Umlando we-methylene blue: kusukela kudayi kuya emuthini nasocwaningweni

I-methylene blue yafinyelela esigulini ngaphambi kokuba ifinyelele ekhemisi.

Umbiko wango-1891 kaPaul Guttmann noPaul Ehrlich ngokusetshenziswa kukadayi kumalaleveva uqukethe amashadi amabili okushisa komzimba. Elesibili lisukela ku-13 July kuya ku-5 August, kanti ukwelashwa kubhalwe eceleni kosuku ngalunye. Okubhalwe ngo-18 no-19 July kuthi "1 × 0,05 Methylenblau". Ezinsukwini ezalandela kubhalwe imithamo emihlanu neyisikhombisa yenani elifanayo, futhi ngo-22 July inani elincane le-quinine selifakiwe emlandweni. Umugqa wokushisa komzimba, oshintshashintsha phakathi kuka-37 °C no-39.5 °C engxenyeni yokuqala yeshadi, uba cishe yisicaba ngemva kokuvela kukadayi futhi uhlale phakathi kuka-36 °C no-37.5 °C cishe amasonto amathathu asele.

Isiguli sasingenye yezimbili, ezachazwa ephepheni njengesisebenzi sasendlini netilosi. Inhlanganisela abayithola yayisineminyaka eyishumi nanhlanu ingudayi wezindwangu othengiswayo, futhi la madoda amabili aphakathi kwabantu bokuqala abaqoshiwe abelashwa ngomuthi owenziwe ngokuphelele owawuqondiswe entweni ephilayo ethile.

Udayi wafika kuqala

Udayi wokuqala wokwenziwa owaphumelela ngokwentengiso wenziwa nguWilliam Henry Perkin ngo-1856. UPerkin wayeneminyaka eyishumi nesishiyagalombili, esebenza elabhorethri yasekhaya ngesikhathi seholide le-Easter, futhi ezama ukuhlanganisa i-quinine. Esikhundleni salokho wathola insalela emnyama, wayincibilikisa, wabe esethola umbala owabambelela ngokugqamile kusilika. Wawutholela ilungelo lobunikazi ngo-August 1856 futhi ekupheleni kuka-1857 wayesenefektri eyayihlinzeka indawo yokudaya usilika eLondon.

Ngo-1875 u-Adolf von Baeyer wahlanganisa udayi obomvu wawuqamba ngokuthi eosin, kusukela ku-Eos, igama lesiGreki elisho ukusa. Ngo-1876 uHeinrich Caro, ngaleso sikhathi owayengumqondisi welabhorethri eBadische Anilin- und Soda-Fabrik, wasungula i-methylene blue noBaeyer njenge-aniline-based dye for cotton. Isakhiwo sayo samakhemikhali asizange sicaciswe kwaze kwadlula cishe iminyaka eyisishiyagalolunye.

Lowo msuka usabonakala endleleni le nto eqanjwe ngayo. "Methylene blue" yigama lokuhweba elivela kukhathalogi kadayi, hhayi incazelo yamakhemikhali. Inhlanganisela ebhekiselwa kuyo yi-methylthioninium chloride, futhi umehluko phakathi kwegama, usawoti nama-hydrate ayo uba semqoka ngokushesha nje lapho umuntu ekala le nto noma efunda i-specification.

Ukudaya amasampula kwaba yibhuloho

Indlela esuka ezindaweni zokwenza udayi iya esibhedlela yadlula ngesibonakhulu, futhi yaqala ngaphambi kokuba i-methylene blue ibe khona. UWilhelm Erb waba ngumuntu wokuqala ukufaka udayi wokwenziwa egazini, esebenzisa i-picric acid ngo-1865, futhi wabona iphethini efana nenethi ngaphakathi kwamanye amaseli abomvu.

Ithesis yobudokotela kaPaul Ehrlich yango-1878 yaqhathanisa ukudaya kwezicubu nokudaya izindwangu futhi yaphikisa ngokuthi kokubili kwakuyizimpendulo zamakhemikhali. Esebenza ngaphansi kukaRobert Koch nge-tubercle bacillus, wahlukanisa odayi be-aniline baba amakilasi e-acid nawe-basic futhi waqinisekisa ukuthi ikilasi ngalinye lalifaka umbala ezingxenyeni ezahlukene zeseli. Ngo-1880 wahlanganisa lezi zinhlobo ezimbili: isixazululo esigcwele se-methylene blue sathelwa ku-acid fuchsin kuze kucace uketshezi olungaphezulu. Umphumela, awubiza ngokuthi neutralen Farbkörper noma i-neutral stain, wakhiqiza imibala emithathu esikhundleni sowodwa, waveza izinhlayiya kumaseli e-polymorphonuclear ezazingakaze zibonakale ngaphambili, futhi wenza kwaba nokwenzeka okokuqala ukubala izinhlobo ezahlukene zama-leukocyte. Ngenxa yokuthi lezo zinhlayiya zamukela zombili izingxenye zengxube, u-Ehrlich waqamba igama elithi neutrophil ngamaseli aziphethe.

Eminyakeni emibili kamuva uKoch wasebenzisa i-methylene blue ukuthola i-tubercle bacillus, futhi ngo-1883 u-Ehrlich wayithuthukisa le ndlela. Ngo-1886 washicilela olunye uhlobo lokuqaphela: wafaka udayi ezilwaneni eziphilayo ngomjovo futhi waqhathanisa ukuthi isitho ngasinye siwumunca ngamandla angakanani, waphetha ngokuthi wawunokuthanda okuphawulekayo izicubu zobuchopho nezinzwa. Lokho kuthanda wakuhlobanisa nomjikelezo we-oxidation-reduction kadayi, ayewuqaphele ngonyaka owandulele. Lowo mjikelezo futhi uyisizathu sokuthi isixazululo se-methylene blue silahlekelwe umbala lapho umoya-mpilo waso usuphelile bese siwuthola futhi lapho umoya ubuya. Ucwaningo lokuqala olwalinganisa imiphumela yalowo mjikelezo lungolweminyaka eyalandela, futhi indlela uqobo esebenza ngayo iyisihloko esehlukile emlandweni.

I-parasite nenucleus ensomi

U-Alphonse Laveran wathola i-parasite kamalaleveva ngo-1880 ngokuhlola igazi elisha elingadaywanga. Ukuyibona njalo ku-smear eyomisiwe kwakudinga i-stain, futhi ama-stain angaleso sikhathi ayekhiqiza umbala obomvu noluhlaza okwesibhakabhaka kuphela.

Ngo-1888 isazi sezifo sasePoland uCzesław Cheçinski sashintsha i-acid fuchsin safaka i-eosin, sakhiqiza ingxube ye-methylene blue ne-eosin. Icala elaholela endleleni yakhe kwakungelesosha elabulawa umalaleveva ngo-30 September 1887. Kuma-film egazi uCheçinski wabona izinhlobo eziluhlaza okwesibhakabhaka ezifana nezimbali ze-daisy, manje ezaziwa ngokuthi Plasmodium malariae, kanye nezinhlobo ezimise okwesikela, manje ezaziwa njengama-gametocyte e-Plasmodium falciparum. Umphumela waqeda ngesikhathi esisodwa izincazelo ezimbili ezazincintisana zesifo: ithiyori ye-miasma, kanye nokushiwo ngu-Edwin Klebs noCorrado Tommasi-Crudeli ukuthi umalaleveva wawubangelwa i-bacterium.

I-parasite yayisibonakala. Inucleus yayo yayingabonakali, okwashiya ubunjalo bayo bungacacile. U-Ernst Malachowski, udokotela waseBreslau, wayixazulula le nkinga ngengozi, kamuva wayenza ngamabomu. Ngo-1889 waqaphela ukudayeka okuhlukile kwenucleus ye-plasmodium ku-preparation kodwa wangakwazi ukuphinda umphumela. Ukwenza i-methylene blue ibe ne-acid kakhulu akusizanga. Ukuyenza ibe yi-alkaline nge-borax kwaveza umphumela njalo. Wabonisa le ndlela emphakathini ngo-15 June 1890 futhi wayishicilela ngawo lowo nyaka, kwalandela indlela eningiliziwe ngo-August 1891.

UDmitri Romanowsky washicilela inguqulo yakhe ngo-September 1891. Imiphumela yakhe emihle kakhulu yavela ebhodleleni elalishiywe isikhathi eside, selinesikhunta, lesixazululo se-methylene blue elalineminyaka engaphezu kwezinyanga ezimbili. Incazelo kaMalachowski yayihlelwe ngamabomu futhi, ngamazwi akhe, kulula ukuyiphinda; ekaRomanowsky yayiyindlela engasayi ndawo eyasebenza kanye kuphela. Noma kunjalo, igama lakhe yilona elagcina lihlotshaniswa nendlela, futhi impikiswano ngokuthi ubani owakhiqiza umbala onsomi owenza inucleus yabonakala iyindaba ehlukile enemibhalo yayo.

Umfanekiso: ishadi lesibili lokushisa komzimba embikweni kaGuttmann no-Ehrlich wango-1891. Ingxenye engenhla ihlanganisa u-13 kuya ku-24 July kanti engezansi u-25 July kuya ku-5 August; okubhalwe eceleni kubalula imithamo enikeziwe, futhi izinga lokushisa lihlala liseduze nokujwayelekile emasontweni amathathu okugcina erekhodi. Kukhiqizwe kabusha kusukela embikweni njengoba waskenelwa uKrafts, Hempelmann noSkórska-Stania, Parasitology Research 111:1–6 (2012), PMID 22411634.

Kwatholakala ukuthi ukuvuthwa kwakuyi-demethylation

Akekho kubantu ababehilelekile ngeminyaka yawo-1890 owayazi ukuthi "ukuvuthwa" kwakwenzani ku-methylene blue. Impendulo yavela ekhemistri yezimboni. UHeinrich August Bernthsen wayehlanganise inhlanganisela eyisisekelo i-phenothiazine ngo-1883, waqinisekisa ngo-1885 ukuthi i-methylene blue yayingeyalo mndeni, futhi ngesikhathi esifanayo wabonisa ukuthi izimo ze-alkaline zisusa amaqembu e-methyl kudayi, zikhiqize izinhlanganisela manje ezibizwa ngokuthi ama-azure.

UBernard Nocht wakhipha ingxenye esebenzayo ngo-1898 nango-1899 futhi wayengakwazi ukuyibiza ngokunye ngaphandle kokuthi Rot aus Methylenblau, okubomvu okuvela ku-methylene blue. UMichaelis wayikhomba njenge-azure I ngo-1901. UJenner wethula i-absolute methanol njenge-solvent ye-precipitate kadayi ngo-1899, okwasusa isidingo sokulungisa ama-film egazi ngokuwashisisa; uLeishman noReuter bahlanganisa lezi ntuthuko zombili; uWright washicilela indlela eyenziwe lula ngo-1902. Iqhaza likaGiemsa, nalo elango-1902, kwakuwukuyeka ukuthembela esixazululweni esivuthwe ngokungahleliwe bese esikhundleni salokho esebenzisa amanani alinganisiwe odayi abaziwayo. Kamuva wenqaba ukushicilela ukuthi wayenza kanjani i-methylene azure emsulwa futhi wathengisa indlela elabhorethri kaDr. Grübler, eyamaketha umkhiqizo njenge-azure I futhi yathi inguqulo yayo kuphela eyayiyi-Giemsa stain yangempela.

Izimpi zomhlaba ezimbili zaqedela umsebenzi ngengozi. Lapho odayi baseJalimane bengasatholakali, uLillie, Roe noWilcox basebenza ngezinto zaseMelika ezazisetshenziswa esikhundleni sazo futhi bathola ukuthi ukudaya okuhle kakhulu kwakutholakala ezingxenyeni ezintathu ezihlukanisiwe: i-methylene blue emsulwa, umkhiqizo wayo wokwephuka azure B, kanye ne-eosin. Lezo ezintathu ziseyizingxenye eziyinhloko ze-stain esetshenziswa namuhla ukuxilonga umalaleveva, ngaphansi kwegama manje elihlanganisa uMalachowski, Wright noGiemsa.

Umfanekiso: izinhlobo eziyindandatho ze-Plasmodium falciparum kumaseli abomvu omuntu, ezidaywe ngendlela yohlobo lwe-Romanowsky. Isakhiwo esinsomi ngaphakathi kwendandatho yi-chromatin i-methylene blue kaMalachowski eyayilashwe nge-borax eyenza yabonakala okokuqala. Isithombe sika-Ernst Hempelmann, esikhishelwe emphakathini ngaphandle kwemikhawulo ye-copyright.

Igama elilodwa, izinto eziningana

Iminyaka eyahlukanisa lezo zingxenye yashiya inkinga eyaphila isikhathi eside kunekhemistri uqobo. URalph Lillie wadweba umugqa ngo-1969 phakathi kwama-stain ebhayoloji, "akhiqizwa ngezincazelo eziqinile ezihambisana nokusetshenziswa kwawo okubucayi nokudinga ukunemba", nama-stain angewona awokusetshenziswa ebhayolojini ayenzelwe ukudaya izindwangu, "adinga amazinga okukhiqiza angaqinile futhi angadingi kangako". Zombili izinhlobo zomkhiqizo zaziphethe igama elifanayo, futhi umehluko phakathi kwazo wawungewona nje umehluko wezinga. I-specification ebhalelwe ukotini ne-specification ebhalelwe i-reagent yokuxilonga azikwazi ukushintshaniswa, futhi into eyenziwe ngokwe-specification yezindwangu yayingahloselwe ukugwinywa.

I-Azure B iyisibonelo esicace kakhulu. Iyindlela ye-methylene blue esuswe iqembu elilodwa le-methyl, inomsebenzi wayo we-pharmacological ongalinganiswa, futhi yayikhona njengengxenye engalawulwa emalungiselelweni e-methylene blue asetshenziswa emitholampilo isikhathi esingaphezu kwekhulu ngaphambi kokuba umuntu ahlukanise lezi zinto ezimbili. Elinye iqembu lathola ukuthi izicubu zomuntu ezathathwa ngesikhathi sokuhlolwa kwesidumbu ngemva kokunikezwa kwe-methylene blue zaziqukethe amaphesenti angu-5 kuya ku-14 e-methylene blue engashintshile kanye namaphesenti angu-86 kuya ku-95 e-azure B. Ukuthi ukulungiselelwa okuthile kufanele kube ne-azure B yini, nokuthi ibe semkhawulweni ongakanani, kuwumbuzo we-specification, futhi ucwaningo nge-azure B njengokungcola nanjenge-metabolite luqhubeka lapho.

I-specification futhi yilapho kutholakala khona umphumela osebenzayo. Ukuhambisana ne-USP kuyindlela eya ebumsulweni obuphezulu kakhulu obutholakala emakethe, ngoba iyizinga lokuhlola eliphelele nelishicilelwe, hhayi isilinganiso esisodwa. Lihlanganisa ukuhlonza, i-assay, ukungcola kwe-organic okuhlanganisa odayi be-azure, ama-solvent asele, ukungcola kwe-elemental, insalela ngemva kokushiswa, imikhawulo yama-microbe, kanye nama-endotoxin ebhaktheriya. Isitifiketi esibika umphumela we-heavy-metal bese sithi lokho kuwukuhambisana ne-USP sibike umugqa owodwa kuphela kulolo hlu.

Blupreme ithola i-methylene blue yayo kumkhiqizi wemithi futhi ishicilela isitifiketi esiphelele sokuhlaziywa, ihlole yonke i-USP specification kunokuhlola ama-heavy metal kuphela. Umhlahlandlela wokufunda isitifiketi sokuhlaziywa kanye nokuthi igama le-USP lifakazela ini nokuthi yini elingayifakazeli kuchaza indlela yokuhlola idokhumenti ngokumelene nesimangalo.

Lokho umlando okuvumela ukuthi kushiwo, nalokho ongakuvumeli

Uchungechunge lomlando lukhona ngempela, futhi lude kunalokho amakhasi amaningi emikhiqizo akusikisela. I-methylene blue yasetshenziswa ukwelapha umalaleveva ngo-1891, kwabikwa ukuthi yasetshenziswa njenge-sedative ku-agitated psychosis ngo-1899, futhi uchungechunge lwayo lwamakhemikhali ludlulela ku-quinacrine, chloroquine, promethazine ne-chlorpromazine. Iphepha lika-Ehrlich lango-1890 no-Arthur Leppmann lachaza ukudamba kobuhlungu be-neuralgic nobu-rheumatic, lase licabangela kodwa lakhetha ukungawuhloli udayi ezifweni zengqondo.

Akukho kulokho okusungula ukusetshenziswa kwanamuhla. Umphumela kamalaleveva wango-1891 wawusekelwe ezigulini ezimbili neshadi lokushisa komzimba. Ukujwayelana isikhathi eside ne-molecule kuyisizathu sokuyicwaninga, hhayi umphumela. Umlando wenhlanganisela njengomuthi kanye nezivivinyo zanamuhla kumalaleveva kuphendula imibuzo ehlukile kuleyo u-Ehrlich ayeyibuza, futhi ama-endpoint kufanele afundwe ngokwemigomo yawo.

Kukhona imininingwane eyodwa erekhodini eyangalesi sikhathi kunokuba ibe ngeyesikhathi esedlule. Lapho abacwaningi benza izivivinyo ze-methylene blue zomalaleveva eBurkina Faso ngeminyaka yawo-2000, bazithola bencintisana ngokuthola into yezinga lemithi, futhi babika ukuthi intengo yezinto ezingavuthiwe yayikhuphuke cishe ngokuphindwe kayikhulu lapho sezinesiqinisekiso se-GMP. Udayi wawungashintshwa ngenye into. Umuthi wawungeke. Umehluko uLillie awudweba ngo-1969 uyefana nalowo onquma ukuthi ibhodlela liqukethe ini namuhla.