kweminyaka emibili nokwelashwa okufushane nge-intravenous ngaphansi kokuqondisa kwezokwelapha kuphendula imibuzo ehlukene. Lowo mehluko uvimbela ukuguqulwa okuqondile kwezinombolo; awususi imiphumela yezilwane. Ukuhlola okuwusizo kuqala ngenhlanganisela nefomula okuyikho, inani, indlela, imvamisa, isikhathi nesizathu sokusetshenziswa. “Amaconsi ambalwa” akuchazi kokubili ukugxila nomthamo olinganisiwe.

Uma i-methylene blue inikezwe ngesizathu sezokwelapha, imiphumela yezimila iyodwa ayikwazi ukunquma ukuthi izinzuzo zalokho kwelashwa zazidlula yini ubungozi bako. Uma kucatshangelwa ukusetshenziswa okuphindaphindiwe okukhethwayo, ubungozi bomdlavuza besikhathi eside obungakalinganiswa akufanele buchazwe njengobungu-zero. Izindaba ezisheshayo kakhulu, kuhlanganise nokusebenzisana kwemithi nokuthambekela ku-haemolysis, kuxoxwa ngazo kokuthi imiphumela engemihle nezimo lapho kungafanele kusetshenziswe khona.

Ukuze ufunde kabanzi, sebenzisa umtapo wocwaningo ukuze uhlukanise izifundo zabantu ekuhlolweni kwezilwane namaseli. Umbuzo obalulekile ngephepha ngalinye ukuthi lalihlola kuphi ukuchayeka nokuthi yimuphi umphumela elawulinganisa ngempela.