Azure B: ukungcola kwe-methylene blue, imetabolite, kunye nekhompawundi yophando

I-Azure B sisalamane se-methylene blue esahlukileyo ngokwemichiza. Isenokuba sele ikhona kwisampuli ye-methylene blue, ivele emva kokuba umzimba uqhubekekise i-methylene blue, okanye inikezelwe ngokwahlukeneyo ukuze kusetyenziswe kuvavanyo. Ezi nkcazelo aziphikisani. Zichaza apho ikhompawundi ivela khona kunye nombuzo umphandi awubuzayo ngayo.

Lo mahluko ubalulekile xa kutolikwa isatifikethi sohlalutyo okanye ibango malunga nomsebenzi webhayoloji. Ukubiza i-Azure B ngokuba yimetabolite esebenzayo akuthethi ukuba isixa esingalawulwanga esisebhotileni sinqweneleka. Ukuyibiza ngokuba kukungcola akuthethi ukuba ayisebenzi ngokwebhayoloji.

Yintoni etshintshayo ngokwemichiza?

I-Azure B sisiphumo se-methylene blue esine-methyl enye esusiweyo. Iqela elinye le-methyl elincamathele kwi-nitrogen litshintshwe nge-hydrogen. Olu nxulumano luchazwe kwingxoxo yemichiza nakuFigure 1 kuphononongo lukaSchirmer noogxa bakhe. Olu lutshintsho oluthile lwesakhiwo, hayi nje elinye igama le-methylene blue.

Ikwahlukile ekuncitshisweni ibe yi-leucomethylene blue. Ukuncitshiswa kutshintsha imeko ye-oxidation; i-N-demethylation itshintsha iqela elincamathele kwi-nitrogen. Ukuphatha zombini ezi nkqubo njengokuthi nje “i-methylene blue iba yingenambala” kususa umahluko ofunekayo ekutolikeni imetabolism. Amagama eedayi anxulumeneyo nawo afuna ingqalelo efanayo: i-Azure A, i-Azure B, kunye ne-methylene blue ayingomagama anokutshintshaniswa. Isikhokelo seekhompawundi ezinamagama afanayo sijongana nale ngxaki yamagama.

Imvelaphi emithathu, imibuzo emithathu eyahlukileyo

Umzobo ongaphandle wohlula iindlela ezintathu kuphando. Itheyibhile yenza kucace ubungqina obufunekayo kwindlela nganye.

Umqolo ophakathi kulula ukuwuphosa. Ukuba i-Azure B ibisele ikhona kwizinto ezinikwe umntu, isampuli yebhayoloji ethathwe kamva inokuqulatha zombini ikhompawundi ebisele ikhona kunye naleyo isandul’ ukwenziwa. Ukuqinisekisa ukuba yenziwe kufuna okungaphezulu kokufumana i-peak emva kokuvezwa.

I-Azure B kwizinto zokuqala

Uphononongo lwembali lohlalutyo lunika umzekelo oluncedo wokuba kutheni icandelo elincinci linokuba libalulekile. Abaphandi ababephanda iodination ye-methylene blue nge-HPLC–mass spectrometry bafumanisa ukuba imveliso ephambili ene-iodine yavela kukungcola kwe-Azure B. Iisampuli ze-methylene blue ezaphononongwa zaziqulathe malunga ne-7–8% Azure B. Phantsi kweemeko zabo zempendulo, i-Azure B ene-iodine yayininzi kakhulu kune-methylene blue ene-iodine.

Ezo pesenti zichaza izinto ezazisetyenziswa kolo phononongo luka-1999. Azimiseli umda owamkelekileyo wanamhlanje wokungcola okanye ukwakheka kwemveliso yomnye umboneleli. Uvavanyo lubonisa ingongoma encinci ngakumbi: ikhompawundi ephambili ekuqaleni akuyomfuneko ukuba ivelise eyona mveliso iphambili yempendulo.

Kwisatifikethi sohlalutyo, jonga isiphumo esithile se-Azure B, iiyunithi, indlela yovavanyo, umda wokunika ingxelo, kunye nesazisi selot. Uvavanyo lwedayi iyonke kunye novavanyo lwezinto ezinxulumeneyo luphendula imibuzo eyahlukileyo. Isiphumo esithi “ayifunyanwanga” naso sifuna umda wokufunyanwa okanye wokunika ingxelo ukuze sitolikeke. Bona indlela yokufunda isatifikethi sohlalutyo se-methylene blue ukuze ufumane uhlolo olubanzi loxwebhu.

I-Azure B eyenziwa ngexesha lemetabolism

Ukufunda imetabolism kufuna uhlalutyo olwahlula ikhompawundi yokuqala kunye nemetabolite yayo. UKim noogxa bakhe baphuhlisa indlela ye-LC–MS/MS yokulinganisa zombini iikhompawundi kwi-plasma yeempuku. Uluhlu lwabo lokulinganisa lwaluyi-1–1,000 ng/mL kwikhompawundi nganye, nomda osezantsi wokulinganisa we-1 ng/mL kusetyenziswa i-20 microlitres ye-plasma yeempuku. Emva koko bayisebenzisa indlela leyo kuphononongo lwe-pharmacokinetics kwiimpuku.

Le nkcukacha ibalulekile kuba indlela yokulinganisa inomxholo wesampuli. Ukuqinisekiswa kwi-plasma yeempuku akumisi ngokuzenzekelayo ukuchaneka kwi-plasma yomntu, kumchamo, okanye kwisisombululo sorhwebo esixineneyo. Le ndlela ibonisa indlela abaphandi abanokulandela ngayo iikhompawundi ezimbini ngokwahlukeneyo; ayiniki mgaqo wokudosa abantu.

Idatha yokuvezwa kwabantu nayo ibonisa ukuba kutheni ipesenti enye engatshintshiyo yemetabolite ingonelanga. Icandelo le-clinical pharmacology kwilebhile yenaliti ye-methylene blue lichaza ukwanda kokuvezwa kwi-Azure B kubathathi-nxaxheba abanokungasebenzi kakuhle kwezintso. Ukuvezwa ekuhambeni kwexesha kubonisa ukwenziwa, ukusasazwa, kunye nokususwa, kungekhona nje ukwakheka kwebhotile. Indlela yokunikwa, ixesha lokuthatha isampuli, kunye necandelo lomzimba elilinganisiweyo zonke zibalulekile xa kuthelekiswa ezi ziphumo.

Oko kuboniswa luvavanyo oluthe ngqo

I-Azure B inomsebenzi we-pharmacology onokulinganiswa. Umbuzo oluncedo ngakumbi kukuba yeyiphi target, phantsi kweziphi iimeko.

Kwi-2012 study using recombinant human monoamine oxidase, i-Azure B yathintela i-MAO-A nge-IC50 ye-11 nM, xa kuthelekiswa ne-70 nM ye-methylene blue phantsi kweemeko ezifanayo. I-IC50 luxinaniso olunxulunyaniswa ne-50% inhibition kolo vavanyo. I-Azure B yathintela ne-MAO-B, kodwa kuxinaniso oluphezulu kakhulu: 968 nM. Abaphandi baxela inhibition ebuyisekayo.

Ezi ziphumo zixhasa ukuba kunokwenzeka kubekho igalelo kwiziphumo zebhayoloji nakunxibelelwano, kuquka imibuzo malunga ne-methylene blue kunye nee-neurotransmitters. Azithethi ukuba i-Azure B ingcono ngokuphindwe kathandathu njengeyeza. Umlinganiselo uchaza inhibition ye-enzyme enye kuthelekiso olunye lovavanyo.

Uvavanyo olwahlukileyo lwe-cholinesterase ebantwini lubonisa umda wolu hlobo lokwenza isishwankathelo. Amaxabiso e-IC50 e-Azure B ayeyi-0.486 micromolar ye-acetylcholinesterase kunye ne-1.99 micromolar ye-butyrylcholinesterase. I-methylene blue yayinamandla ngakumbi kwezo assay zifanayo, ngamaxabiso e-0.214 kunye ne-0.389 micromolar ngokulandelelana. Ulandelelwano lwatshintsha ngokuxhomekeke kwi-target yebhayoloji. Akukho nasinye kwezi ziphumo esizimeleyo esiqinisekisa ukuphucuka kokuqonda okanye unyango lwe-Alzheimer's disease.

Ukusuka kumsebenzi wovavanyo ukuya kutoliko lweklinikhi

Uvavanyo kwizilwanyana ezipheleleyo longeza elinye inqanaba lobungqina ngaphandle kokusombulula ukusebenza kweklinikhi. Kwi-phononongo lweempuku lukaDelport noogxa bakhe, i-Azure B yanciphisa ukungashukumi kuvavanyo olukhawulezileyo lwe-forced-swim, kunye ne-methylene blue kunye ne-imipramine phakathi kwezithelekisi. Iphepha likubiza oku ngokuba sisiphumo esifana neseyeza lokudakumba. Yayiluvavanyo lokuziphatha kwiimpuku, hayi uvavanyo olulinganisa ukubuyela kwimeko entle kwizigulana ezinokudakumba.

Kulo naliphi na ibango malunga ne-Azure B, qala uchonge izinto ezivavanyiweyo. Emva koko chonga isilwanyana okanye i-assay, ukuvezwa, kunye nesiphelo esilinganisiweyo. Ekugqibeleni, jonga ukuba isigqibo sichaphazela ukwakheka, imetabolism, umsebenzi we-enzyme, ukuziphatha kwesilwanyana, okanye inzuzo yeklinikhi. La manyathelo athintela isiphumo somgangatho we-batch ukuba singaphazanyiswa nebango lonyango, kwaye athintela indlela yokusebenza efunyenwe kuvavanyo ukuba ingaphazanyiswa nesiphumo esele siqinisekisiwe kwizigulana.