UPaul Ehrlich ne-methylene blue: indlela idayi eyanceda ngayo ekubumbeni ukufunyanwa kwamachiza

Igalelo likaPaul Ehrlich kwezonyango lalingelilo ichiza. Yayiyindlela yokuqiqa ngendlela yokulihlolisisa.

Ngo-1878 wanikezela ngethisisi yobugqirha eyayinecandelo lokuqala elinesihloko esithi "Ingcamango Yekhemistri Yokudyobha Ngedayi." Ingxoxo yayo yayikukuba ukudyobha isiqwenga sethishu nokudaya ilaphu kulandela umgaqo ofanayo. Kuzo zombini, umbala unamathela ngenxa yokutsalana ngokwekhemistri phakathi kwedayi naloo nto idaywayo, kungekhona ngenxa yokuba ithishu iyafunxa, inamafutha, okanye imile ngendlela ebamba isakhi sombala. UEhrlich wayekhule ebukele umzala wakhe, ingcali yezifo uKarl Weigert, elungisa iziqwenga zethishu ezidayiweyo, yaye into eyayitsala ingqalelo yakhe yayingeyomifanekiso kodwa yayikukuba idayi yayikhetha apho iya khona.

Eli bango livakala lincinane. Alinjalo. Ukuba idayi ibophelela kwithishu ngenxa yezizathu zekhemistri, indlela umbala osasazeka ngayo iba yingxelo yekhemistri yaloo thishu. Isilayidi esidayiweyo siyayeka ukuba ngumfanekiso nje size sibe ngumlinganiselo.

Ngoko nangoko wakhela phezu kwaloo ngcamango. Ngo-1880 wadibanisa i-methylene blue ne-acid fuchsin waza wawubiza loo mxube ngokuba yidayi engathathi cala, neutralen Farbkörper, eyayisahlula iintlobo ezahlukeneyo zeeseli ezimhlophe zegazi apho iidayi ezazisetyenziswa zodwa ngelo xesha zazingenako ukwenza oko. Kwiminyaka emibini kamva wanikezela ngendlela yokudyobha iintsholongwane zesifo sephepha nge-methyl violet, yaye uKoch wayisebenzisa loo nkqubo kumsebenzi wakhe.

Ingcingane eyathi kamva yanika ezi nkqubo isiseko esinye ngumcimbi owahlukileyo, yaye ixesha layo lidla ngokudityaniswa nelomsebenzi wangaphambili. Ingcingane kaEhrlich yetsheyini esecaleni, ingcamango yokuba into isebenza kwiseli ngenxa yokuba ezi zimbini ziyahambelana ngokwekhemistri, yeyeminyaka yee-1890, kungekhona eyeminyaka yomsebenzi wedayi. Into eyayinikelwa ngumsebenzi wangaphambili yayiyinkolelo eyayisele ikhona: ukukhetha kuxhomekeke kwikhemistri, ngoko ke kunokufunwa endaweni yokuba kufunyanwe ngengozi.

Uvavanyo olwaguqula idayi yaba yimephu

Ngo-1885 uEhrlich wapapasha incwadi yophando ngeemfuno zeoksijini zomzimba, enesihlokwana esithi luphononongo lokuhlalutya ngemibala. Indlela yayo yayikukutofa iidayi ezinemibala exhomekeke kwimeko ye-oxidation, kuze kuthelekiswe indlela amalungu ahlukeneyo azinciphisa okanye azigcina ngayo. Idayi yayisetyenziswa njengesixhobo, ngendlela esetyenziswa ngayo ithemometha: yayibonisa iimeko ezingaphakathi kwithishu ezazingenakuhlolwa ngokuthe ngqo. UEhrlich ngokwakhe wachaza injongo njengokumisela, ngoncedo lweedayi ezithile, amandla okunciphisa ngokwekhemistri amalungu aphilayo.

Isiphumo se-methylene blue safika ngo-1886, kwinqaku elimalunga nokusabela kwedayi kwithishu yemithambo-luvo ephilayo, elalifundelwe umbutho wezonyango ngoDisemba wangaphambili. I-methylene blue yafakwa kumjikelezo wegazi wesilwanyana esiphilayo, kwaza kwasuswa iziqwenga ezibhityileyo zethishu zavezwa emoyeni ukuze idayi engenambala eyayiqokelelene ibuye ibe luhlaza okwesibhakabhaka nge-oxidation, ibonise apho yayiqokelelene khona. Iiseli zemithambo-luvo nemicu yemithambo-luvo zathatha umbala, yaye zakwenza oko ngokukhetha ngokwaneleyo ukuba le nkqubo ibe yindlela eqhelekileyo yokubonisa ithishu yemithambo-luvo. Le khompawundi yayingaseyonto yokufaka umbala kwisiqwenga esifileyo esibekwe etafileni kuphela. Yayisisiphawuli esizisasaza ngaphakathi komzimba ophilayo, yaye indlela esasazeke ngayo yayinokufundwa.

Uphawu olusisiseko kuzo zombini ezi mvavanyo lufanele luchazwe ngokucacileyo, kuba yonke enye into kweli bali ixhomekeke kulo. I-methylene blue inokuguquka ibuyele kwimo yayo yangaphambili. Imo yayo encitshisiweyo, i-leucomethylene blue, ayinambala, yaye xa idibana neoksijini ibuyela kwi-cation eluhlaza okwesibhakabhaka. Umxube wedayi nesinyibilikiso seglucose kwingqayi evaliweyo awunambala; xa ingqayi ivulwa ujika ube luhlaza okwesibhakabhaka. Kuxelwa ukuba uEhrlich wakubonisa oku ngokuthe ngqo ngokufaka i-iron chloride kwizicucu ezidayiweyo nangokuziveza emoyeni, ebukele umbala ubuya. Idayi etshintsha umbala ngenxa yemeko ye-redox yendawo ekuyo sisixhobo sokuhlola loo ndawo.

Ngoko kwakukho iimpawu ezimbini ecaleni kwenye. Idayi yayinokwahlula ithishu kwenye. Yaye umbala wedayi wawunokubonakala okanye unyamalale xa imeko ye-oxidation itshintsha.

Xa kujongwa emva, uphawu lwesibini sisiqalo sonyango ngamachiza ekhemistri. Ukuba ikhompawundi ibophelela kolunye uhlobo lwethishu kodwa ingabopheleli kolunye, loo khompawundi isenokufikelela kolunye uhlobo lwesidalwa kodwa ingafikeleli kolunye. UEhrlich wasichaza ngokuthe ngqo eso sigqibo: ukuba intsholongwane ebangela isifo inokudaywa ngokukhethekileyo, loo mbala usenokubonisa ukwenzakala okujoliswe kuloo ntsholongwane. Ngoko idayi yayinokusetyenziswa njengechiza, ijoliswe kumhlaseli kungekhona kwisigulana.

Uvavanyo lokuqala kwisigulana lwalungelolwemalariya. Ngo-1890, ekunye nogqirha wezifo zengqondo uArthur Leppmann, uEhrlich waxela ukuba i-methylene blue yathomalalisa iintlungu kwiimeko ze-neuralgia ne-rheumatism ezichaphazela izihlunu, amalungu omzimba adibanayo neetendon. La madoda mabini axoxa ngokuba ingaba ichiza lingasebenza kwizifo zengqondo aza agqiba ekubeni angalizami. Ugqirha waseItali, uPietro Bodoni waseGenoa, waqhubeka noko. Inqaku lakhe lango-1899 linesihloko esimalunga nesenzo sokuthomalalisa kwiintlobo ezahlukeneyo ze-psychosis: wachaza ukuzola kwezigulana ezilishumi elinesine ezaziphazamisekile, waza waqaphela ukuba abanye oogqirha baseGenoa babesele besebenzisa idayi ngenjongo efanayo. Ukuthomalalisa akuthethi kuchaphazela isifo ngokwaso, yaye lo mahluko uhlala uvela kule mbali.

Umsebenzi wemalariya wafika ngo-1891, kunye nengcali yezifo uPaul Guttmann, kwisibhedlele saseMoabit eBerlin. I-methylene blue yanikwa izigulana ezibini, yaye ingxelo yavela kwi-Berliner klinische Wochenschrift yangomhla wama-28 kuSeptemba 1891. Kwimeko yokuqala isigulana sathatha i-0.5 g yedayi ngexesha elinye ngokuhlwa komhla wama-29 kuJuni; uhlaselo olwalulindelwe aluzange luvele ngokupheleleyo, yaye ekuphela kwesikhalazo esabhalwa emva koko yayibubunzima obuncinane bokuchama obuhamba neentlungu nomchamo oluhlaza okwesibhakabhaka. Uhlaselo lomkhuhlane lwanyamalala kwiintsuku zokuqala, yaye izifunxi-gazi zazisele zingasekho egazini, kungadlulanga usuku lwesibhozo. Isishwankathelo sababhali ngokwabo sasikukuba oko babekulindele kwakuzalisekiswe ngokupheleleyo. Iimeko ezimbini ezingenalo iqela lothelekiso azibobungqina obuqinisekisayo. Inkcazelo ebanzi ye-methylene blue nemalariya, equka iimvavanyo zale mihla, inephepha layo, yaye umbuzo onomdla apha ucuthene ngakumbi: kungakanani ukuqiqa kukaEhrlich okwasala kuchanile xa kujongene nesifunxi-gazi.

Apho ukuqiqa kwachaneka khona nalapho kwasilela khona

Akukho nto ingako yendlela yokusebenza eyasala ichanile, ubuncinane ngendlela uEhrlich awayeyicebise ngayo. Inkcazelo elungeleleneyo, ethi i-cation ethe tyaba enezangqa ezithathu ingena phakathi kwezibini zeziseko zeDNA yesifunxi-gazi, ayimelani nobungqina obuphathelele Plasmodium. I-methylene blue incitshiswa lula kakhulu yiseli ebomvu yegazi eyosulelekileyo kangangokuba ayifiki nakancinane kwisifunxi-gazi njenge-cation ethe tyaba, yaye inkcazelo yokungena phakathi kweziseko efanelana needayi ze-acridine ayifanelani nale.

Into exhaswa bubungqina ayilungelelananga kangako. I-methylene blue ithintela i-glutathione reductase yesifunxi-gazi kumanqanaba oxinaniso isigulana esinokufikelela kuwo. Ivala ukuguqulwa kwe-haem ibe yi-haemozoin, isakhi sombala esingasebenziyo esenziwa sisifunxi-gazi ukuze siphephe ukutyhefwa kukwetyisa kwaso ihaemoglobin, phantse ngokulinganayo ne-chloroquine nangaphezu kakhulu kwe-quinine. Ukujikeleza kwayo kwe-redox kukwavelisa iintlobo zeoksijini ezisebenzayo kwiseli esele izivelisa. Akukacaci ukuba yeyiphi kwezi eyona ndlela yokusebenza, okanye ukuba zonke zinegalelo.

Kukho enye into eyenza lo mcimbi ube nzima ngakumbi, yaye kufanele iphembelele indlela afundwa ngayo onke amabango embali ngale khompawundi. I-methylene blue eyayithengiswa ngelo xesha yayingeyonto enye. Iisampulu zaziqulethe i-azure B, ikhompawundi ehlobene nayo esuswe iqela elinye le-methyl, yaye izinyibilikiso ezindala zaziqokelela engakumbi kuyo. I-Azure B yidayi etshintsha umbala ngokuxhomekeke kwinto ebophelela kuyo, yaye ineendawo ezahlukeneyo ejolisa kuzo: idaya iDNA enemisonto emibini ibe luhlaza okwesibhakabhaka obumnyama neRNA ibe luhlaza. Umxube weedayi ezimbini ezineendawo ezahlukeneyo eziya kuzo, ngomlinganiselo ongazange ubhalwe mntu, awunakuxhasa ingxelo ecacileyo yento eyenziwa yi-methylene blue ekuloo mxube.

Idayi ngokwayo ayizange ithathe indawo ye-quinine. Indlela yophando yaphumelela ngakumbi. Umfundi kaEhrlich uWilhelm Roehl, owayesebenzela indibaniselwano yeenkampani zedayi namachiza i-IG Farben, waqhubeka ekhuthaza izinto eziphuma kwiidayi njengamayeza ezifo zemimandla eshushu waza wanika uphando isixhobo esasinqongophele: intaka i-canary, eyosulelwe yimala riya yeentaka, njengovavanyo oluqhelekileyo lokuhlola iikhompawundi ezinokusetyenziswa. UWerner Schulemann emva koko watshintsha itsheyini esecaleni, yaye ityuwa ye-phenothiazinium eyavelayo yanyanga usulelo lovavanyo. Yayisajika izigulana zibe luhlaza okwesibhakabhaka.

Into eyahlala iluncedo ekugqibeleni yayingeyodayi okanye inkqubo yezangqa kodwa yayiyitsheyini esecaleni. Ukongeza iqela le-dialkylaminoalkylamino kwatshintsha indlela imolekyuli eziphatha ngayo, yaye eso siqwenga sasala sikho kulo lonke utshintsho loyilo olwalandelayo. Gcina elo qela uze endaweni yesangqa se-phenothiazinium ufake i-acridine, isiphumo siba yi-quinacrine. Faka i-quinoline endaweni yaso, isiphumo siba yi-chloroquine. I-pamaquine, i-primaquine ne-amodiaquine, zonke ezisekho kuluhlu lwamachiza alwa nemalariya, zinele qela linye. Ikhompawundi eyasilelayo njengonyango yanika uphando isiqwenga esaphumelelayo.

Unxibelelwano namachiza alwa ne-psychosis ludlula kwisakhiwo sesangqa kunokuba ludlule kwichiza. Ukucacisa isakhiwo se-methylene blue koko kwakhokelela uHeinrich August Bernthsen kwisiseko se-phenothiazine ngo-1883, yaye eso sakhiwo sisisiseko, esifakelwe amaqela ngeendlela ezahlukeneyo, sasisebenza kuso iingcali zekhemistri zaseRhône-Poulenc kwiminyaka yee-1940 xa zazifuna amachiza athintela ihistamine. Enye yezo khompawundi yenziwa malunga nokuphela kuka-1950 yaza yavavanywa ngugqirha wotyando uHenri Laborit, owaqaphela ukuba yayishiya izigulana zizolile yaye zingenamdla kwizinto ezizingqongileyo. Ukusetyenziswa kwayo kokuqala okupapashiweyo kunyango lwezifo zengqondo, kwisigulana esine-mania, kwenzeka ngoJanuwari 1952. Ichiza lokuqala elilwa ne-psychosis alizalwanga ngokuthe ngqo lichiza likaEhrlich elilwa nemalariya; kunoko lisisalamane esikude sedayi awaqala ngayo.

Imikhwa emithathu efanele igcinwe kwesi siganeko

1. "Ichiza lokuqala elenziwe ngokupheleleyo ngokwekhemistri elasetyenziswa kwezonyango" lichaza udidi, yaye imida yelo bango mikhulu kunokuba eli binzana libonisa. Eli binzana sele liqhelekile; uphononongo lukaSchirmer noogxa bakhe olucatshulwa kakhulu kwi-Neurobiology of Aging lubiza i-methylene blue ngokuba lelona chiza lokuqala lenziwe ngokupheleleyo ngokwekhemistri elasetyenziswa kwezonyango. I-chloral hydrate yaziswa njengechiza lokuthomalalisa elenziwe ngokwekhemistri ngo-1869, ngaphezu kweminyaka engamashumi amabini ngaphambili. Inqaku lango-1891 ngokwalo linika inxalenye yempendulo, kuba ababhali balo bakhankanya amachiza okwehlisa umkhuhlane enziwe ngokwekhemistri awayesele esilele ekulweni nemalariya, kuquka i-quinoline, i-antipyrine ne-antifebrin. Ichiza likaEhrlich ngokwakhe elalinearsenic lokulwa negcushuwa lafika kamva nangakumbi. Indlela enokuthethelelwa ngayo eli bango imalunga nendlela yophando kunokuba imalunga nokuba ngowokuqala: i-methylene blue iphakathi kweekhompawundi zokuqala ezenziwe ngokwekhemistri ezakhethwa ukuba zisebenze kwisidalwa esithile ngokusekelwe kwingcingane yekhemistri yokukhetha.
2. Ukusasazeka ngokukhetha akufani nenzuzo ejoliswe kwindawo ethile. Isiphumo sikaEhrlich sango-1886 sasikukuba idayi iya kwithishu yemithambo-luvo. Apho ikhompawundi iya khona noko ikwenzayo xa ifika yimilinganiselo emibini eyahlukileyo, yaye owokuqala kulula kakhulu ukuwenza. Lo msantsa yindawo athe uninzi lwamabango nge-methylene blue nengqondo ahlala kuyo ukususela ngelo xesha.
3. Ucoceko yinxalenye yobungqina, kungekhona yentengiso. Ingxelo yembali ayicacanga kanye ngenxa yesi sizathu. Umahluko omncinane kwisakhiwo utshintsha apho le khompawundi iya khona, yiyo loo nto isatifikethi sohlalutyo kufuneka sibotshelelwe kwibhetshi ethile kunokuba sinikelwe njengengxelo nje yokuba imveliso ivavanyiwe. Umthengisi obanga ukuthobela inkcazelo esemthethweni yekhompawundi ekwincwadi yemigangatho yamachiza ngoxa evavanya iintsimbi ezinzima kuphela ubanga okungaphezu koko kuxhaswa yingxelo. I-Blupreme ifumana i-methylene blue kumvelisi wamachiza ize ivavanye yonke imiqathango ebekwe kuloo nkcazelo: isazisi, ucoceko, ukungcola okuvela kwiikhompawundi ze-organic, izinyibilikisi eziseleyo, ukungcola kwee-elementi, intsalela emva kokutshiswa, imida yeentsholongwane nee-endotoxin zebhaktiriya. Ingxelo ipapashwa ecaleni kwemveliso, yaye iphepha le-methylene blue yodidi lwe-USP lichaza loo mida nokuba kutheni isiphumo se-azure B sisokuqala ekufanele sijongwe.

Umkhondo wemithombo onemihla

Ulandelelwano lweziganeko ezibalulekileyo olunemihla, kuquka ikhemistri yedayi eyandulela uEhrlich neendidi nemigangatho eyalandela emva kwakhe, luchazwe ngokwahlukeneyo kwimbali ye-methylene blue, yaye isazisi sekhompawundi ngokwayo sichazwe kwiphepha elithi yintoni i-methylene blue.

Imifanekiso yamaxwebhu exhasa le nkcazelo, ephinde yashicilelwa kuphononongo lwango-2012 lukaKrafts, Hempelmann noSkórska-Stania, ayinaxabiso lobungqina elilinganayo, yaye umzekelo omnye ubonisa isizathu. Umfanekiso wango-1891 yingxelo yokuqala yovavanyo; umfanekiso wakhe wango-1910 osecaleni kwawo ubeka ixesha lodumo lwakhe kuphela. Amaphepha encwadi yamanqaku kaAndersag yango-1934 ngumkhondo othe ngqo wokufakwa kwe-quinoline endaweni yesangqa sangaphambili, obhalwe ngesandla sengcali yekhemistri ngokwayo.

Isishwankathelo esinyanisekileyo seemvavanyo zedayi zikaEhrlich sesokuba wachaneka malunga nokukhetha, wachaneka nangento ekujoliswe kuyo, kodwa waphazama ngendlela yokusebenza. I-methylene blue ngokwenene iyaqokelelana kwithishu yemithambo-luvo yaye iyasenzakalisa isifunxi-gazi semalariya. Ayenzi eyesibini ngenxa yeyokuqala, yaye isizathu sekhemistri awasinikayo ngazo zombini sasingachananga. Into awayibonisa ngaphandle kwamathandabuzo yayihlala iluncedo ngakumbi kunendlela yokusebenza echanileyo: ikhompawundi inokukhethwa kunokuba ifunyanwe nje, yaye inokukhethwa ngokusekelwe kubungqina obuqokelelwe ngaphambi kokuba nabani na ayinike isigulana.