UPaul Ehrlich ne-methylene blue: ukuhlolwa ngodayi

Umnikelo kaPaul Ehrlich kwezokwelapha wawungewona umuthi. Kwakuyimpikiswano yokuthi umuthi kufanele ubhekwe kanjani.

Ngo-1878 wethula ithisisi yobudokotela eyayinengxenye yokuqala enesihloko esithi "Ukuqonda Ukufaka Umbala Ngokwekhemistri." Yayiphikisa ngokuthi ukufaka umbala ocezwini lwesicubu nokudaya ucezu lwendwangu kulandela umqondo ofanayo. Kukho kokubili, umbala unamathela ngenxa yokuhambisana ngokwamakhemikhali phakathi kukadayi nento efakwa umbala, hhayi ngoba isicubu siyamunca, sinamafutha, noma sinesimo esibamba into enombala. U-Ehrlich wayekhule ebuka umzala wakhe, udokotela wezifo uKarl Weigert, elungisa izingcezu zezicubu ezifakwe umbala, futhi okwamdonsa kwakungezona izithombe kodwa iqiniso lokuthi udayi wawukhetha ukuthi uye kuphi.

Lokhu kungase kuzwakale njengomqondo omncane. Akunjalo. Uma udayi ubophezela esicutshini ngenxa yezizathu zamakhemikhali, khona-ke indlela umbala osabalala ngayo iwumbiko wekhemistri yaleso sicubu. Ingilazi yesibonakhulu enesicubu esifakwe umbala iyeka ukuba umfanekiso nje, ibe yisilinganiso.

Waqhubeka nokwakhela kulokho ngokushesha. Ngo-1880 wahlanganisa i-methylene blue ne-acid fuchsin, wabiza le ngxube ngokuthi udayi ongathathi hlangothi, i-neutralen Farbkörper, owawuhlukanisa izinhlobo ezahlukene zamangqamuzana egazi amhlophe lapho odayi ababesetshenziswa ngamunye ngaleso sikhathi behluleka khona. Ngemva kweminyaka emibili wethula indlela yokufaka umbala kuma-bacillus esifo sofuba nge-methyl violet, futhi uKoch wasebenzisa leyo ndlela emsebenzini wakhe.

Umbono owagcina unikeze lezi zinqubo isisekelo esifanayo uyindaba ehlukile, futhi isikhathi owaqala ngaso sivame ukuhlanganiswa ngokungafanele nesomsebenzi wangaphambili. Umbono ka-Ehrlich wamaketango asemaceleni, wokuthi into isebenza engqamuzaneni ngoba lezi ezimbili ziyahambisana ngokwamakhemikhali, ungoweminyaka yawo-1890, hhayi oweminyaka yomsebenzi ngodayi. Umsebenzi wangaphambili wanikeza inkolelo eyandulela lowo mbono: ukukhetha kuncike kumakhemikhali, ngakho ukukhetha kungafunwa kunokuba kutholakale ngenhlanhla.

Ukuhlola okwaguqula udayi waba ibalazwe

Ngo-1885 u-Ehrlich washicilela incwadi yocwaningo ngezidingo zomoya-mpilo zesidalwa esiphilayo, enesihlokwana esiyichaza njengocwaningo oluhlaziya ngemibala. Indlela yayo yayiwukujova odayi umbala wabo oncike esimweni se-oxidation, bese kuqhathaniswa indlela izitho ezahlukene ezibanciphisa ngayo ngokwamakhemikhali noma ezibalondoloza ngayo. Udayi wawusetshenziswa njengethuluzi, ngendlela kusetshenziswa ngayo ithemometha: wawubika ngezimo ezingaphakathi kwezicubu ezazingeke zihlolwe ngokuqondile. U-Ehrlich ngokwakhe wathi inhloso kwakuwukunquma, ngosizo lodayi abathile, amandla ezitho eziphilayo okunciphisa izinto ngokwamakhemikhali.

Umphumela we-methylene blue wavela ngo-1886, ephepheni elikhuluma ngokusabela kukadayi entweni yezinzwa ephilayo, elalifundelwe inhlangano yezokwelapha ngoDisemba owandulele. I-methylene blue yafakwa egazini elijikelezayo lesilwane esiphilayo, kwase kususwa izingcezu zezicubu ezizacile zabekwa emoyeni ukuze udayi ongenambala owawunqwabelene ubuyele ekubeni luhlaza okwesibhakabhaka nge-oxidation, ubonise lapho wawuqoqene khona. Amangqamuzana ezinzwa nemicu yezinzwa kwathatha umbala, futhi kwakwenza ngokukhetha okwakucace ngokwanele ukuthi le ndlela yaba indlela ejwayelekile yokubonisa izicubu zezinzwa. Le nhlanganisela yamakhemikhali yayingaseyona nje into yokufaka umbala ocezwini lwesicubu esifile phezu kwetafula lokusebenza. Yayisiwuphawu oluzisabalalisa ngaphakathi komzimba ophilayo, futhi ukusabalala kwalo kwakungafundwa.

Isici esiyisisekelo sakho kokubili lokhu kuhlola kufanele sishiwo ngokucacile, ngoba konke okunye kule ndaba kuncike kuso. I-methylene blue iyakwazi ukushintsha ibuyele esimweni sayo sangaphambili. Isimo sayo esincishisiwe, i-leucomethylene blue, asinambala, futhi lapho sithintana nomoya-mpilo sibuyela ekubeni yi-cation eluhlaza okwesibhakabhaka. Isixazululo sikadayi esine-glucose esitsheni esivalekile asinambala; vula isitsha bese siba luhlaza okwesibhakabhaka. Kubikwa ukuthi u-Ehrlich wakubonisa lokhu ngokuqondile ngokufaka i-iron chloride ezingcezwini ezifakwe umbala, nangokuzichaya emoyeni, ebuka umbala ubuya. Udayi oshintsha umbala ngesimo se-redox sendawo owukuyo uyithuluzi lokuhlola leyo ndawo.

Ngakho kwakunezici ezimbili ezihambisanayo. Udayi wawukwazi ukuhlukanisa isicubu esithile kwesinye. Futhi udayi wawungavulwa noma ucinywe ngokushintsha kwesimo se-oxidation.

Uma kubhekwa kusukela kokwenzeka kamuva, isici sesibili siyisiqalo sokwelapha ngamakhemikhali. Uma inhlanganisela yamakhemikhali ibophezela ohlotsheni olulodwa lwesicubu kodwa ingabophezeli kolunye, le nhlanganisela efanayo ingase ifinyelele ohlotsheni olulodwa lwesidalwa kodwa ingafinyeleli kolunye. U-Ehrlich wasisho ngokuqondile lesi siphetho: uma into edala isifo yayingafakwa umbala ngokukhetha, lokho kufakwa kombala kwakungase kubonise ukulimala okuqondene naleyo nto edala isifo. Ngakho udayi wawungase usetshenziswe njengomuthi, oqondiswe entweni ehlaselayo kunokuba uqondiswe esigulini.

Ukuhlolwa kokuqala esigulini kwakungekona okumalaleveva. Ngo-1890, esebenza nodokotela wezifo zengqondo u-Arthur Leppmann, u-Ehrlich wabika ukuthi i-methylene blue yayidambisa ubuhlungu ezimweni ze-neuralgia nezifo ze-rheumatism zemisipha, amalunga nemisipha exhumanisa imisipha namathambo. Laba bobabili baxoxa ngokuthi lo muthi ungase usebenze yini ekuguleni kwengqondo, base benquma ukungawuzami. Udokotela wase-Italy, uPietro Bodoni waseGenoa, waqhubeka nokho. Iphepha lakhe lango-1899 linesihloko esiphathelene nomphumela wokuthulisa ezinhlotsheni ezahlukene ze-psychosis: wachaza ukuthula ezigulini eziyishumi nane ezaziyaluza, futhi waphawula ukuthi abanye odokotela baseGenoa base bewusebenzisa udayi ngenhloso efanayo. Ukuthulisa akuwona umphumela esifweni uqobo, futhi lo mehluko ulokhu uvela kulo mlando.

Umsebenzi wokumalaleveva waqala ngo-1891, nodokotela wezifo uPaul Guttmann, esibhedlela saseMoabit eBerlin. I-methylene blue yanikezwa iziguli ezimbili, futhi umbiko wavela ku-Berliner klinische Wochenschrift yango-28 Septhemba 1891. Esimweni sokuqala isiguli sathatha u-0.5 g kadayi ngesikhathi esisodwa kusihlwa ngo-29 Juni; ukuhlasela okwakulindelwe akuzange kufike ngokuphelele, futhi isikhalo esisodwa esabhalwa kamuva kwakuwukuchama okubuhlungu nokunzima okuncane, nomchamo oluhlaza okwesibhakabhaka. Ukuhlasela komkhuhlane kwanyamalala ezinsukwini zokuqala, futhi izimuncagazi zazingasekho egazini kungakadluli usuku lwesishiyagalombili. Isifinyezo sababhali ngokwabo sasithi ababekulindele kwakufezeke ngokuphelele. Izimo ezimbili ezingenalo iqembu lokuqhathanisa azibona ubufakazi obuqinisekisayo. Incazelo egcwele ye-methylene blue nomalaleveva, kuhlanganise nokuhlolwa kwanamuhla, inendawo yayo ekhasini elihlukile, futhi umbuzo othakazelisayo lapha uncane: kungakanani ukucabanga kuka-Ehrlich okwasala kusebenza lapho kuhlangana nesimuncagazi.

Lapho ukucabanga kwasebenza khona nalapho kwehluleka khona

Kuncane okwasebenza encazelweni yendlela esebenza ngayo, okungenani ngendlela u-Ehrlich ayehlongoze ngayo. Incazelo ehleleke kahle, lapho i-cation eyisicaba enamasongo amathathu ingena phakathi kwamapheya ezisekelo ze-DNA yesimuncagazi, ayihambisani ne-Plasmodium. I-methylene blue incishiswa ngokwamakhemikhali kalula kakhulu yingqamuzana legazi elibomvu elinegciwane kangangokuthi ayifiki nhlobo esimuncagazini iyi-cation eyisicaba, futhi indaba yokungena phakathi kwezisekelo ehambisana nodayi be-acridine ayihambisani nalo.

Okusekelwa ubufakazi akuhlelekile kangako. I-methylene blue ivimbela i-glutathione reductase yesimuncagazi emazingeni isiguli esingafinyelela kuwo. Ivimba ukuguqulwa kwe-haem kube yi-haemozoin, into enombala engasebenzi ngamakhemikhali eyakhiwa yisimuncagazi ukuze singafakwa ubuthi yindlela sona esigaya ngayo i-haemoglobin, cishe ngezinga elifanayo nele-chloroquine nangempumelelo enkulu kakhulu kune-quinine. Ukujikeleza kwayo kwe-redox kuphinde kukhiqize izinhlobo zomoya-mpilo ezisabela kalula engqamuzaneni eselivele lizikhiqiza. Ukuthi iyiphi kulezi okuyindlela yangempela yokusebenza, noma ukuthi zonke ziyafaka yini isandla, akukanqunywa.

Kunobunye ubunzima, futhi kufanele bulolonge indlela efundwa ngayo noma yisiphi isimangalo somlando ngale nhlanganisela yamakhemikhali. I-methylene blue eyayidayiswa ngaleso sikhathi yayingeyona into eyodwa kuphela. Amasampula ayene-azure B, inhlanganisela ehlobene nayo esuswe iqembu elilodwa le-methyl, futhi izixazululo ezindala zaziqongelela eyengeziwe. I-Azure B ingudayi we-metachromasia onezinto ezihlukile oqondana nazo: ifaka i-DNA enemicu emibili umbala oluhlaza okwesibhakabhaka ojulile, ne-RNA umbala oluhlaza okotshani. Ingxube yodayi ababili abaya ezindaweni ezahlukene, ngezilinganiso ezingabhalwanga muntu, ayikwazi ukusekela isitatimende esicacile sokuthi i-methylene blue ekuyo yenzani.

Udayi uqobo awuzange uthathe indawo ye-quinine. Indlela yokusebenza yona yaphumelela kangcono. Umfundi ka-Ehrlich uWilhelm Roehl, owayesebenzela inhlanganisela yezinkampani zikadayi nemithi i-IG Farben, waqhubeka ephusha izinto ezisuselwa kodayi njengemithi yezifo zasezindaweni ezishisayo futhi wanikeza ithuluzi elalishoda: inyoni i-canary, itheleleke ngomalaleveva wezinyoni, njengendlela ejwayelekile yokuhlola izinhlanganisela ezazingase zisetshenziswe. UWerner Schulemann wabe eseguqula iketango eliseceleni, futhi usawoti we-phenothiazinium owavela lapho welapha ukutheleleka kokuhlola. Wawusazenza iziguli zibe luhlaza okwesibhakabhaka.

Umphumela owahlala isikhathi eside wagcina ungeyena udayi noma uhlelo lwamasongo, kodwa iketango eliseceleni. Ukwengeza iqembu le-dialkylaminoalkylamino kwashintsha indlela i-molecule eyayiziphatha ngayo, futhi leyo ngxenye yasala ikhona kukho konke ukwakhiwa kabusha okwalandela. Gcina lelo qembu bese ushintsha isongo le-phenothiazinium ufake ele-acridine, umphumela uba yi-quinacrine. Faka ele-quinoline esikhundleni salo, umphumela uba yi-chloroquine. I-pamaquine, i-primaquine ne-amodiaquine, konke okusekhona ohlwini lwemithi yokumalaleveva, kuthwala lelo qembu elifanayo. Inhlanganisela eyahluleka njengokwelapha yanikeza ingxenye eyaphumelela.

Ukuxhumana nemithi ye-antipsychotic kudlula esongweni kunokuba kudlule emuthini. Ukucacisa ukwakheka kwe-methylene blue yikho okwaholela uHeinrich August Bernthsen engqikithini eyisisekelo ye-phenothiazine ngo-1883, futhi leso sakhiwo, siguqulwe ngezindlela ezahlukene, yiso osokhemisi baseRhône-Poulenc ababesebenza kuso eminyakeni yawo-1940 ngesikhathi befuna ama-antihistamine. Enye yalezo zinhlanganisela yenziwa ngokuhlanganiswa kwamakhemikhali ngasekupheleni kuka-1950 futhi yahlolwa ngudokotela ohlinzayo uHenri Laborit, owabona ukuthi yayishiya iziguli zizolile futhi zingenandaba. Ukusetshenziswa kwayo kokuqala kwezokwelapha ingqondo okwashicilelwa, esigulini esine-mania, kwenzeka ngoJanuwari 1952. Umuthi wokuqala we-antipsychotic awuyona inzalo yomuthi ka-Ehrlich wokumalaleveva kangako; uyisihlobo esikude sikadayi aqala ngawo.

Imikhuba emithathu okufanele igcinwe kulesi sehlakalo

"Umuthi wokuqala owenziwe ngokuhlanganiswa kwamakhemikhali owasetshenziswa kwezokwelapha" uchaza isigaba, futhi imibandela yalesi simangalo mikhulu kunalokho okusikiselwa yileli binzana. Leli binzana selijwayelekile; ukubuyekezwa okucashunwa kakhulu kukaSchirmer nozakwabo ku-Neurobiology of Aging kubiza i-methylene blue ngomuthi wokuqala ngqa owenziwe ngokuphelele ngokuhlanganiswa kwamakhemikhali owasetshenziswa kwezokwelapha. I-chloral hydrate yethulwa njengomuthi wokuthulisa owenziwe ngokuhlanganiswa kwamakhemikhali ngo-1869, eminyakeni engaphezu kwamashumi amabili ngaphambili. Iphepha lango-1891 ngokwalo linikeza ingxenye yempendulo, ngoba ababhali balo babala imithi yokwehlisa umkhuhlane eyenziwe ngokuhlanganiswa kwamakhemikhali eyayisivele yehlulekile ukumelana nomalaleveva, phakathi kwayo kukhona i-quinoline, i-antipyrine ne-antifebrin. Umuthi ka-Ehrlich uqobo owawune-arsenic wokwelapha ugcunsula wafika kamuva nakakhulu. Uhlobo lwesimangalo olungavikelwa luphathelene nendlela kunokuba luphathelene nokuba ngowokuqala: i-methylene blue iphakathi kwezinhlanganisela zokuqala ezenziwe ngokuhlanganiswa kwamakhemikhali ezakhethwa ukuze zisebenze ngokumelene nesidalwa esithile ngokusekelwe embonweni wamakhemikhali wokukhetha.
Ukusabalala ngokukhetha akuyona inzuzo eqondiswe ngokukhetha. Umphumela ka-Ehrlich wango-1886 wawuwukuthi udayi uya ezicutshini zezinzwa. Ukuthi inhlanganisela iya kuphi nokuthi yenzani lapho ifika kuyizilinganiso ezimbili ezahlukene, futhi esokuqala kulula kakhulu ukusenza. Kulelo gebe yilapho iningi lezimangalo nge-methylene blue nobuchopho lihlale khona kusukela ngaleso sikhathi.
Ubumsulwa buyingxenye yobufakazi, hhayi yokumaketha. Umlando awucaci ngenxa yalesi sizathu uqobo. Umehluko omncane ekwakhekeni ushintsha ukuthi le nhlanganisela iya kuphi, yingakho isitifiketi sokuhlaziywa kufanele sihlotshaniswe nenqwaba ethile yokukhiqiza kunokuba sinikezwe njengesitatimende sokuthi umkhiqizo uyahlolwa. Umthengisi othi uhambisana nencazelo esemthethweni ye-pharmacopoeia kodwa ehlola izinsimbi ezisindayo kuphela usho okungaphezu kwalokho okusekelwa umbiko. I-Blupreme ithola i-methylene blue kumkhiqizi wemithi futhi ihlola zonke izimfuneko ezibekwe yileyo ncazelo: ubuwena bento, ubumsulwa, ukungcola kwezinhlanganisela eziphilayo, izincibilikisi ezisele, ukungcola kwezakhi zamakhemikhali, insalela ngemva kokushiswa, imikhawulo yamagciwane kanye nama-endotoxin ebhaktheriya. Umbiko ushicilelwa kanye nomkhiqizo, futhi ikhasi le-methylene blue yezinga le-USP lichaza leyo mikhawulo nokuthi kungani umphumela we-azure B kungowokuqala okufanele ubhekwe.

Umkhondo wemithombo onezinsuku

Usuku	Okwenziwa	Lapho kubhalwe khona
1878	Ithisisi yobudokotela iphikisa ngokuthi ukufaka umbala nokudaya izindwangu kulandela umqondo ofanayo wokuhambisana ngokwamakhemikhali	Ehrlich, ithisisi, Leipzig, 1878; ingxenye yayo yokuqala inesihloko esithi "Ukuqonda Ukufaka Umbala Ngokwekhemistri"
1880	I-methylene blue ene-acid fuchsin, "udayi ongathathi hlangothi", ihlukanisa izinhlobo zamangqamuzana egazi amhlophe	Krafts, Hempelmann noSkórska-Stania, Parasitol Res 111:1-6, 2012
1882	Indlela ye-methyl violet yokufaka umbala kuma-bacillus esifo sofuba yethulwa eNhlanganweni Yezokwelapha yaseBerlin, bese ishicilelwa ngonyaka olandelayo	Ehrlich, Berliner klinische Wochenschrift 20:13, 1883
1885	Incwadi yocwaningo ehlaziya ngemibala isebenzisa odayi be-redox ukuqhathanisa amandla ezitho okunciphisa izinto ngokwamakhemikhali	Ehrlich, Das Sauerstoff-Bedürfniss des Organismus, Berlin, 1885
1886	I-methylene blue ejovwe esilwaneni esiphilayo imaka izicubu zezinzwa ngokukhetha	Ehrlich, "Ngokusabela kwe-methylene blue entweni yezinzwa ephilayo", Deutsche Medizinische Wochenschrift 12(4):49-52, 1886
1888	I-methylene blue ene-eosin ifaka umbala esimuncagazini sikamalaleveva ezingqimbeni zegazi ezizacile	Chęciński, Centralblatt für Bakteriologie und Parasitenkunde 3(15):457-460, 1888
1890	Kubikwa ukuthi i-methylene blue idambisa ubuhlungu be-neuralgia ne-rheumatism	Ehrlich noLeppmann, Deutsche Medizinische Wochenschrift 16(23):493-494, 1890
1891	I-methylene blue inikezwa iziguli ezimbili ezinomalaleveva esibhedlela saseMoabit, eBerlin	Guttmann noEhrlich, "Ngomphumela we-methylene blue kumalaleveva", Berliner klinische Wochenschrift 28(39):953-956
1897	Umbono wamaketango asemaceleni uchazwa ngendlela yawo esithuthuke ngokuphelele, ephepheni elikhuluma ngeseramu ye-diphtheria	Ehrlich, Klinisches Jahrbuch 6:299-326, 1897
1899	Kubikwa umphumela wokuthulisa we-methylene blue ezinhlotsheni ezahlukene ze-psychosis	Bodoni, Clinica Medica Italiana 24:217-222, 1899
1926	I-canary ethelelekile iba indlela ejwayelekile yokuhlola izinto ezimelene nomalaleveva	Roehl, Deutsche Medizinische Wochenschrift 52, 1926
1932	Ukufaka enye ingxenye eketangweni eliseceleni kwelapha ukutheleleka kokuhlola	Schulemann, Proc R Soc Med 25:897-905, 1932
1934	Isongo le-acridine lithathelwa indawo yele-quinoline, kukhiqizwe i-chloroquine	Krafts nozakwabo, 2012, besebenzisa imibhalo yomlando egcinwe kwaBayer
1950	I-phenothiazine enezingxenye ezifakwe esikhundleni sezinye, kamuva eyaqanjwa ngokuthi i-chlorpromazine, yenziwa ngokuhlanganiswa kwamakhemikhali eRhône-Poulenc; ishicilelwa ngo-1952	Charpentier nozakwabo, Comptes rendus de l'Académie des Sciences 235:59-60, 1952
1952	Ukusetshenziswa kokuqala kwe-chlorpromazine kwezokwelapha ingqondo okwashicilelwa	Delay, Deniker noHarl, Annales médico-psychologiques 110:112-117, 1952

Ukulandelana kwezigigaba ezibalulekile ngokwezinsuku, kuhlanganise nekhemistri kadayi eyandulela u-Ehrlich kanye namazinga nezimfuneko ezalandela yena, kuchazwe ngokuhlukile emlandweni we-methylene blue, futhi ubuwena bale nhlanganisela buchazwe kokuthi iyini i-methylene blue.

Amashidi emifanekiso asekela le ndaba, aphinde avezwa ekubuyekezweni kwango-2012 kukaKrafts, Hempelmann noSkórska-Stania, awalingani njengobufakazi, futhi isibonelo esisodwa sibonisa ukuthi kungani. Ishidi lango-1891 liyirekhodi lokuqala lokuhlolwa; isithombe somuntu sango-1910 esiseduze kwalo sibeka isikhathi sedumela, akukho okunye. Amakhasi encwadi ka-Andersag yamanothi yango-1934 awumkhondo oqondile wokufakwa kwe-quinoline esikhundleni sesinye isongo, abhalwe ngesandla sosokhemisi uqobo.

Isifinyezo esithembekile sokuhlola kuka-Ehrlich ngodayi siwukuthi wayeqinisile ngokukhetha, eqinisile nangalokho okuqondiwe, kodwa wayephambukile ngendlela yokusebenza. I-methylene blue iyaqoqana ngempela ezicutshini zezinzwa futhi iyasilimaza ngempela isimuncagazi sikamalaleveva. Ayenzi lokhu kwesibili ngenxa yalokhu kokuqala, futhi isizathu samakhemikhali asinikeza ngakho kokubili sasingalungile. Lokho akubonisa ngaphandle kokungabaza kwahlala isikhathi eside kunencazelo elungile yendlela yokusebenza: inhlanganisela ingakhethwa kunokuba ivele itholakale, futhi ingakhethwa ngobufakazi obuqoqwe ngaphambi kokuba noma ubani ayinike isiguli.