Nhoroondo yemethylene blue: kubva kudhayi kusvika kumushonga netsvakurudzo

Methylene blue yakasvika kumurwere isati yasvika mufamasi.

Mushumo wa1891 waPaul Guttmann naPaul Ehrlich pamusoro pekushandiswa kwedhayi iyi pamalaria une machati maviri etembiricha. Wechipiri unotangira 13 July kusvika 5 August, uye marapirwo akanyorwa pamucheto zuva nezuva. Zvinyorwa zve18 na19 July zvinoti "1 × 0,05 Methylenblau". Mazuva akatevera anoratidza madosi mashanu nemanomwe ehuwandu ihwohwo, uye pakazosvika 22 July huwandu hudiki hwequinine hwakanga hwawedzerwa muchinyorwa. Mutsetse wefivha, uyo unokwira nekudzika pakati pe37 °C ne39.5 °C muchikamu chekutanga chechati, unotsetseka mushure mekuonekwa kwedhayi uye unoramba uri pakati peinenge 36 °C ne37.5 °C kwemavhiki matatu asara.

Murwere uyu aiva mumwe wevaviri, vakatsanangurwa muchinyorwa semushandi wepamba nemufambisi wengarava. Mushonga wemakemikari wavakapiwa wakanga watove dhayi yekutengesa yemachira kwemakore gumi nemashanu, uye varume vaviri ava vari pakati pevanhu vekutanga vakanyorwa sevakarapwa nemushonga wakagadzirwa zvizere nemakemikari uchinangiswa kuchinhu chipenyu chakati.

Dhayi ndiyo yakatanga

Dhayi yekutanga yakagadzirwa nemakemikari yakabudirira pakutengeswa yakagadzirwa naWilliam Henry Perkin muna 1856. Perkin aiva nemakore gumi nemasere, achishanda murabhoritari yepamba panguva yezororo reEaster, uye achiedza kugadzira quinine. Panzvimbo pezvo akawana tsvina nhema, akaiputsa mumvura yakakodzera, ndokuwana ruvara rwaibata zvakajeka pasirika. Akaiwanira patent muna August 1856 uye pakupera kwa1857 akanga ava nefekitari yaipa dhayi kunzvimbo yekudhaya sirika muLondon.

Muna 1875 Adolf von Baeyer akagadzira dhayi tsvuku ndokuitumidza eosin, kubva kuna Eos, izwi rechiGiriki rinoreva mambakwedza. Muna 1876 Heinrich Caro, panguva iyoyo ari director werabhoritari paBadische Anilin- und Soda-Fabrik, akagadzira methylene blue pamwe naBaeyer se dhayi yakavakirwa paaniline yekushandisa padonje. Chimiro chayo chemakemikari hachina kuzonyatsosimbiswa kusvika makore anenge mapfumbamwe gare gare.

Mabviro iwayo achiri kuoneka pamazita anoshandiswa pachinhu ichi. "Methylene blue" izita rekutengeserana rakabva mukatalogi yedhayi, kwete tsananguro yemakemikari. Compound yarinoreva imethylthioninium chloride, uye misiyano pakati pezita, munyu wacho, nemahydrate awo inotanga kukosha kana munhu achangotanga kuyera chinhu ichi kana kuverenga specification.

Staining ndiyo yaiva zambuko

Nzira yakabva kunzvimbo dzekugadzira dhayi ichienda kuchipatara yakapfuura nepamaikorosikopu, uye yakatanga methylene blue isati yatombovapo. Wilhelm Erb ndiye munhu wekutanga kushandisa dhayi yakagadzirwa nemakemikari paropa, achishandisa picric acid muna 1865, uye akaona chimiro chakaita semambure mukati memamwe masero matsvuku eropa.

Thesis yaPaul Ehrlich yedoctorate ya1878 yakaenzanisa histological staining nekudhayiwa kwemachira uye yakati zvose zvaiva maitiro emakemikari. Achishanda pasi paRobert Koch patubercle bacillus, akaronga madhayi eaniline kuita mapoka easidhi neebhesi uye akaratidza kuti boka rimwe nerimwe raipenda zvikamu zvakasiyana zvesero. Muna 1880 akasanganisa maviri acho: solution yakazara yemethylene blue yakadururwa muacid fuchsin kusvikira supernatant yajeka. Mhedzisiro yacho, yaakadana kuti neutralen Farbkörper kana neutral stain, yakaburitsa mavara matatu panzvimbo perimwe, yakaratidza magranule mumasero epolymorphonuclear akanga asingamboonekwi kare, uye yakaita kuti leukocyte differential count yekutanga ikwanisike. Nekuti magranule iwayo aitora zvikamu zvose zviri zviviri zvemusanganiswa, Ehrlich akagadzira izwi rekuti neutrophil remasero aiva nawo.

Makore maviri gare gare Koch akashandisa methylene blue kutsvaga tubercle bacillus, uye muna 1883 Ehrlich akavandudza nzira yacho. Muna 1886 akaburitsa imwe mhando yecherechedzo: akabaya dhayi iyi mumhuka mhenyu ndokuenzanisa kuti nhengo imwe neimwe yaiitora nesimba rakadii, uye akagumisa kuti yaiva nekukwezvwa kwakanyanya nehuropi nematishu etsinga. Akati kukwezvwa ikoko kwaibva pakutenderera kweoxidation-reduction kwedhayi, kwaakanga aona gore rakapfuura. Kutenderera ikoko ndiko zvakare kunoita kuti solution yemethylene blue irasikirwe neruvara kana oxygen yayo yashandiswa uye iruwanezve kana mhepo yadzoka. Zviedzo zvekutanga kuyera migumisiro yekutenderera ikoko ndezvemakore gumi akazotevera, uye mechanism yacho pachayo inyaya yakasiyana nenhoroondo.

Parasite nenucleus yepepuru

Alphonse Laveran akawana parasite yemalaria muna 1880 achiongorora ropa idzva risina kuiswa stain. Kuti ionekwe nguva dzose musmear weropa wakaomeswa zvaida stain, uye mastain epanguva iyoyo aingoburitsa tsvuku nebhuruu chete.

Muna 1888 pathologist wekuPoland Czesław Cheçinski akatsiva acid fuchsin neeosin, achigadzira musanganiswa wemethylene blue neeosin. Nyaya yakatungamira kunzira yake yaiva yemusoja akafa nemalaria musi wa30 September 1887. Mumafirimu eropa Cheçinski akaona zvimiro zvebhuruu zvakaita sedaisy, zvino zvinozivikanwa sePlasmodium malariae, uye zvimiro zvakaita sejeko, zvino zvinozivikanwa semagametocyte ePlasmodium falciparum. Mhedzisiro iyi yakapedza tsananguro mbiri dzaiikwikwidza dzechirwere panguva imwe chete: miasma theory, uye chirevo chaEdwin Klebs naCorrado Tommasi-Crudeli chekuti malaria yaikonzerwa nebacterium.

Parasite yacho yaioneka. Nucleus yayo yakanga isingaonekwi, izvo zvakasiya chimiro chayo chisina kujeka. Ernst Malachowski, chiremba muBreslau, akagadzirisa dambudziko iroro netsaona, ndokuzoriita nemaune. Akaona differential staining yenucleus yeplasmodium mune imwe preparation muna 1889 uye haana kukwanisa kuidzokorora. Kuita methylene blue acidic hakuna kubatsira. Kuiita alkaline neborax kwakaita kuti mhedzisiro yacho ibude nguva dzose. Akaratidza nzira iyi pachena musi wa15 June 1890 uye akaiburitsa mugore rimwe chetero, aine nzira yakatsanangurwa zvakazara muna August 1891.

Dmitri Romanowsky akaburitsa shanduro yake muna September 1891. Mhedzisiro yake yakanakisisa yakabva mubhodhoro remethylene blue solution rakanga raregeredzwa, rave nemould, uye rave nemwedzi inopfuura miviri. Tsananguro yaMalachowski yaiva yakaitwa nemaune uye, mumashoko ake, yaikwanisa kudzokororwa zviri nyore; yaRomanowsky yaiva nzira isina kuenderera mberi yakashanda kamwe chete. Zita reeponym rakangopihwa Romanowsky zvakadaro, uye gakava rekuti ndiani akagadzira ruvara rwepepuru rwakaita kuti nucleus ionekwe inyaya yakasiyana ine magwaro ayo.

Figure: chati yechipiri yetembiricha kubva mushumo waGuttmann naEhrlich wa1891. Panel yepamusoro inobata 13 kusvika 24 July uye yepasi 25 July kusvika 5 August; zvinyorwa zviri pamucheto zvinotaura madosi akapiwa, uye tembiricha inoramba iri pedyo neyakajairika kwemavhiki matatu ekupedzisira echinyorwa. Yakabudiswazve kubva mushumo wakascanwa waKrafts, Hempelmann naSkórska-Stania, Parasitology Research 111:1–6 (2012), PMID 22411634.

Ripening yakazoratidzwa kuva demethylation

Hapana mumwe wevaibatanidzwa kuma1890s aiziva kuti "ripening" yaiitei kumethylene blue. Mhinduro yakabuda muindustrial chemistry. Heinrich August Bernthsen akanga agadzira parent compound phenothiazine muna 1883, akasimbisa muna 1885 kuti methylene blue yaiva yemhuri iyoyo, uye panguva imwe cheteyo akaratidza kuti alkaline conditions dzinobvisa methyl groups kubva kudhayi, zvichigadzira macompound ava kunzi azures.

Bernard Nocht akabvisa active fraction muna 1898 na1899 uye aigona kungoidana kuti Rot aus Methylenblau, tsvuku kubva kumethylene blue. Michaelis akairatidza seazure I muna 1901. Jenner akaunza absolute methanol sesolvent yedye precipitate muna 1899, izvo zvakabvisa chikonzero chekuheat-fix mafirimu eropa; Leishman naReuter vakabatanidza kufambira mberi kwose kuri kuviri; Wright akaburitsa nzira yakarerutswa muna 1902. Chikamu chaGiemsa, zvakare muna 1902, chaiva kurega kuvimba nesolution yakanga yaripenwa zvisina kurongwa uye panzvimbo pezvo kushandisa huwandu hwakayerwa hwemadhayi aizivikanwa. Akazorega kuburitsa nzira yaaigadzira nayo pure methylene azure ndokutengesa nzira yacho kurabhoritari yaDr. Grübler, iyo yakatengesa chigadzirwa ichi seazure I uye ikati shanduro yayo chete ndiyo yaiva Giemsa stain yechokwadi.

Hondo dzenyika mbiri dzakapedzisa basa iri netsaona. Madhayi eGermany paakanga asisawanikwi, Lillie, Roe naWilcox vakashanda pane zvinotsiva zveAmerica uye vakaona kuti staining yakanakisisa yaibva kuzvikamu zvitatu zvakaparadzaniswa: pure methylene blue, breakdown product yayo azure B, uye eosin. Zvitatu izvi zvichiri zvikamu zvikuru zve stain inoshandiswa kuongorora malaria nhasi, pasi pezita rava kubatanidza Malachowski, Wright naGiemsa.

Figure: ring forms dzePlasmodium falciparum mumasero matsvuku eropa remunhu, dzakaiswa stain nenzira yerudzi rweRomanowsky. Chimiro chepepuru chiri mukati mering ndicho chromatin chakaita kuti methylene blue yaMalachowski yakarapwa neborax ionekwe kekutanga. Mufananidzo naErnst Hempelmann, wakaburitswa kupublic domain.

Zita rimwe, zvinhu zvakati wandei

Makore akaparadzanisa zvikamu izvozvo akasiya dambudziko rakagara kupfuura chemistry yacho. Ralph Lillie akatsanangura mutsauko muna 1969 pakati pemastain ebiology, "akagadzirwa achitevedza specifications dzakasimba dzinoenderana nekushandiswa kwawo kunoda kunyatsorurama", nemastain asiri ebiology ekupenda machira, ayo "anoda manufacturing standards dzisina kuomarara zvakanyanya". Mhando dzose mbiri dzechigadzirwa dzaiva nezita rimwe chete, uye musiyano wadzo waisambova kungoti imwe yaiva nani zvishoma pane imwe. Specification yakanyorerwa donje nespecification yakanyorerwa diagnostic reagent hazvichinjani, uye material yakagadzirwa zvinoenderana neyekumachira yakanga isina kuitirwa kumedzwa.

Azure B ndiyo muenzaniso wakajeka zvikuru. Ndiyo monodemethylated form yemethylene blue, ine pharmacological activity yayo inogona kuyerwa, uye yaive constituent isingadzorwi mumethylene blue preparations dzekiriniki kweanopfuura makore zana vanhu vasati vapatsanura zviviri izvi. Rimwe boka rakaona kuti tissue yemunhu yakatorwa paautopsy mushure mekupiwa methylene blue yaiva ne5 kusvika 14 per cent yemethylene blue isina kuchinja uye 86 kusvika 95 per cent azure B. Kuti preparation yakati inofanira kuva neazure B here, uye pamuganhu upi, mubvunzo wespecification, uye tsvakurudzo pamusoro peazure B seimpurity nemetabolite inoenderera kubva ipapo.

Specification ndiyo zvakare ine mhedzisiro inoshanda. Kutevedzera USP ndiyo nzira inoenda kupurity yepamusoro-soro inopihwa nemusika, nekuti iwoyo muyero wakazara wakaburitswa wemiedzo kwete measurement imwe chete. Unosanganisira identity, assay, organic impurities kusanganisira madhayi eazure, residual solvents, elemental impurities, residue on ignition, microbial limits, uye bacterial endotoxins. Certificate inongotaura heavy-metal result yobva yati ndiyo USP compliance inenge yataura mutsetse mumwe chete werondedzero iyoyo.

Blupreme inowana methylene blue yayo kubva kumugadziri wemishonga uye inoburitsa certificate of analysis yakazara, ichiedza USP specification yose panzvimbo peheavy metals chete. Gwaro rekuti ungaverenga sei certificate of analysis uye zvinoratidzwa nezita reUSP nezvarisingaratidzi zvinotsanangura maitiro ekutarisa gwaro iri uchienzanisa nechirevo chacho.

Zvinobvumidzwa nenhoroondo, nezvaisingabvumidzi

Mutsara wenhoroondo uyu ndewechokwadi, uye wakareba kupfuura zvinoratidzwa nemapeji mazhinji ezvigadzirwa. Methylene blue yakashandiswa kurapa malaria muna 1891, yakataurwa sesedative muagitated psychosis muna 1899, uye side chain yayo inoenderera kuburikidza nequinacrine, chloroquine, promethazine nechlorpromazine. Chinyorwa chaEhrlich cha1890 naArthur Leppmann chakatsanangura kuderedzwa kwemarwadzo eneuralgic nerheumatic, ndokuzofunga nezvekushandisa dhayi iyi muchirwere chepfungwa asi vakaramba kuiyedza.

Hapana chimwe chezvinhu izvozvo chinoratidza kushandiswa kwemazuva ano. Mhedzisiro yemalaria ya1891 yaiva yevarwere vaviri nechati yetembiricha. Kuzivikanwa kwemolecule kwenguva refu chikonzero chekuiongorora, kwete mhedzisiro pachayo. Nhoroondo yecompound iyi semushonga uye modern trials mumalaria zvinopindura mibvunzo yakasiyana neyaibvunzwa naEhrlich, uye endpoints dzacho dzinofanira kuverengwa maererano nezvadzinoyera pachadzo.

Pane chinhu chimwe chete chiri muchinyorwa ichi chine chekuita nenguva yazvino kwete yakapfuura. Vatsvakurudzi pavakaita methylene blue malaria trials muBurkina Faso muma2000s, vakazviwana vachikwikwidzana kuwana pharmaceutical-grade material, uye vakataura kuti mutengo weraw material wakanga wakwira nefactor inosvika zana kana yangowana GMP validation. Dhayi yaigona kutsiviwa. Mushonga waisagona. Musiyano wakatsanangurwa naLillie muna 1969 ndiwo musiyano mumwe chete uchiri kuona kuti chii chiri mubhodhoro nhasi.