Paul Ehrlich da methylene blue: yadda wani rini ya taimaka wajen tsara gano magunguna

Gudummawar Paul Ehrlich ga likitanci ba magani ba ce. Hujja ce kan yadda ya kamata a binciki magani.

A 1878 ya gabatar da kundin digirin digirgir wanda sashe na farkonsa yake da take "Fahimtar Sanya Launi ta Fuskar Sinadarai." Hujjarsa ita ce sanya launi a yankakken naman jiki da rina ɗan kyalle suna bin ƙa'ida ɗaya. A dukansu, launi yana manne wa abin ne saboda alaƙar sinadarai tsakanin rini da kayan, ba don naman jiki yana tsotse ruwa, ko yana da kitse, ko kuma siffarsa tana kama sinadarin launi ba. Ehrlich ya taso yana kallon ɗan uwansa, masanin cututtuka Karl Weigert, yana shirya yankakkun naman jiki da aka sanya wa launi, kuma abin da ya ɗauki hankalinsa ba hotunan ba ne, sai yadda rini yake zaɓar inda zai je.

Da'awar tana kama da ƙarama. Amma ba haka ba ce. Idan rini yana ɗaurewa da naman jiki saboda dalilan sinadarai, to tsarin yadda launin ya bayyana rahoto ne kan sinadaran wannan naman jiki. Gilashin bincike da aka sanya wa launi ya daina zama hoton bayani kawai, ya zama ma'auni.

Nan da nan ya ci gaba da gina bincikensa a kan wannan. A 1880 ya haɗa methylene blue da acid fuchsin, ya kira haɗin rini mai tsaka-tsaki, neutralen Farbkörper, wanda ya bambanta nau'o'in fararen ƙwayoyin jini a inda rinuka guda-guda da ake amfani da su a lokacin ba su iya yi ba. Bayan shekaru biyu ya gabatar da hanyar amfani da methyl violet wajen sanya launi ga ƙwayoyin cutar tarin fuka, kuma Koch ya ɗauki wannan hanyar a aikinsa.

Ka'idar da daga baya ta ba waɗannan hanyoyi tushe guda batu ne daban, kuma sau da yawa ana rage bambancin lokacinta da na ayyukan farko. Ka'idar Ehrlich ta sarƙar gefe, wato ra'ayin cewa wani sinadari yana aiki a kan ƙwayar halitta saboda sun dace da juna ta fuskar sinadarai, ta fito ne a shekarun 1890s, ba a shekarun gwaje-gwajen rini ba. Abin da aikin farko ya samar shi ne imanin da ya gabaci ka'idar: zaɓin inda abu yake aiki yana da tushen sinadarai, saboda haka ana iya binciko wannan zaɓi maimakon a same shi kawai bisa sa'a.

Gwajin da ya mayar da rini taswira

A 1885 Ehrlich ya wallafa littafin bincike kan buƙatar oxygen ta jiki, wanda ƙaramin takensa ya bayyana shi a matsayin nazarin launi. Hanyarsa ita ce yin allurar rinuka waɗanda launinsu ya dogara da yanayin oxidation, sannan a kwatanta yadda sassan jiki daban-daban suke mayar da su zuwa yanayin reduction ko kuma suke barinsu yadda suke. Ana amfani da rinin a matsayin kayan aunawa, kamar yadda ake amfani da ma'aunin zafi: yana bayyana yanayin da ke cikin naman jiki wanda ba za a iya bincikawa kai tsaye ba. Ehrlich da kansa ya bayyana manufarsa a matsayin tantance ƙarfin sassan jiki masu rai na haifar da reduction, tare da taimakon wasu takamaiman rinuka.

Sakamakon methylene blue ya zo a 1886, cikin wata takarda kan martanin rinin da kayan jijiyoyi masu rai, wadda aka karanta wa ƙungiyar likitoci a Disamban shekarar da ta gabata. An shigar da methylene blue cikin zagayawar jinin dabba mai rai, sannan aka cire siraran yankakken naman jiki aka fallasa su ga iska domin rinin da ya taru ba tare da launi ba ya sake fuskantar oxidation ya koma shuɗi, ya nuna inda ya taru. Ƙwayoyin jijiyoyi da zaruruwan jijiyoyi sun ɗauki launin, kuma sun ɗauke shi da irin zaɓin da ya sa wannan dabara ta zama hanyar da aka saba amfani da ita don nuna naman jijiyoyi. Sinadarin ya daina zama abin launi kawai da ake shafawa a yankakken naman jiki matacce a kan teburin gwaji. Ya zama alama da take rarraba kanta cikin jiki mai rai, kuma ana iya karanta wannan rarrabuwar.

Dole ne a bayyana siffar da take ƙarƙashin duk waɗannan gwaje-gwaje a sarari, domin duk sauran labarin nan ya dogara da ita. Canjin methylene blue yana iya komawa baya. Nau'insa da ya fuskanci reduction, leucomethylene blue, ba shi da launi, kuma idan ya haɗu da oxygen yana komawa ion mai caji tabbatacce na shuɗi. Maganin glucose da aka narkar da rinin a cikinsa, a cikin kwalba rufaffiya, ba shi da launi; idan aka buɗe kwalbar sai ya koma shuɗi. An ruwaito cewa Ehrlich ya nuna wannan kai tsaye ta hanyar sanya iron chloride da kuma iska a yankakkun naman jiki da aka rina, yana kallon launin yana dawowa. Rini da yake sauya launi bisa yanayin redox na kewayensa kayan bincike ne na wannan kewayen.

Saboda haka an samu siffofi biyu tare. Rini zai iya bambanta wani nau'in naman jiki da wani. Kuma ana iya bayyana ko ɓoye launin rini ta sauya yanayin oxidation.

Idan aka duba wannan daga abin da ya biyo baya, siffa ta biyu ita ce farkon jiyya da sinadarai. Idan wani sinadari yana ɗaurewa da wani nau'in naman jiki amma ba wani ba, to wannan sinadarin zai iya isa ga wani nau'in halitta amma ba wani ba. Ehrlich ya bayyana abin da ya fahimta kai tsaye: idan ana iya sanya launi ga ƙwayar cuta ta hanyar zaɓe, wannan launin zai iya nuna cutarwa ta musamman ga wannan ƙwayar cuta. Saboda haka ana iya amfani da rini a matsayin magani, wanda aka nufa ga abin da ya mamaye jiki maimakon ga majiyyaci.

Gwajin farko a kan majiyyaci ba don zazzabin cizon sauro ba ne. A 1890, tare da likitan tabin hankali Arthur Leppmann, Ehrlich ya ruwaito cewa methylene blue ya rage ciwo a yanayin ciwon jijiyoyi da na rheumatism a tsokoki, gaɓoɓi da jijiyoyin da ke haɗa tsoka da ƙashi. Mutanen biyu sun tattauna ko maganin zai iya yin tasiri ga cutar tabin hankali, suka yanke shawarar kada su gwada shi. Wani likita ɗan Italiya, Pietro Bodoni na Genoa, ya ci gaba ya gwada shi duk da haka. Takardar da ya wallafa a 1899 tana da take kan tasirin kwantar da hankali a nau'o'in psychosis daban-daban: ya bayyana kwantar da hankali a majiyyata goma sha huɗu masu tsananin rashin natsuwa, kuma ya lura cewa wasu likitocin Genoa sun riga sun fara amfani da rinin don wannan manufa. Kwantar da hankali ba tasiri ba ne a kan cutar kanta, kuma wannan bambanci yana ci gaba da bayyana a cikin wannan tarihin.

Aikin kan zazzabin cizon sauro ya zo a 1891, tare da masanin cututtuka Paul Guttmann, a asibitin Moabit da ke Berlin. An ba majiyyata biyu methylene blue, kuma rahoton ya bayyana a cikin Berliner klinische Wochenschrift na 28 ga Satumba 1891. A lamari na farko, majiyyacin ya sha 0.5 g na rinin lokaci guda da yammacin 29 ga Yuni; zazzabin da ake sa ran zai taso bai bayyana sosai ba, kuma korafin da aka rubuta bayan haka shi ne ɗan wahalar yin fitsari tare da fitsari shuɗi. Zazzabi mai zuwa lokaci-lokaci ya ɓace a cikin kwanakin farko, kuma ƙwayoyin cutar sun daina kasancewa a jinin kafin ko a rana ta takwas. Taƙaitawar marubutan da kansu ita ce abin da suke tsammani ya cika gaba ɗaya. Lamura biyu ba tare da rukunin kwatantawa ba ba su zama hujjar tabbatarwa ba. Cikakken bayani kan methylene blue da zazzabin cizon sauro, har da gwaje-gwajen zamani, yana da shafinsa na daban, kuma tambayar da take da muhimmanci a nan ta fi ƙanƙanta: wane ɓangare ne na tunanin Ehrlich ya tsaya bayan an gwada shi da ƙwayar cutar.

Inda tunanin ya yi daidai da inda ya gaza

Ba wani babban ɓangare na bayanin yadda yake aiki ya tsaya ba, aƙalla ba a yadda Ehrlich ya gabatar da shi ba. Bayanin mai sauƙi, cewa wani ion mai caji tabbatacce, mai zobba uku kuma mai shimfiɗa, yana shiga tsakanin nau'i-nau'in tushen DNA na ƙwayar cutar, bai dace da Plasmodium ba. Ƙwayar jan jini mai ɗauke da cutar tana mayar da methylene blue zuwa yanayin reduction cikin sauƙi har ba ya isa ga ƙwayar cutar a matsayin ion mai caji tabbatacce mai shimfiɗa ko kaɗan, kuma bayanin shiga tsakanin sassan DNA da ya dace da rinukan acridine bai dace da wannan ba.

Abin da shaidu suke goyon baya ya fi rikitarwa. Methylene blue yana hana glutathione reductase na ƙwayar cutar aiki a matakan taro da ake iya samu a jikin majiyyaci. Yana hana sauya haem zuwa haemozoin, sinadarin launi marar aiki da ƙwayar cutar take samarwa don kare kanta daga gubar da narkar da haemoglobin ɗinta ke haifarwa, da tasiri kusan daidai da na chloroquine kuma fiye da na quinine sosai. Zagayawarsa tsakanin yanayin redox kuma tana samar da nau'o'in oxygen masu saurin yin martani a cikin ƙwayar halitta da tuni take samar da su. Har yanzu ba a tabbatar da wanne ne ainihin hanyar aikinsa ba, ko kuma ko dukkansu suna ba da gudummawa.

Akwai ƙarin abin da ke rikitarwa, kuma ya kamata ya tsara yadda ake karanta duk wata da'awar tarihi game da wannan sinadari. Methylene blue da ake sayarwa a wancan lokacin ba sinadari guda ɗaya ba ne. Samfurori suna ɗauke da Azure B, sinadari mai kama da shi wanda aka cire masa rukunin methyl guda ɗaya, kuma magungunan da aka narkar suka daɗe suna tara ƙarin wannan sinadarin. Azure B rini ne da yake nuna launuka daban-daban gwargwadon abin da ya ɗaure da shi, kuma yana da wuraren aiki daban: yana sanya DNA mai igiyoyi biyu shuɗi mai zurfi, yana sanya RNA kore. Haɗin rinuka biyu masu wuraren zuwa daban-daban, a rabon da ba wanda ya rubuta, ba zai iya ba da hujjar bayani bayyananne kan abin da methylene blue da ke cikinsa ya yi ba.

Rinin kansa bai taɓa maye gurbin quinine ba. Hanyar binciken ta fi samun nasara. Ɗalibin Ehrlich, Wilhelm Roehl, wanda yake aiki ga haɗaɗɗiyar masana'antar rinuka da magunguna IG Farben, ya ci gaba da inganta sinadaran da aka samo daga rini a matsayin magungunan yankunan zafi, kuma ya samar da kayan aikin da aka rasa: tsuntsun canary da aka saka wa zazzabin cizon sauro na tsuntsaye, a matsayin hanyar gwaji ta yau da kullum don sinadaran da za su iya zama magunguna. Daga nan Werner Schulemann ya sauya sarƙar gefe, kuma gishirin phenothiazinium da aka samu ya warkar da cutar da aka haifar don gwaji. Har yanzu yana mayar da majiyyata shuɗi.

Abin da ya dawwama ba rinin ba ne, ba kuma tsarin zobban ba, sai sarƙar gefe. Ƙara rukunin dialkylaminoalkylamino ya sauya yadda kwayar sinadarin take aiki, kuma wannan ɓangaren ya tsira daga duk wani sake fasali da ya biyo baya. Idan aka riƙe wannan rukunin aka maye gurbin zoben phenothiazinium da acridine, sakamakon shi ne quinacrine. Idan aka sanya quinoline a madadinsa, sakamakon shi ne chloroquine. Pamaquine, primaquine da amodiaquine, waɗanda duk suke cikin jerin magungunan zazzabin cizon sauro har yanzu, suna ɗauke da wannan rukuni. Sinadarin da ya gaza a matsayin magani ya samar da ɓangaren da ya yi nasara.

Alaƙar da magungunan psychosis tana bi ta zoben ne maimakon ta maganin. Bayyana tsarin methylene blue ne ya kai Heinrich August Bernthsen ga tushen phenothiazine a 1883, kuma wannan tsarin tushe, da aka sauya ta hanyoyi daban-daban, shi ne abin da masana sinadarai a Rhône-Poulenc suke aiki a kai a shekarun 1940s yayin neman magungunan hana aikin histamine. An haɗa ɗaya daga cikin waɗannan sinadaran wajen ƙarshen 1950, kuma likitan tiyata Henri Laborit ya gwada shi, ya lura cewa yana barin majiyyata cikin natsuwa ba tare da damuwa da abin da ke kewaye da su ba. Amfani na farko da aka wallafa a fannin tabin hankali, a kan majiyyaci mai mania, ya faru a Janairu 1952. Maganin psychosis na farko bai samo asali kai tsaye daga maganin zazzabin cizon sauro na Ehrlich ba; ya fi kama da dangi na nesa na rinin da ya fara da shi.

Halaye uku da ya kamata a riƙe daga wannan lamari

1. "Magani na farko da aka haɗa ta hanyar sinadarai aka yi amfani da shi a likitanci" yana bayyana wani rukuni ne, kuma sharuddan da ke tattare da shi sun fi abin da kalmomin suke nunawa. Wannan magana ta zama ruwan dare; wani bita da Schirmer da abokan aikinsa suka yi, wanda ake yawan ambata a Neurobiology of Aging, ya kira methylene blue magani na farko ƙwarai da aka haɗa gaba ɗaya ta hanyar sinadarai aka yi amfani da shi a likitanci. An fara amfani da chloral hydrate a matsayin maganin kwantar da hankali da aka haɗa ta hanyar sinadarai a 1869, fiye da shekaru ashirin kafin haka. Takardar 1891 kanta ta samar da wani ɓangare na amsar, domin marubutanta sun ambaci magungunan rage zazzabi da aka haɗa ta hanyar sinadarai waɗanda tuni suka gaza kan zazzabin cizon sauro, ciki har da quinoline, antipyrine da antifebrin. Maganin Ehrlich mai arsenic don syphilis ya zo daga baya ma. Sigar da'awar da za a iya karewa ta shafi hanya ce maimakon wanda ya fara: methylene blue yana cikin sinadaran farko da aka haɗa, waɗanda aka zaɓa su yi aiki a kan wata takamaiman halitta bisa ka'idar sinadarai ta zaɓin wurin aiki.
2. Zaɓin wurin taruwa ba yana nufin zaɓin amfanin da ake samu ba. Sakamakon Ehrlich na 1886 shi ne rinin yana zuwa naman jijiyoyi. Inda sinadari yake zuwa da abin da yake yi idan ya isa auna abubuwa biyu ne daban, kuma na farko ya fi sauƙin aunawa sosai. Wannan rata ce yawancin da'awoyi game da methylene blue da ƙwaƙwalwa suka zauna a cikinta tun daga lokacin.
3. Tsarki yana cikin shaidar bincike, ba cikin tallace-tallace ba. Rubuce-rubucen tarihi ba su ba da cikakken tabbaci ba saboda wannan dalili. Ƙananan bambance-bambancen tsari suna sauya inda wannan sinadari yake zuwa, shi ya sa dole ne takardar shaidar nazari ta kasance da alaƙa da wani takamaiman rukuni na samarwa maimakon a gabatar da ita a matsayin magana kawai cewa an gwada samfur. Mai sayarwa da yake da'awar bin ƙa'idodin bayanin sinadari a kundin magunguna amma yake gwada ƙarafa masu nauyi kawai yana da'awar abin da ya fi ƙarfin shaidar rahoton. Blupreme yana samo methylene blue daga masana'antar magunguna kuma yana gwada duk ƙa'idodin da bayanin ya shimfiɗa: tantance ainihin sinadari, tsarki, gurɓatattun sinadaran organic, ragowar sinadaran narkarwa, gurɓatattun abubuwan sinadarai, ragowar ƙonewa, iyakokin ƙananan halittu da endotoxins na ƙwayoyin bacteria. Ana wallafa rahoton tare da samfurin, kuma shafin methylene blue mai matakin USP yana bayyana waɗannan iyakoki da dalilin da ya sa sakamakon Azure B shi ne na farko da ya kamata a nema.

Jerin madogara bisa kwanan wata

An bayyana jerin muhimman matakai bisa kwanan wata, har da ilimin sinadaran rini da ya gabaci Ehrlich da matakan inganci da ƙa'idodin da suka biyo bayansa, a wani shafi na daban na tarihin methylene blue, kuma an bayyana ainihin sinadarin a shafin menene methylene blue.

Hotuna da shafukan da suka zama tushen wannan bayani, waɗanda aka sake bugawa a bitar 2012 ta Krafts, Hempelmann da Skórska-Stania, ba su da nauyin shaida iri ɗaya, kuma misali guda yana nuna dalilin. Shafin hoton 1891 shi ne asalin rubutaccen bayanin gwajin; hoton mutum na 1910 da ke gefensa yana nuna lokacin shahararsa ne kawai, ba wani abu dabam ba. Shafuka daga littafin bayanan Andersag na 1934 su ne shaidar kai tsaye ta maye gurbin da quinoline, a cikin rubutun hannun masanin sinadaran da kansa.

Taƙaitawa cikin gaskiya game da gwaje-gwajen rini na Ehrlich ita ce ya gane zaɓin wurin aiki kuma ya gano abin da ake nufi, amma ya kuskure bayanin yadda aikin yake faruwa. Methylene blue yana taruwa a naman jijiyoyi kuma yana cutar da ƙwayar cutar zazzabin cizon sauro. Ba ya yin na biyun saboda na farkon, kuma dalilin sinadarai da ya bayar don dukansu ba daidai ba ne. Abin da ya tabbatar ba tare da shakka ba ya fi sahihin bayanin yadda aiki yake faruwa dawwama: ana iya zaɓar sinadari maimakon a same shi kawai, kuma a zaɓe shi bisa shaidar da aka tattara kafin kowa ya ba majiyyaci shi.