Tarihin methylene blue: daga rinin yadi na 1876 zuwa magani

Methylene blue ya isa ga majiyyaci kafin ya isa kantin magani.

Rahoton 1891 na Paul Guttmann da Paul Ehrlich game da amfani da rinin kan malaria yana ɗauke da jadawalin zafin jiki guda biyu. Na biyu ya fara daga 13 Yuli zuwa 5 Agusta, tare da rubuta maganin da aka bayar a gefen jadawalin kowace rana. Rubutun 18 da 19 Yuli ya ce "1 × 0,05 Methylenblau". Kwanakin da suka biyo baya sun lissafo allurai biyar da bakwai na adadin iri ɗaya, kuma zuwa 22 Yuli an ƙara ƙaramin adadin quinine a rikodin. Layin zazzabin, wanda ke motsawa tsakanin 37 °C da 39.5 °C a rabin farko na jadawalin, ya daidaita bayan bayyanar rinin kuma ya kasance tsakanin kusan 36 °C da 37.5 °C na sauran makonni uku.

Majiyyacin yana ɗaya daga cikin mutane biyu, waɗanda takardar ta bayyana a matsayin ma'aikacin gida da matuƙin jirgin ruwa. Sinadarin da suka karɓa ya kasance rinin yadi na kasuwanci tsawon shekaru goma sha biyar, kuma mutanen biyu suna cikin mutane na farko da aka rubuta cewa an yi musu magani da wani maganin da aka ƙera ta hanyar sinadarai gaba ɗaya domin wani takamaiman kwayar halitta.

Rinin ne ya fara

William Henry Perkin ne ya ƙirƙiri rinin roba na farko da ya samu nasarar kasuwanci a 1856. Perkin yana da shekaru goma sha takwas, yana aiki a dakin gwaje-gwaje na gida yayin hutun Easter, yana ƙoƙarin haɗa quinine. Maimakon haka ya samu wani baƙin saura, ya narkar da shi, sannan ya gano wani launi da ke manne wa siliki sosai. Ya samu haƙƙin mallaka a Agusta 1856 kuma zuwa ƙarshen 1857 yana da masana'antar da ke samar wa masana'antar rina siliki a London.

A 1875 Adolf von Baeyer ya haɗa wani jan rini kuma ya ba shi suna eosin, daga Eos, kalmar Girkanci ta wayewar gari. A 1876 Heinrich Caro, wanda a lokacin shi ne daraktan dakin gwaje-gwaje a Badische Anilin- und Soda-Fabrik, ya haɓaka methylene blue tare da Baeyer a matsayin rini mai tushen aniline don auduga. Ba a tabbatar da tsarin sinadarinsa ba sai kusan shekaru tara bayan haka.

Har yanzu ana iya ganin wannan asali a yadda ake kiran sinadarin. "Methylene blue" suna ne na kasuwanci daga kundin rini, ba bayanin sinadarai ba. Sinadarin da sunan ke nufi shi ne methylthioninium chloride, kuma bambance-bambancen da ke tsakanin sunan, gishirin, da hydrates ɗinsa suna da muhimmanci da zarar wani ya auna sinadarin ko ya karanta ƙayyadaddun bayanansa.

Yin rini ya zama gada

Hanyar daga masana'antar rini zuwa asibiti ta bi ta madubin hangen ƙananan abubuwa, kuma ta fara tun kafin samuwar methylene blue. Wilhelm Erb shi ne mutum na farko da ya shafa rinin roba ga jini, yana amfani da picric acid a 1865, kuma ya ga wani tsari mai kama da raga a cikin wasu jajayen ƙwayoyin jini.

Takardar digirin Paul Ehrlich ta 1878 ta kwatanta rinin histoloji da rina yadi, sannan ta yi hujjar cewa duka biyun halayen sinadarai ne. Yayin aiki ƙarƙashin Robert Koch kan tubercle bacillus, ya rarraba rinayen aniline zuwa rukunan acid da basic kuma ya tabbatar cewa kowane rukuni yana sanya launi ga sassa daban-daban na ƙwayar halitta. A 1880 ya haɗa su biyun: an zuba cikakken maganin methylene blue cikin acid fuchsin har sai ruwan da ke sama ya bayyana. Sakamakon, wanda ya kira neutralen Farbkörper ko tabon tsaka-tsaki, ya samar da launuka uku maimakon ɗaya, ya bayyana granules a cikin ƙwayoyin polymorphonuclear waɗanda ba a iya gani a baya, kuma ya ba da damar yin ƙididdigar bambancin leukocyte ta farko. Saboda waɗannan granules sun ɗauki ɓangarorin cakuda biyu, Ehrlich ya ƙirƙiri kalmar neutrophil ga ƙwayoyin da ke ɗauke da su.

Shekaru biyu bayan haka Koch ya yi amfani da methylene blue wajen gano tubercle bacillus, kuma a 1883 Ehrlich ya inganta hanyar. A 1886 ya wallafa wani nau'in lura dabam: ya yi wa dabbobi masu rai allurar rinin sannan ya kwatanta yadda kowace gaɓa ke ɗaukarsa, kuma ya kammala cewa yana da ƙaƙƙarfan sha'awa ga naman kwakwalwa da jijiyoyi. Ya danganta wannan sha'awar da zagayen oxidation-reduction na rinin, wanda ya lura da shi shekarar da ta gabata. Wannan zagayen ne kuma ya sa maganin methylene blue ke rasa launinsa idan an cinye oxygen ɗinsa, sannan ya dawo da launin idan iska ta sake shiga. Gwaje-gwajen da suka fara auna sakamakon wannan zagayen sun kasance na wani shekaru goma na gaba, kuma tsarin kansa batu ne daban da tarihin.

Parasite da cibiyar halitta mai launin shunayya

Alphonse Laveran ya gano parasite na malaria a 1880 ta hanyar duba sabon jini da ba a yi wa rini ba. Ganinsa akai-akai a samfurin jini da aka busar ya buƙaci rini, kuma rinayen zamanin suna samar da ja da shuɗi kawai.

A 1888 masanin cututtukan nama ɗan Poland Czesław Cheçinski ya maye gurbin acid fuchsin da eosin, yana samar da cakuda methylene blue da eosin. Shari'ar da ta haifar da hanyarsa ta shafi wani soja da ya mutu sakamakon malaria a 30 Satumba 1887. A cikin finafinan jinin Cheçinski ya ga siffofi shuɗi masu kama da furen daisy, waɗanda yanzu ake gane su a matsayin Plasmodium malariae, da siffofi masu kama da lauje, waɗanda yanzu ake gane su a matsayin gametocytes na Plasmodium falciparum. Sakamakon ya kawo ƙarshen bayanai biyu masu gasa game da cutar lokaci guda: ka'idar miasma, da ikirarin Edwin Klebs da Corrado Tommasi-Crudeli cewa wata bacteria ce ke haifar da malaria.

Ana iya ganin parasite ɗin. Amma ba a iya ganin nucleus ɗinsa ba, wanda ya bar yanayinsa ba a tantance ba. Ernst Malachowski, wani likita a Breslau, ya warware matsalar da kuskure sannan daga baya da gangan. Ya lura da bambancin rinin plasmodial nucleus a wani shiri a 1889 amma bai iya sake samar da sakamakon ba. Sanya methylene blue ya zama acidic bai taimaka ba. Sanya shi alkaline da borax ya samar da sakamakon a kowane lokaci. Ya nuna dabarar a bainar jama'a a 15 Yuni 1890 kuma ya wallafa ta a wannan shekarar, tare da cikakkiyar hanya a Agusta 1891.

Dmitri Romanowsky ya wallafa nasa sigar a Satumba 1891. Mafi kyawun sakamakonsa ya fito ne daga wata kwalbar maganin methylene blue da aka yi sakaci da ita, mai ƙwari, kuma wadda ta wuce watanni biyu. Bayanin Malachowski an yi shi da gangan kuma, a cewarsa, yana da sauƙin maimaitawa; na Romanowsky hanya ce marar ci gaba da ta yi aiki sau ɗaya. Duk da haka, sunan da aka ɗora wa hanyar ya tafi ga Romanowsky, kuma gardamar kan wanda ya samar da launin shunayyar da ya sa nucleus ya bayyana wani labari ne dabam mai takardunsa na kansa.

Hoto:** jadawalin zafin jiki na biyu daga rahoton Guttmann da Ehrlich na 1891. Sashen sama ya ƙunshi 13 zuwa 24 Yuli, sashen ƙasa kuma 25 Yuli zuwa 5 Agusta; rubutun gefen yana bayyana alluran da aka bayar, kuma zafin jiki ya kasance kusa da na al'ada a makonni uku na ƙarshe na rikodin. An sake bugawa daga rahoton kamar yadda aka yi masa scanning don Krafts, Hempelmann da Skórska-Stania, Parasitology Research 111:1–6 (2012), PMID 22411634.

Abin da ake kira ripening ya zama demethylation

Babu wanda ke cikin aikin a shekarun 1890 da ya san abin da "ripening" ke yi wa methylene blue. Amsar ta fito daga sinadarai na masana'antu. Heinrich August Bernthsen ya haɗa sinadarin asali phenothiazine a 1883, ya tabbatar a 1885 cewa methylene blue yana cikin wannan iyali, kuma a wannan lokacin ya nuna cewa yanayin alkaline yana cire methyl groups daga rinin, yana samar da sinadaran da yanzu ake kira azures.

Bernard Nocht ya ware ɓangaren mai aiki a 1898 da 1899 kuma bai iya kiran shi da wani suna ba sai Rot aus Methylenblau, ja daga methylene blue. Michaelis ya gano shi a matsayin azure I a 1901. Jenner ya gabatar da absolute methanol a matsayin solvent ga precipitate na rinin a 1899, wanda ya kawar da buƙatar amfani da zafi wajen daidaita finafinan jini; Leishman da Reuter suka haɗa ci gaban biyun; Wright ya wallafa hanya mai sauƙi a 1902. Gudummawar Giemsa, ita ma a 1902, ita ce daina dogaro da maganin da ya yi ripening ba tare da sarrafawa ba, maimakon haka ya yi amfani da adadin rinaye sanannu da aka auna. Daga baya ya ƙi wallafa yadda yake yin methylene azure mai tsabta kuma ya sayar da hanyar ga dakin gwaje-gwajen Dr. Grübler, wanda ya tallata samfurin a matsayin azure I kuma ya yi ikirarin cewa sigarsa kaɗai ce tabon Giemsa na gaske.

Yaƙe-yaƙen duniya guda biyu sun kammala aikin ba da gangan ba. Lokacin da rinayen Jamus suka zama ba a iya samu, Lillie, Roe da Wilcox suka yi aiki kan madadin Amurka kuma suka gano cewa mafi kyawun rini yana fitowa daga ɓangarori uku da aka ware: methylene blue mai tsabta, samfurin rushewarsa azure B, da eosin. Waɗannan ukun har yanzu su ne manyan sinadaran tabon da ake amfani da shi wajen tantance malaria a yau, ƙarƙashin suna da yanzu ke haɗa Malachowski, Wright da Giemsa.

Hoto:** siffofin zobe na Plasmodium falciparum a cikin jajayen ƙwayoyin jinin ɗan adam, waɗanda aka yi wa rini da hanyar irin Romanowsky. Tsarin shunayyar da ke cikin zoben shi ne chromatin da methylene blue na Malachowski da aka sarrafa da borax ya sa aka iya gani a karon farko. Hoton Ernst Hempelmann ne, an saki shi zuwa public domain.

Suna ɗaya, kayayyaki daban-daban

Shekarun da suka raba waɗannan ɓangarorin sun bar matsalar da ta fi sinadarai ɗorewa. Ralph Lillie ya ja layi a 1969 tsakanin rinayen halittu, waɗanda ake "ƙerawa bisa ƙa'idoji masu tsauri da suka dace da amfaninsu masu matuƙar laushi da buƙatar daidaito", da rinayen da ba na halittu ba don rina yadi, waɗanda "ke buƙatar ƙa'idojin ƙera da ba su da tsauri sosai". Nau'ikan samfurin biyu suna ɗauke da suna ɗaya, kuma bambancin da ke tsakaninsu bai taɓa zama bambancin mataki kawai ba. Ƙayyadaddun bayanin da aka rubuta don auduga da wanda aka rubuta don reagent na tantancewa ba za a iya musanya su ba, kuma kayan da aka yi bisa ƙayyadaddun yadi ba a nufa a haɗiye shi ba.

Azure B shi ne misali mafi bayyana. Shi ne nau'in methylene blue da aka cire methyl group guda ɗaya daga gare shi, yana da aikin pharmacological da za a iya aunawa na kansa, kuma ya kasance a matsayin wani ɓangare da ba a sarrafa adadinsa ba a cikin shirye-shiryen methylene blue na asibiti fiye da ƙarni guda kafin a taɓa ware su biyun. Wata ƙungiya ta gano cewa naman ɗan adam da aka ɗauka a autopsy bayan an ba da methylene blue ya ƙunshi kashi 5 zuwa 14 na methylene blue da bai canza ba da kashi 86 zuwa 95 na azure B. Ko wani shiri ya kamata ya ƙunshi azure B, da kuma iyakarsa, tambaya ce ta ƙayyadaddun bayanai, kuma binciken kan azure B a matsayin impurity da metabolite ya ci gaba daga nan.

Ƙayyadaddun bayanai kuma su ne inda sakamakon aikace-aikace yake. Bin USP ita ce hanyar zuwa mafi girman tsarkin da kasuwa ke bayarwa, domin cikakken ma'aunin gwaji ne da aka wallafa maimakon ma'auni guda ɗaya. Ya ƙunshi tabbatar da ainihi, assay, organic impurities ciki har da rinayen azure, residual solvents, elemental impurities, residue on ignition, microbial limits, da bacterial endotoxins. Takardar shaida da ta bayar da sakamakon heavy-metal sannan ta kira shi bin USP ta bayar da layi guda ne kawai daga wannan jerin.

Blupreme yana samun methylene blue ɗinsa daga masana'antar magunguna kuma yana wallafa cikakkiyar certificate of analysis, yana gwada duk ƙayyadaddun USP maimakon heavy metals kaɗai. Jagorar karanta certificate of analysis da abin da alamar USP take tabbatarwa da abin da ba ta tabbatarwa suna bayyana yadda ake kwatanta takardar da ikirarin.

Abin da tarihin ke ba da damar faɗa, da abin da ba ya ba da damar faɗa

Asalin tarihin yana nan da gaske, kuma ya fi tsawon yadda yawancin shafukan samfur ke nuna. An yi amfani da methylene blue wajen maganin malaria a 1891, an ruwaito shi a matsayin sedative a agitated psychosis a 1899, kuma reshen sinadarinsa ya ratsa quinacrine, chloroquine, promethazine da chlorpromazine. Takardar Ehrlich ta 1890 tare da Arthur Leppmann ta bayyana sauƙaƙawar neuralgic da rheumatic pain, sannan ta yi la'akari da amfani da rinin a cututtukan tabin hankali amma ta ƙi gwada shi.

Babu wani daga cikin wannan da ke tabbatar da wani amfani na zamani. Sakamakon malaria na 1891 ya ƙunshi majiyyata biyu da jadawalin zafin jiki. Dogon sanin wani molecule dalili ne na yin nazarinsa, ba sakamako ba. Tarihin sinadarin a matsayin magani da gwaje-gwajen zamani kan malaria suna amsa tambayoyi daban da waɗanda Ehrlich yake yi, kuma dole ne a karanta endpoints bisa ma'anarsu ta kansu.

Akwai bayani guda a rikodin da ya shafi yanzu fiye da baya. Lokacin da masu bincike suka gudanar da gwaje-gwajen methylene blue kan malaria a Burkina Faso a shekarun 2000s, sun samu kansu suna fafatawa wajen samun kayan pharmaceutical-grade, kuma sun ruwaito cewa farashin raw material ya tashi da kusan ninki ɗari bayan samun GMP validation. Ana iya maye gurbin rini. Ba za a iya maye gurbin magani ba. Bambancin da Lillie ya ja a 1969 shi ne bambancin da har yanzu ke ƙayyade abin da kwalba ke ƙunshe da shi a yau.