Methylene blue pakukanganisika kweuropi kunokonzerwa neifosfamide: ongororo yeuchapupu

Ifosfamide mushonga unoshandiswa zvakanyanya mukurapa kenza, unoshanda nealkylation, uchishandiswa pakurapa sarcoma, lymphoma, kenza yemuromo wechibereko, nekenza yemapapu, pakati pedzimwe. Muchikamu chidiki chevarwere, unokonzera chinhu chinotyisa: maawa kusvika kumazuva mushure mekunge kupinzwa kwawo nomutsinga kwatanga, murwere anovhiringidzika, anosagadzikana, anotsimwaira, uye dzimwe nguva anova nepsychosis iri pachena kana kusapindura zvachose. Mifananidzo yekuongorora inowanzoratidza kuti zvinhu zvakajairika. Zvadaro, muzviitiko zvakawanda, mamiriro acho anopera mukati memazuva mashoma kana mushonga wamiswa. Nyanzvi dzekenza dzinoti uku kukanganisika kwekushanda kweuropi kunokonzerwa neifosfamide, uye kusafungidzirika kwazvo ndiko kunoita kuti mushumo wemuma1990 wekubviswa kwazvo nedhayi rebhuruu uchiri kukurukurwa mumawadhi nhasi.

Mubvunzo unopindurwa nechinyorwa ichi wakanyatsoganhurirwa. Methylene blue inorapa kana kudzivirira kukanganisika uku kweuropi here, uye uchapupu hwacho hwakasimba zvakadii? Mhinduro pfupi ndeyekuti nyaya dzekurapwa kwekukurumidzira dzinokatyamadza asi uchapupu husina kusimba, uye uchapupu hwekudzivirira hwakatonyanya kusasimba. Musiyano uyu unokosha nokuti ichi chisarudzo chinoitwa muchipatara pasi pekumanikidzwa, kwete chisarudzo chekuwedzera zvinovaka muviri chinoitwa kumba.

Kukanganisika kweuropi uku kunoratidzika sei

Zviratidzo zvinowanzotanga panguva kana nguva pfupi mushure mekupinzwa kweifosfamide nomutsinga: kusaziva nzvimbo kana nguva, kusagadzikana, kuona kana kunzwa zvinhu zvisipo, kutsimwaira, uye dzimwe nguva kugwinha kana kuva mucoma. EEG inowanzoratidza kuderera kwekumhanya kwekushanda kwemagetsi muuropi kwese. Njodzi inowedzera kana huwandu hwemushonga hwakakwira, kana uchipinzwa nokukurumidza, kana itsvo dzisingashandi zvakanaka, kana albumin iri shoma, kana murwere akambova nechirwere cheuropi, uye kana achishandisa mimwe mishonga inotsimwairisa panguva imwe chete. Zviitiko zvakawanda zvinopera nekuchengetwa kunotsigira murwere chete muzuva rimwe kusvika kumatatu, kunyange zvazvo zvimwe zvichinyanya kuoma kana kutora nguva refu, uye kupiwa ifosfamide zvakare kunogona kukonzera kudzoka kwechiitiko chacho.

Mafambiro aya echirwere pachacho ndiwo aunofanira kunzwisisa usati waverenga chero mushumo wemethylene blue. Mushonga wakapiwa pazuva rechipiri rekuvhiringidzika uchiteverwa nekupora pazuva rechitatu unogona kunge usina chawakaita zvachose. Zvose zvinotaurwa pazasi zvinofanira kuyerwa zvichienzaniswa nekupora kunoitika kwega.

Pfungwa yekushandisa methylene blue yakabva kupi

Muna 1994 boka rekuBern rakashuma zvakaonekwa muweti yevarwere vaipiwa ifosfamide zvaifanana nechirwere chisingawanzoitiki chinogarwa nhaka chekufambiswa kwemaelectron mumitochondria, paine glutaric acid nesarcosine zvakawandisa, uye rakatsanangura kupera nokukurumidza kwekukanganisika kweuropi mushure mekupiwa methylene blue mumushumo mupfupi weLancet. Ongororo yakatevera yenzira yekushanda yakafungidzira kwete nzira imwe chete asi nhatu dzinoshanda pamwe chete.

Kutanga, ifosfamide inoputswa muchiropa ichibudisa chloroethylamine yakawanda, iyo inobatana necysteine ichigadzira chinhu chine sulfur chine chimiro chedenderedzwa chinonzi thialysine ketimine. Chinhu ichi chinodzivisa flavoproteins mumaketani ekufema emitochondria, chichivhara oxidation yeNADH yakajairika. Methylene blue, sechimwe chinhu chinogamuchira maelectron, inogona kutsiva danho ravharwa, pfungwa yakatorwa kubva pakushandiswa kwayo kare mune mamwe marudzi eglutaric aciduria.

Chechipiri, kuvharwa kweketani yeredox pamwe nealdehyde yakawandisa inobva pakushandurwa kweifosfamide mumuviri zvinoderedza reshiyo yeNAD kuNADH, zvichikanganisa kubviswa kwealdehyde nekugadzirwa kweglucose. Methylene blue inoita kuti NADH iite oxidation zvakare ichienda kuNAD, ichidzorera chikamu chekuenzana ikoko. Maitiro mamwe chete aya ekutakura maelectron muredox ndiwo ari pasi pezvimwe zvakawanda zvinofungidzirwa kuti inoita mumasero, uye zvakakodzera kunzwisisa pfungwa yekuti methylene blue inotakura sei maelectron zvakasiyana nekushandiswa uku chaiko pakurapa.

Chechitatu, methylene blue inodzivisa maenzyme eamine oxidase ayo aizoshandura chloroethylamine kuita chloroacetaldehyde, chinhu chinobva pakushandurwa kwemushonga chinokuvadza tsinga neitsvo zvakananga uye chinowanikwa chisina kusungwa muplasma yevarwere vanopiwa ifosfamide. Chloroacetaldehyde shoma inoreva kukuvadzwa kushoma kunotevera, kusanganisira kukanganiswa kushoma kweoxidation yemafuta acids kwakaratidzwa mumitochondria yakaparadzaniswa.

Nzira iyi yekushanda inonzwisisika uye yakatsanangurwa zvakadzama zvisingawanzoitiki. Kunzwisisika hakurevi kuti yakaratidzwa kuva yechokwadi, asi kunotsanangura kuti nei nyanzvi dzekenza dzakakoshesa zviitiko zvekutanga.

Mishumo yekurapwa kwekukurumidzira: kunokurumidza, asi pasina mapoka ekuenzanisa

Chiitiko chinonyanya kutaurwa chichiri mushumo wa1995 wemukadzi ane makore 68 aiva nekenza yemuromo wechibereko, akavhiringidzika uye akasagadzikana mushure mekupiwa ifosfamide 5 g paskweya mita mumaawa 24. CT yake yakanga yakajairika uye EEG yake yakaratidza kuderera kwekumhanya kwekushanda kwemagetsi muuropi kwese. Akapiwa 50 mg yemethylene blue nomutsinga mumaminitsi mashanu uye akatsanangurwa seakanga akamuka achitaura zvinonzwisisika mukati memaminitsi gumi. Maminitsi gumi anokurumidza zvikuru kupfuura mafambiro echirwere pachacho, ndicho chikonzero chiitiko ichi chimwe chete chakapiwa uremu hwakawanda kudaro.

Mapoka ezviitiko akazotevera haana kunyanya kukatyamadza. Muongororo yezvakaitika kare pavarwere 52 vaipiwa ifosfamide, 12 vakava nekukanganisika kweuropi kwegiredhi 2 kana kupfuura, vasere vacho vakapiwa methylene blue 50 mg nomutsinga katanhatu pazuva. Vana vakapora zvizere mukati memaawa 24, kusanganisira mumwe aiva nechiitiko chakanyanya kuoma akapora munenge muawa imwe chete; vamwe vaviri vakapora pakazosvika maawa 48, uye vaviri pakazosvika maawa 72. Asi varwere vose vana vasina kurapwa vakaporawo mukati memaawa 48, sezvakataurwa nevanyori pachavo. Ongororo yeboka rezviitiko 15 zvevana yakawana kubatsira kunoratidzwa mune mumwe chete pavana vashanu vakarapwa. Zviitiko zviviri zvevakuru zvakabudiswa muna 2018, zvakarapwa ne50 mg maawa mana oga oga, zvakatanga kuvandudzika chete mushure memaawa 12 kusvika ku16 uye zvakadzokera pamamiriro azvaimbova nawo mushure memazuva maviri kusvika kumatatu, nguva dzisingasiyanisiki nedzekuchengetwa kunotsigira murwere.

Ongororo yezvinyorwa ya2020 yakaverenga varwere 38 vakarapwa nemethylene blue vane mishumo yakabudiswa, vanenge zvikamu zvitatu muzvina vachitsanangurwa sevakapindura zvakanaka. Nhamba iyoyo inonzwika ichikurudzira kusvikira warangarira kuti kupora kunokurumidza kunonyorwa, asi kunononoka hakuwanzo nyorwa. Kurerekera pakubudiswa kwemishumo kunoita kuti kuunganidzwa kwemishumo yezviitiko kuonekwe kuri nani kupfuura mamiriro chaiwo.

Tafura yeuchapupu: siyanisa magadzirirwo eongororo

Tafura iri pazasi ndiyo musimboti weongororo iyi. Mishumo yezviitiko inogona kungopa fungidziro; mapoka ezviitiko asina mapoka ekuenzanisa anogona kungotsanangura; uye pamubvunzo uyu hapana miedzo yekushanda kwemushonga inogovera varwere mumapoka zvisina kurongwa.

Chikamu cheuchapupu	Ongororo	Magadzirirwo eongororo nevarwere	Maitiro ekupiwa methylene blue	Zvakaitika
Mushumo wechiitiko	Kupfer et al., Lancet 1994	Chiitiko chekutanga chekurapwa pamwe nechiitiko chimwe chekudzivirira; zvakaonekwa pamakemikari emuviri zvine patani yakafanana neglutaric aciduria	Kurapa 50 mg IV; kudzivirira nomuromo	Kupera nokukurumidza kwakashumwa; murwere wechipiri haana kudzokerwa pakapiwa ifosfamide zvakare
Mushumo wechiitiko	Zulian et al., N Engl J Med 1995	Mukadzi ane makore 68, kenza yemuromo wechibereko, kuvhiringidzika mushure meifosfamide 5 g/m2 mukati me24 h	50 mg IV mukati me5 min, mushonga wakanyungudutswa une 1 percent	Akamuka uye aitaura zvinonzwisisika mukati me10 min
Boka rezviitiko, ongororo yezvakaitika kare ine vasina kurapwa vekuenzanisa navo	Pelgrims et al., Br J Cancer 2000	Varwere 52 vaipiwa ifosfamide; 12 vane kukanganisika kweuropi kwegiredhi 2 kana kupfuura; 8 vakarapwa, 4 havana	Kurapa 50 mg IV katanhatu pazuva; kudzivirira 50 mg kana pazuva muvarwere 3	Vakarapwa: 4 pa8 vakapora mukati me24 h, vose mukati me72 h. Vasina kurapwa: vose 4 vakapora mukati me48 h
Boka rezviitiko	Turner et al., Clin Oncol 2003	Zviitiko 4 zvakangoerekana zvatanga, 2 vakazopiwa mushonga wekudzivirira	Kazhinji 50 mg nomuromo katatu pazuva	Kuvandudzika kukuru mukati me24 h kwakashumwa; mamiriro akareruka pakapiwa ifosfamide zvakare pamwe nemushonga wekudzivirira
Boka rezviitiko zvevana	Dufour et al., Arch Pediatr 2006	Zviitiko 15 zvekukanganisika kweuropi muvana	Kurapa 50 mg IV 4 h dzoga dzoga; kudzivirira 6 h dzoga dzoga	Kubatsira kwakanzi kwaivapo muna 1 pa5 vakarapwa; 2 pa2 vezviitiko zvekudzivirira havana kudzokerwa
Ongororo yekufamba kwemushonga mumuviri, isina boka rekuenzanisa kushanda kwawo	Aeschlimann et al., Drug Metab Dispos 1998	Varwere 9 vane kenza yemapapu vaipiwa ifosfamide, mesna, etoposide	50 mg nomuromo katatu pazuva kubva manheru asati atanga kurapwa kenza nemishonga	Yakatsungirirwa; hapana shanduko yakakosha mukuitwa kuti ifosfamide ishande; kudzivirirwa kwetsinga kwakataurwa asi pasina boka rekuenzanisa
Ongororo yezvakaitika kare, yakanangana nekudzivirira	Sweiss et al., Drug Safety 2008	Varwere 19 vaipiwa ifosfamide yakawanda; 8 vane kukanganisika kweuropi; 5 vakapiwa zvakare pamwe nemushonga wekudzivirira	Methylene blue yekudzivirira, maitiro ekuipa akasiyana	Vose 5 vakapiwa ifosfamide zvakare pamwe nemushonga wekudzivirira vakava nekukanganisika kweuropi zvakare
Kuenzanisa kutenderera kwekurapwa kwakaitika kare	Richards et al., J Oncol Pharm Pract 2011	Kutenderera kwekurapwa 166 kwaishandiswa methylene blue, thiamine, kana albumin kudzivirira, zvichienzaniswa nekusashandisa chinhu	Nzira dzakasiyana dzekudzivirira	Kukanganisika kweuropi mu21.1 percent yekutenderera kwaiva nekudzivirira zvichienzaniswa ne8.4 percent kusina; zvingangodaro kuti kuenzanisa kwakakanganiswa nezvikonzero zvekupa mushonga
Boka rezviitiko zvakaongororwa kubva mune zvakaitika kare	Boka rezviitiko zvevana nevechidiki veMD Anderson, 2025	Varwere 24 vane kukanganisika kweuropi; 20 vakapiwa methylene blue	Kazhinji 50 mg IV 6 h dzoga dzoga, nhamba yepakati yekupiwa mushonga iri 5	19 pa20 vakapora mukati me24 kusvika ku120 h, pasina vasina kurapwa vekuenzanisa navo; 3 pa5 vakapiwa ifosfamide zvakare pamwe nemushonga wekudzivirira vakadzokerwa

Verenga pasi muchikamu chezvakaitika uye patani yacho yakafanana: nyaya dzekutanga dzinokatyamadza, dzichiteverwa nemigumisiro inoramba ichinonoka uye ichisiyana apo mapoka evarwere anokura uye kuenzanisa kunovapo. Ichi chiratidzo chenzira yekurapa ine kubatsira kwechokwadi, kana kuripo, kusiri kukuru.

Uchapupu hwekudzivirira hahuna kusimba

Zvinotaurwa nezvekudzivirira zvinofanira kuongororwa zvazvo nokuti ndizvo zvinotungamirira kupiwa kwemishonga chaiko. Mushure mezvakaitika pakutanga kuBern, paishandiswa ifosfamide nomuromo pamwe ne50 mg katatu pazuva uye pasina kukuvadzwa kwetsinga kwakaonekwa, nzvimbo dzakawanda dzakaedza methylene blue yekudzivirira pakupa ifosfamide zvakare. Migumisiro yacho inosiyana zvikuru. Vamwe varwere vakapiwa zvakare vakava nezviitiko zvakareruka kana kusava nazvo; mune mamwe mapoka ezviitiko, vose vakapiwa zvakare pamwe nemushonga wekudzivirira vakaramba vachiva nekukanganisika kweuropi, uye kumwe kuenzanisa kwezvakaitika kare kwakawana kukanganisika kweuropi kwakawanda mukutenderera kwekurapwa kwaiva nekudzivirira kupfuura mukusina, zvinenge zviri chokwadi kuti izvi zvakakonzerwa nokusarudzwa kwevarwere vane njodzi huru kuti vapiwe mushonga wekudzivirira.

Vanyori vemirayiridzo vakazvicherechedza. Mirayiridzo yakabatana yekukuvadzwa kwetsinga yakabva kumasangano eEuropean enyanzvi dzekenza neetsinga yakagumisa kuti miedzo ine mapoka ekuenzanisa haipo uye kuti methylene blue haigoni kukurudzirwa pakudzivirira kana kurapa zvichibva pauchapupu huripo. Mashoko ekupa mushonga nemimwe mitemo yezvipatara zvinotaura nenzira isina kuomarara zvakadaro, zvichiti inogona kufungwa nezvayo kana kukanganisika kweuropi kuri pakati nepakati kana kwakanyanya. Maonero ose ari maviri anotsanangura uchapupu humwe chete; anosiyana chete pauremu hunofanira kupiwa nyaya dzezviitiko kana pasina imwe nzira iri nani.

Mamiriro ekushandiswa nenyanzvi anofanira kuzivikanwa nemunhu asiri nyanzvi yekenza

Zvinhu zvitatu zvinoshanda ndizvo zvinotungamirira chisarudzo choga choga chinoitwa pamubhedha wemurwere. Kutanga, kushandiswa kwemethylene blue pano hakuna kubvumirwa zviri pamutemo pachinangwa ichi, uye inopiwa nomutsinga muchipatara, kazhinji 50 mg maawa mana kusvika kumasere oga oga kusvikira zviratidzo zvapera. Haisi mushonga wekushandisa kumba uye chinyorwa ichi hachisi gwara rehuwandu hwekupa mushonga.

Chechipiri, methylene blue inodzivisa monoamine oxidase A uye ine yambiro yakaiswa mubhokisi pamusoro peserotonin syndrome kana yasanganiswa nemishonga yekuora mwoyo inoshanda paserotonin uye nemamwe maopioid; serotonin syndrome yakashumwa chaizvo panguva yekurapwa kwekukanganisika kweuropi kunokonzerwa neifosfamide. Haifaniriwo kushandiswa kana paine kushomeka kweglucose-6-phosphate dehydrogenase nokuda kwenjodzi yekuputsika kwemasero matsvuku eropa. Ruzivo rwekuchengeteka nekudyidzana nemimwe mishonga pamwe nemubvunzo wakakura wekuti kushandiswa kwemethylene blue kwakachengeteka here mumurwere wacho zvinofanira kuverengerwa muchisarudzo bhodhoro ripi neripi remushonga webhuruu risati ravhurwa.

Chechitatu, kumisa ifosfamide, kupa mvura yakakwana, kugadzirisa electrolytes nemimwe mishonga iri kupiwa, uye kuongorora kuti hapana zvimwe zvinokonzera kuvhiringidzika zvinoramba zviri hwaro. Methylene blue, painoshandiswa, inowedzerwa pahwaro ihwohwo, kwete kuputsiva. Kudzidza maverengerwo eongororo yemethylene blue kunobatsira pano: bvunza kana mushumo wacho waiva neboka rekuenzanisa, kuti kukanganisika kweuropi kwakaiswa sei mumagiredhi, kuti chii chimwe chakachinja panguva imwe chete, uye kana nguva yekupora ichisiyana nenguva inozivikanwa yezuva rimwe kusvika kumatatu yekupora kwega.

Pfupiso

Kushandiswa kwemethylene blue pakukanganisika kweuropi kunokonzerwa neifosfamide kwakavakirwa panzira yekushanda mumitochondria inonzwisisika, panyaya shoma dzekurapwa kwekukurumidzira dzinoratidza kupora kunokurumidza uye kunokatyamadza zvechokwadi, uye pahuwandu hukuru hwemapoka ezviitiko umo varwere vakarapwa nevasina kurapwa vanopora munguva dzakafanana. Sekurapwa kwekukurumidzira kwekukanganisika kweuropi kwakanyanya kana kwatora nguva refu, dzimwe nyanzvi dzekenza dzinoona kushandiswa kwayo kuchikodzera nokuda kwekushayikwa kwedzimwe nzira. Sekudzivirira kunoitwa nguva dzose, uchapupu hahuitsigiri. Chero munhu anosangana nemubvunzo uyu, angava murwere, muchengeti, kana murapi, anofanira kuuona sechisarudzo chenyanzvi chinoitwa murwere ari muchipatara, zvichienderana nechiitiko chimwe nechimwe, uye otora kupora kunokurumidza sefungidziro inoda kuongororwa, kwete seuchapupu hunosimbisa.