Mbiri ya methylene blue: kuchokera ku utoto kupita ku mankhwala ndi kafukufuku

Methylene blue idafika kwa wodwala isanafike ku pharmacy.

Lipoti la 1891 la Paul Guttmann ndi Paul Ehrlich lonena za kugwiritsa ntchito utotowu pa malungo lili ndi ma chart awiri a kutentha kwa thupi. Lachiwiri limayambira 13 July mpaka 5 August, ndipo chithandizo chalembedwa m’mphepete tsiku ndi tsiku. Zolemba za 18 ndi 19 July zimati "1 × 0,05 Methylenblau". Masiku otsatira akutchula ma dose asanu ndi asanu ndi awiri a kuchuluka komweko, ndipo pofika 22 July quinine yochepa yalowanso m’mbiriyo. Mzere wa kutentha kwa thupi, womwe umakwera ndi kutsika pakati pa 37 °C ndi 39.5 °C m’gawo loyamba la chart, umakhala wosasinthasintha kwambiri utotowo utayamba kugwiritsidwa ntchito ndipo umakhala pakati pa pafupifupi 36 °C ndi 37.5 °C kwa milungu itatu yotsalayo.

Wodwalayo anali mmodzi mwa awiri, omwe m’pepala limenelo anafotokozedwa ngati wantchito wapakhomo ndi woyendetsa sitima yapamadzi. Chinthu chomwe analandira chinali chitagwiritsidwa ntchito ngati utoto wa nsalu wogulitsa kwa zaka khumi ndi zisanu, ndipo amuna awiriwa ali m’gulu la anthu oyambirira olembedwa kuti anathandizidwa ndi mankhwala opangidwa kwathunthu mwakupanga omwe analunjika pa chamoyo chenicheni.

Utoto ndi umene unayamba

Utoto woyamba wopangidwa mwakupanga umene unachita bwino pa malonda unapangidwa ndi William Henry Perkin mu 1856. Perkin anali ndi zaka khumi ndi zisanu ndi zitatu, ankagwira ntchito mu labotale yapakhomo pa tchuthi cha Isitala, ndipo ankayesa kupanga quinine mwakupanga. M’malo mwake anapeza zotsalira zakuda, anazisungunula, ndipo anapeza mtundu womwe unkakhazikika bwino kwambiri pa silika. Analandira patent yake mu August 1856 ndipo pofika kumapeto kwa 1857 anali ndi fakitale yopereka utoto ku malo odayera silika ku London.

Mu 1875 Adolf von Baeyer anapanga utoto wofiira mwakupanga n’kuutcha eosin, kuchokera ku Eos, liwu la Chigiriki lotanthauza m’bandakucha. Mu 1876 Heinrich Caro, yemwe panthawiyo anali director wa labotale ku Badische Anilin- und Soda-Fabrik, anapanga methylene blue limodzi ndi Baeyer ngati utoto wa aniline wa thonje. Kapangidwe kake ka mankhwala sikunatsimikizidwe mpaka patadutsa pafupifupi zaka zisanu ndi zinayi.

Chiyambi chimenecho chikuwonekabe m’mene chinthucho chimatchulidwira. "Methylene blue" ndi dzina la malonda lochokera m’katalogi ya utoto, osati kufotokoza kapangidwe ka mankhwala. Chinthu chimene dzinali limatanthauza ndi methylthioninium chloride, ndipo kusiyana pakati pa dzina, salt, ndi hydrates zake kumakhala kofunika munthu akangoyamba kuyeza chinthucho kapena kuwerenga specification.

Kudetsa mitundu kunali mlatho

Njira yochokera ku malo opangira utoto kupita kuchipatala inadutsa pa microscope, ndipo inayamba methylene blue isanapangidwe. Wilhelm Erb anali munthu woyamba kugwiritsa ntchito utoto wopangidwa mwakupanga pa magazi, pogwiritsa ntchito picric acid mu 1865, ndipo anaona mawonekedwe ngati ukonde mkati mwa maselo ena ofiira a magazi.

Thesis ya udokotala ya Paul Ehrlich ya 1878 inayerekezera kudetsa minofu kuti ioneke pa microscope ndi kudaya nsalu ndipo inanena kuti zonsezi zinali chemical reactions. Akugwira ntchito motsogozedwa ndi Robert Koch pa tubercle bacillus, anagawa utoto wa aniline m’magulu a acid ndi basic ndipo anatsimikizira kuti gulu lililonse limadetsa mbali zosiyana za selo. Mu 1880 anasakaniza magulu awiriwo: solution yodzaza ya methylene blue inathiridwa mu acid fuchsin mpaka madzi apamwamba atayera. Zotsatira zake, zomwe anazitcha neutralen Farbkörper kapena neutral stain, zinatulutsa mitundu itatu m’malo mwa umodzi, zinawonetsa ma granule m’maselo a polymorphonuclear omwe sanali kuwoneka kale, ndipo zinapangitsa kuti kuwerengera koyamba kosiyanitsa mitundu ya leukocyte kutheke. Chifukwa ma granule amenewo ankatenga zigawo zonse ziwiri za chisakanizocho, Ehrlich anayambitsa liwu loti neutrophil kutanthauza maselo omwe anali nawo.

Patadutsa zaka ziwiri Koch anagwiritsa ntchito methylene blue kupeza tubercle bacillus, ndipo mu 1883 Ehrlich anasintha njirayo kuti ikhale yabwino. Mu 1886 anafalitsa mtundu wina wa zomwe anaona: anabaya utotowo m’zinyama zamoyo n’kuyerekezera mphamvu imene chiwalo chilichonse chinkautengera, ndipo ananena kuti unali ndi kukopeka kwakukulu ndi minofu ya ubongo ndi ya mitsempha. Anati kukopeka kumeneku kunachokera ku kusinthasintha kwa oxidation-reduction kwa utotowo, komwe anali ataona chaka chapitacho. Kusinthasintha kumeneku ndi komwenso kumachititsa solution ya methylene blue kutaya mtundu wake oxygen yake ikagwiritsidwa ntchito ndi kubwezeretsanso mtunduwo mpweya ukabweranso. Mayesero omwe anayamba kuyeza zotsatira za kusinthasintha kumeneku ndi a zaka khumi zina pambuyo pake, ndipo mechanism yakeyo ndi nkhani yosiyana ndi mbiriyi.

Tizilombo toyambitsa malungo ndi nyukiliyasi yofiirira

Alphonse Laveran anapeza tizilombo toyambitsa malungo mu 1880 poyang’ana magazi atsopano osadetsedwa. Kuti tizilomboto tizioneka nthawi zonse pa smear youma pamafunika stain, ndipo ma stain a nthawi imeneyo ankangotulutsa wofiira ndi wabuluu.

Mu 1888 pathologist wa ku Poland Czesław Cheçinski anachotsa acid fuchsin n’kuika eosin, motero kupanga chisakanizo cha methylene blue ndi eosin. Mlandu umene unachititsa kuti apange njirayi unali wa msilikali amene anamwalira ndi malungo pa 30 September 1887. M’ma film a magazi Cheçinski anaona mawonekedwe abuluu ngati maluwa a daisy, omwe tsopano amadziwika kuti Plasmodium malariae, komanso mawonekedwe ngati zikwakwa, omwe tsopano amadziwika kuti ma gametocyte a Plasmodium falciparum. Zotsatira zake zinathetsa nthawi imodzi mafotokozedwe awiri opikisana a matendawa: miasma theory, ndi zonena za Edwin Klebs ndi Corrado Tommasi-Crudeli zoti malungo ankayambitsidwa ndi bacterium.

Tizilomboto tinkawoneka. Nyukiliyasi yake sinkawoneka, zomwe zinasiya mtundu wake weniweni wosatsimikizika. Ernst Malachowski, dokotala ku Breslau, anathetsa vutoli mwangozi kenako mwadala. Mu 1889 anaona kuti nyukiliyasi ya plasmodium inkadetsedwa mosiyana m’chitsanzo chimodzi koma sanathe kubwereza zotsatirazo. Kuonjezera acidity ku methylene blue sikunathandize. Kuipanga alkaline ndi borax kunatulutsa zotsatirazo nthawi zonse. Anaonetsa njirayo poyera pa 15 June 1890 ndipo anaifalitsa chaka chomwecho, kenako anafalitsa njira yatsatanetsatane mu August 1891.

Dmitri Romanowsky anafalitsa mtundu wake mu September 1891. Zotsatira zake zabwino kwambiri zinachokera ku botolo la solution ya methylene blue lomwe linali litasiyidwa, lili ndi nkhungu, ndipo linali la miyezi yoposa iwiri. Kufotokoza kwa Malachowski kunali kwa dala ndipo, monga iye ananenera, kunali kosavuta kubwerezanso; kwa Romanowsky kunali njira yopanda kupitirira yomwe inagwira ntchito kamodzi. Komabe dzina la njirayo linapita kwa Romanowsky, ndipo mkangano wokhudza amene anatulutsa mtundu wofiirira womwe unapangitsa nyukiliyasi kuoneka ndi nkhani ina yokhala ndi zikalata zake.

Chithunzi: chart yachiwiri ya kutentha kwa thupi kuchokera mu lipoti la Guttmann ndi Ehrlich la 1891. Gawo lapamwamba limafotokoza 13 mpaka 24 July ndipo lapansi 25 July mpaka 5 August; zolemba za m’mphepete zimatchula ma dose omwe anaperekedwa, ndipo kutentha kwa thupi kumakhala pafupi ndi kwabwinobwino kwa milungu itatu yomaliza ya mbiriyo. Yatulutsidwanso kuchokera mu lipotilo monga momwe linasungidwira mu scan ya Krafts, Hempelmann ndi Skórska-Stania, Parasitology Research 111:1–6 (2012), PMID 22411634.

Kukalamba kunapezeka kuti kunali demethylation

Palibe aliyense mwa anthu omwe ankagwira ntchito imeneyi m’ma 1890s amene ankadziwa zomwe "ripening" inkachita ku methylene blue. Yankho linachokera ku industrial chemistry. Heinrich August Bernthsen anali atapanga parent compound phenothiazine mu 1883, anatsimikizira mu 1885 kuti methylene blue inali ya m’banja limenelo, ndipo nthawi yomweyo anaonetsa kuti malo a alkaline amachotsa methyl groups mu utotowo, n’kupanga zinthu zomwe tsopano zimatchedwa azures.

Bernard Nocht anachotsa active fraction mu 1898 ndi 1899 ndipo anangotha kuitcha Rot aus Methylenblau, red from methylene blue. Michaelis anazindikira kuti inali azure I mu 1901. Jenner anayambitsa kugwiritsa ntchito absolute methanol ngati solvent ya dye precipitate mu 1899, zomwe zinachotsa kufunika kotenthetsa ma film a magazi kuti akhazikike; Leishman ndi Reuter anaphatikiza patsogolo pa njira ziwirizi; Wright anafalitsa njira yosavuta mu 1902. Chinthu chimene Giemsa anawonjezera, nachonso mu 1902, chinali kusiya kudalira solution yokalamba mwachisawawa n’kugwiritsa ntchito m'malo mwake kuchuluka koyezedwa kwa utoto wodziwika. Kenako anakana kufalitsa mmene amapangira methylene azure yoyera ndipo anagulitsa njirayo ku labotale ya Dr. Grübler, yomwe inagulitsa mankhwalawo ngati azure I ndipo inanena kuti mtundu wake wokha ndi umene unali Giemsa stain yeniyeni.

Nkhondo ziwiri zapadziko lonse zinamaliza ntchitoyi mwangozi. Pamene utoto wa ku Germany sunapezekenso, Lillie, Roe ndi Wilcox anagwira ntchito pa zolowa m’malo za ku America ndipo anapeza kuti kudetsa bwino kwambiri kunkachokera ku zigawo zitatu zosiyanitsidwa: methylene blue yoyera, breakdown product yake azure B, ndi eosin. Zitatuzi zikadali zigawo zazikulu za stain yomwe imagwiritsidwa ntchito pozindikira malungo masiku ano, pansi pa dzina lomwe tsopano limaphatikiza Malachowski, Wright ndi Giemsa.

Chithunzi: ring forms za Plasmodium falciparum m’maselo ofiira a magazi a munthu, zodetsedwa ndi njira ya mtundu wa Romanowsky. Kapangidwe kofiirira mkati mwa mpheteyo ndi chromatin yomwe methylene blue ya Malachowski yochitiridwa ndi borax inachititsa kuti ioneke kwa nthawi yoyamba. Chithunzi cha Ernst Hempelmann, chomwe chinatulutsidwa kuti chigwiritsidwe ntchito pagulu popanda zoletsa.

Dzina limodzi, zinthu zingapo

Zaka zomwe zinadutsa zigawozi zisanasiyanitsidwe zinasiya vuto lomwe linapitirira kuposa chemistry yomwe inalipangitsa. Ralph Lillie mu 1969 anasiyanitsa biological stains, "zopangidwa motsatira specifications zolimba zogwirizana ndi ntchito zake zosakhululukira zolakwa komanso zolondola kwambiri", ndi non-biological stains za kudaya nsalu, zomwe "zimafuna miyezo yopangira yosakhwima kwambiri". Mitundu yonse iwiri ya mankhwala inkakhala ndi dzina lomwelo, ndipo kusiyana pakati pawo sikunali kungoti imodzi inali yabwinoko pang’ono kuposa inzake. Specification yolembedwa ya thonje ndi specification yolembedwa ya diagnostic reagent sizingasinthanitsidwe, ndipo chinthu chopangidwa motsatira ya nsalu sichinapangidwe kuti chimezedwe.

Azure B ndi chitsanzo chomveka kwambiri. Ndi mtundu wa methylene blue womwe methyl group imodzi yachotsedwa, uli ndi pharmacological activity yake yomwe ingayesedwe, ndipo unali ngati constituent yosalamulidwa m’ma preparation a methylene blue a kuchipatala kwa zaka zoposa zana limodzi asanapatulidwe. Gulu lina linapeza kuti minofu ya munthu yomwe inatengedwa pa autopsy pambuyo popereka methylene blue inali ndi 5 mpaka 14 per cent methylene blue yosasinthidwa ndi 86 mpaka 95 per cent azure B. Kaya preparation inayake iyenera kukhala ndi azure B, komanso pamlingo wotani, ndi funso la specification, ndipo kafukufuku wa azure B ngati impurity ndi metabolite ukupitiriza nkhaniyo kuchokera pamenepo.

Specification ndi kumenenso zotsatira zake zothandiza zimakhala. Kutsatira USP ndi njira yopita ku purity yapamwamba kwambiri yomwe msika umapereka, chifukwa ndi test standard yathunthu yofalitsidwa osati measurement imodzi yokha. Imaphatikiza identity, assay, organic impurities kuphatikizapo azure dyes, residual solvents, elemental impurities, residue on ignition, microbial limits, ndi bacterial endotoxins. Certificate yomwe imangonena zotsatira za heavy-metal n’kuitcha USP compliance yangonena mzere umodzi wokha wa mndandanda umenewo.

Blupreme imapeza methylene blue yake kuchokera kwa pharmaceutical manufacturer ndipo imafalitsa certificate of analysis yonse, ikuyesa USP specification yonse osati heavy metals zokha. Buku lotsogolera mmene mungawerengere certificate of analysis ndi zomwe designation ya USP imatsimikizira ndi zomwe simatsimikizira zikufotokoza mmene mungayerekezere chikalatacho ndi zomwe akunena.

Zomwe mbiriyi imalola kunena, ndi zomwe siyilola

Mzere wa mbiriyi ndi weniweni, ndipo ndi wautali kuposa momwe masamba ambiri a malonda amanenera. Methylene blue idagwiritsidwa ntchito pochiza malungo mu 1891, idanenedwa ngati sedative pa agitated psychosis mu 1899, ndipo side chain yake imadutsa mu quinacrine, chloroquine, promethazine ndi chlorpromazine. Pepala la Ehrlich la 1890 limodzi ndi Arthur Leppmann linafotokoza kuchepa kwa neuralgic ndi rheumatic pain, kenako linaganizira za kuyesa utotowo pa matenda a maganizo koma silinachite mayesowo.

Palibe mwa zimenezo chomwe chimatsimikizira kugwiritsidwa ntchito kwamakono. Zotsatira za malungo za 1891 zinali za odwala awiri ndi chart ya kutentha kwa thupi. Kudziwika kwa molekyulu kwa nthawi yaitali ndi chifukwa choiphunzirira, osati zotsatira. Mbiri ya chinthuchi ngati mankhwala ndi mayesero amakono a malungo amayankha mafunso osiyana ndi omwe Ehrlich ankafunsa, ndipo ma endpoint ake ayenera kuwerengedwa mogwirizana ndi tanthauzo lawo.

Pali tsatanetsatane umodzi m’mbiriyi womwe ndi wa masiku ano osati wakale. Ofufuza atachita mayesero a methylene blue pa malungo ku Burkina Faso m’ma 2000s, anapeza kuti ankachita mpikisano wopeza pharmaceutical-grade material, ndipo ananena kuti mtengo wa raw material unali utakweza pafupifupi nthawi zana limodzi utangokhala ndi GMP validation. Utoto ukhoza kusinthidwa ndi wina. Mankhwala sakanatha. Kusiyana komwe Lillie ananena mu 1969 ndi komweku komwe masiku ano kumatsimikizira zomwe zili m’botolo. :::