Imethylene blue kwi-encephalopathy ebangelwa yi-ifosfamide: uhlaziyo lobungqina

I-ifosfamide lichiza elisetyenziswa kakhulu kunyango lomhlaza, elisebenza ngokongeza amaqela e-alkyl, nelisetyenziselwa i-sarcoma, i-lymphoma, umhlaza womlomo wesibeleko, nomhlaza wemiphunga, phakathi kweminye. Kwigcuntswana lezigulana ibangela into eyothusayo: kwiiyure ukuya kwiintsuku emva kokuqalisa ukufakwa kwechiza ngomthambo, isigulana siyadideka, siphazamiseke, sozele, maxa wambi sibonise ngokucacileyo ukulahlekelwa kukuqonda inyani okanye singaphenduli. Imifanekiso yezikena idla ngokungabonisi nto ingaqhelekanga. Emva koko, kwiimeko ezininzi, le meko iyaphela kwiintsuku ezimbalwa xa ichiza liyekiwe. Iingcali zomhlaza ziyibiza ngokuba yi-encephalopathy ebangelwa yi-ifosfamide, yaye ukungaqikeleleki kwayo sisizathu sokuba ingxelo yeminyaka yoo-1990 yedayi eluhlaza eyayibuyisela umva le meko isaxoxwa kwiindawo zokunyanga izigulana ezilaliswe esibhedlele nanamhlanje.

Umbuzo ophendulwa leli nqaku ugxile kumba othile. Ngaba imethylene blue iyayinyanga okanye iyayithintela loo encephalopathy, yaye bomelele kangakanani ubungqina? Impendulo emfutshane kukuba iingxelo zoncedo olungxamisekileyo ziyamangalisa kodwa ubungqina bubuthathaka, yaye obothintelo bubuthathaka ngakumbi. Loo mahluko ubalulekile kuba esi sisigqibo sasesibhedlele esenziwa phantsi koxinzelelo, kungekhona isigqibo sesongezelelo esenziwa ekhaya.

Indlela ebonakala ngayo i-encephalopathy

Iimpawu zidla ngokuqala ngexesha okanye kungekudala emva kokufakwa kwe-ifosfamide ngomthambo: ukungazi apho ukhoyo okanye ixesha, ukungazinzi, ukubona okanye ukuva izinto ezingekhoyo, ukozela, yaye ngamanye amaxesha ukuxhuzula okanye isiqaqa esinzulu. I-EEG idla ngokubonisa ukucotha okusasazekileyo komsebenzi wombane wobuchopho. Umngcipheko uyanda ngeedosi eziphezulu, ukufakwa ngokukhawuleza, ukusebenza kakubi kwezintso, i-albumin ephantsi, isifo sobuchopho ebesikho ngaphambili, kunye namachiza abangela ukozela asetyenziswa ngaxeshanye. Uninzi lwezi ziganeko luphela ngokhathalelo oluxhasayo kuphela kusuku olunye ukuya kwezintathu, nangona kukho iimeko ezinzima okanye ezithatha ixesha elide, yaye ukuphinda kunikwe i-ifosfamide kunokubangela ukuba le meko iphinde yenzeke.

Le ndlela imeko edla ngokuqhubeka ngayo ngokwayo yingcamango ekufuneka uyiqonde ngaphambi kokufunda nayiphi na ingxelo ngemethylene blue. Ichiza elinikwe ngosuku lwesibini lokudideka, kuze kulandele ukuchacha ngosuku lwesithathu, lisenokuba alenzanga nto kwaphela. Ibango ngalinye elingezantsi kufuneka lithelekiswe nokuchacha okuzenzekelayo.

Imvelaphi yengcamango yemethylene blue

Ngo-1994 iqela laseBern lanika ingxelo ngeziphumo zovavanyo lomchamo kwizigulana ezisebenzisa i-ifosfamide ezazifana nesifo esinqabileyo esizuzwa njengelifa sokudluliselwa kwee-elektroni kwi-mitochondria, kukho i-glutaric acid ne-sarcosine ezingaphezulu komlinganiselo, laza lachaza ukubuyela umva ngokukhawuleza kwe-encephalopathy emva kwemethylene blue kwingxelo emfutshane yeLancet. Uhlaziyo olulandelayo lwendlela yokusebenza lwacebisa ukuba azikho ndlela inye kuphela, kodwa zintathu ezisebenza kunye.

Okokuqala, i-ifosfamide iyaqhekeka esibindini ibe zizixa ezikhulu ze-chloroethylamine, ethi idibane ne-cysteine yenze ikhompawundi enesakhiwo esiringi nesinesalfure ebizwa ngokuba yi-thialysine ketimine. Loo khompawundi ithintela ii-flavoprotein kwikhonkco lokuphefumla le-mitochondria, ivale ukwenziwa kwe-oxidation eqhelekileyo ye-NADH. Imethylene blue, njengenye into eyamkela ii-elektroni, inokuthatha indawo yenyathelo elivaliweyo; le ngqiqo ivela ekusetyenzisweni kwayo kwakudala kwezinye iintlobo ze-glutaric aciduria.

Okwesibini, ukuvaleka kwekhonkco le-redox kunye nomthwalo ogqithisileyo wee-aldehyde ovela ekucutshungulweni kwe-ifosfamide emzimbeni kwehlisa umlinganiselo we-NAD ukuya kwi-NADH, nto leyo ephazamisa ukususwa kwee-aldehyde nokuveliswa kweglucose. Imethylene blue iphinda yenze i-oxidation ye-NADH ibe yi-NAD, ibuyisele inxalenye yolo lungelelwano. Kwale ndlela yokuthutha ii-elektroni kwi-redox isisiseko soninzi lwezinye iimpembelelo zayo ezicetywayo kwiiseli, yaye umgaqo jikelele wendlela imethylene blue ethutha ngayo ii-elektroni ufanele ukuqondwa ngokwahlukeneyo kolu setyenziso luthile lonyango.

Okwesithathu, imethylene blue ithintela ii-enzyme ze-amine oxidase ebezinokuguqula i-chloroethylamine ibe yi-chloroacetaldehyde, imveliso yokucutshungulwa kwechiza enetyhefu ngokuthe ngqo kwimithambo-luvo nasezintsweni, efumaneka ingabophelelekanga kwiplasma yezigulana ezisebenzisa i-ifosfamide. I-chloroacetaldehyde encinane ithetha umonakalo omncinane olandelayo, kuquka ukuphazamiseka okuncinane kokwenziwa kwe-oxidation yee-asidi ezinamafutha okuboniswe kwi-mitochondria ezikhutshwe kwiiseli.

Le ndlela yokusebenza iyavakala kwaye ichazwe ngokweenkcukacha ezingaqhelekanga. Ukuvakala akukokungqinwa, kodwa kuyacacisa ukuba kutheni iingcali zomhlaza zazithathela ingqalelo kakhulu iimeko zokuqala.

Iingxelo zoncedo olungxamisekileyo: lukhawuleza, kodwa alunamaqela othelekiso

Eyona meko icatshulwa kakhulu iseyingxelo yango-1995 yomfazi oneminyaka engama-68 onomhlaza womlomo wesibeleko owadidekayo waza waphazamiseka emva kokunikwa i-ifosfamide eyi-5 g ngemitha yesikwere kwiiyure ezingama-24. I-CT yakhe yayingabonisi nto ingaqhelekanga, yaye i-EEG yakhe yayibonisa ukucotha okusasazekileyo. Wanikwa imethylene blue eyi-50 mg ngomthambo kwimizuzu emihlanu, waza wachazwa njengovukileyo nothetha ngengqiqo kwimizuzu elishumi. Imizuzu elishumi ikhawuleza kakhulu kunendlela imeko edla ngokuqhubeka ngayo ngokwayo, yiyo loo nto le meko inye yayinikwa ukubaluleka okungaka.

Uthotho lwezigulana lwamva aluchukumisi kangako. Kuthotho olujonga ngasemva lwezigulana ezingama-52 ezazinikwe i-ifosfamide, ezili-12 zaba ne-encephalopathy yebanga lesi-2 okanye embi ngakumbi; ezisibhozo kuzo zanikwa imethylene blue eyi-50 mg ngomthambo izihlandlo ezithandathu ngosuku. Ezine zachacha ngokupheleleyo kwiiyure ezingama-24, kuquka enye eyayikwimeko enzima eyachacha kwisithuba esimalunga neyure; ezinye ezimbini zachacha ngeeyure ezingama-48, nezimbini ngeeyure ezingama-72. Kodwa zonke izigulana ezine ezingazange zinyangwe ngayo nazo zachacha kwiiyure ezingama-48, njengoko ababhali ngokwabo baxelayo. Uthotho lweemeko ezili-15 ebantwaneni lwafumana inzuzo ebonakalayo kumntwana omnye kuphela kwabahlanu abanyangwayo. Iimeko ezimbini zabantu abadala ezapapashwa ngo-2018, zaza zanyangwa nge-50 mg rhoqo kwiiyure ezine, zaqala ukuphucuka kuphela emva kweeyure ezili-12 ukuya kwezili-16, zaza zabuyela kwimeko yazo yangaphambili emva kweentsuku ezimbini ukuya kwezintathu, ixesha elingahlukanga kwelokhathalelo oluxhasayo.

Uhlaziyo loncwadi lwango-2020 lwabala izigulana ezingama-38 ezapapashwa njengezinyangwe ngemethylene blue, malunga neekota ezintathu kuzo zichazwe njengeziphendule kakuhle. Elo nani livakala likhuthaza de ukhumbule ukuba ukuchacha okukhawulezayo kudla ngokubhalelwa iingxelo, kodwa okucothayo kudla ngokungabhalelwa. Ucalucalulo lokupapasha lwenza ingqokelela yeengxelo zezigulana ibonakale ingcono kunento eyenzeka ngokwenene.

Itheyibhile yobungqina: hlula iindlela zophando

Itheyibhile engezantsi ingundoqo wolu hlaziyo. Iingxelo zezigulana zinokucebisa kuphela; uthotho lwezigulana olungenamaqela othelekiso lunokuchaza kuphela; yaye kulo mbuzo akukho zilingo zokusebenza konyango ezabela izigulana kumaqela ngokungakhethiyo.

Inqanaba lobungqina	Uphononongo	Indlela yophando nezigulana	Inkqubo yokunikwa kwemethylene blue	Okwenzekayo
Ingxelo yesigulana	Kupfer et al., Lancet 1994	Imeko yokuqala yonyango kunye nemeko enye yothintelo; kufunyenwe ipateni yemichiza yomzimba efana ne-glutaric aciduria	Unyango 50 mg IV; uthintelo ngomlomo	Kubikwe ukubuyela umva ngokukhawuleza; isigulana sesibini asiphindanga saba nayo xa sanikwa ichiza kwakhona
Ingxelo yesigulana	Zulian et al., N Engl J Med 1995	Umfazi oneminyaka engama-68, umhlaza womlomo wesibeleko, ukudideka emva kwe-ifosfamide 5 g/m2 kwi-24 h	50 mg IV kwi-5 min, isisombululo esi-1 ekhulwini	Uvukile kwaye ethetha ngengqiqo kwi-10 min
Uthotho lwezigulana, olujonga ngasemva noluthelekisa nabanganyangwanga	Pelgrims et al., Br J Cancer 2000	Izigulana ezingama-52 ezinikwe i-ifosfamide; ezili-12 ezine-encephalopathy yebanga lesi-2 okanye embi ngakumbi; ezisi-8 zinyangiwe, ezi-4 azinyangwanga	Unyango 50 mg IV izihlandlo ezithandathu ngosuku; uthintelo 50 mg izihlandlo ezine ngosuku kwizigulana ezi-3	Ezinyangiweyo: ezi-4 kwezisi-8 zachacha kwi-24 h, zonke kwi-72 h. Ezinganyangwanga: zonke ezi-4 zachacha kwi-48 h
Uthotho lwezigulana	Turner et al., Clin Oncol 2003	Iimeko ezi-4 eziqatha, ezi-2 zanikwa uthintelo kamva	Rhoqo 50 mg ngomlomo izihlandlo ezithathu ngosuku	Kubikwe ukuphucuka okukhulu kwi-24 h; imeko yaba buthathaka ngakumbi xa ichiza laphinda lanikwa kunye nothintelo
Uthotho lwezigulana, ebantwaneni	Dufour et al., Arch Pediatr 2006	Iimeko ezili-15 ze-encephalopathy ebantwaneni	Unyango 50 mg IV rhoqo kwi-4 h; uthintelo rhoqo kwi-6 h	Inzuzo yagwetywa njengekhoyo kumntwana o-1 kwabasi-5 abanyangiweyo; iimeko ezi-2 kwezi-2 zothintelo aziphindanga zaba nayo
Uphononongo lokuhamba kwechiza emzimbeni, olungenalo iqela lothelekiso lokusebenza konyango	Aeschlimann et al., Drug Metab Dispos 1998	Izigulana ezisi-9 zomhlaza wemiphunga ezinikwe i-ifosfamide, i-mesna, ne-etoposide	50 mg ngomlomo izihlandlo ezithathu ngosuku ukususela ngorhatya lwangaphambi konyango ngamachiza	Yanyamezeleka; akukho tshintsho lubalulekileyo ekwenziweni kwe-ifosfamide isebenze; kwabangwa ukukhuselwa kwemithambo-luvo kodwa kungekho qela lothelekiso
Uphononongo olujonga ngasemva, lugxile kuthintelo	Sweiss et al., Drug Safety 2008	Izigulana ezili-19 ezinikwe i-ifosfamide yedosi ephezulu; ezisi-8 ezine-encephalopathy; ezisi-5 zaphinda zanikwa ichiza kunye nothintelo	Imethylene blue yokuthintela, iinkqubo zokuyinika zahluka	Zonke izigulana ezi-5 ezaphinda zanikwa ichiza kunye nothintelo zaphinda zaba ne-encephalopathy
Uthelekiso lwemijikelo olujonga ngasemva	Richards et al., J Oncol Pharm Pract 2011	Imijikelo eli-166 enothintelo ngemethylene blue, i-thiamine, okanye i-albumin xa ithelekiswa nengenalo	Uthintelo olwahlukeneyo	I-encephalopathy kwi-21.1 ekhulwini yemijikelo enothintelo xa ithelekiswa ne-8.4 ekhulwini engenalo; kusenokwenzeka ukuba izizathu zokukhetha uthintelo zaluphazamisa uthelekiso
Uthotho lwezigulana olujonga ngasemva	Uthotho lweMD Anderson lwabantwana nabantu abadala abaselula, 2025	Izigulana ezingama-24 ezine-encephalopathy; ezingama-20 zanikwa imethylene blue	Amaxesha amaninzi 50 mg IV rhoqo kwi-6 h, inani eliphakathi leedosi liyi-5	Ezili-19 kwezingama-20 zachacha kwisithuba se-24 ukuya kwi-120 h, kungekho qela labanganyangwanga lokuthelekisa; ezi-3 kwezisi-5 ezaphinda zanikwa ichiza kunye nothintelo zaphinda zaba nayo

Funda ikholamu yeziphumo ukusuka phezulu uye ezantsi, yaye ipateni iyafana: iingxelo zokuqala ezimangalisayo, kulandele iziphumo ezicotha ngakumbi nezixubeneyo njengoko inani lezigulana likhula namaqela othelekiso evela. Olu luphawu longenelelo olunempembelelo yokwenene enokuba ncinane, ukuba ikhona.

Uthintelo aluxhaswa bubungqina

Ibango lothintelo lifanele isigwebo salo kuba lichaphazela ukumiselwa kwamachiza ngokwenene. Emva kwamava okuqala aseBern nge-ifosfamide yomlomo kunye ne-50 mg izihlandlo ezithathu ngosuku, kungekho tyhefu kwimithambo-luvo ibonwayo, amaziko amaninzi azama uthintelo ngemethylene blue xa enika i-ifosfamide kwakhona. Iziphumo ziyahluka. Ezinye izigulana ezaphinda zanikwa ichiza zaba nezigigaba ezibuthathaka ngakumbi okanye azazange zibe nazo; kolunye uthotho zonke izigulana ezaphinda zanikwa ichiza kunye nothintelo zaba ne-encephalopathy, yaye olunye uthelekiso olujonga ngasemva lwafumana i-encephalopathy engaphezulu kwimijikelo enothintelo kunengenalo, phantse ngokuqinisekileyo ngenxa yokuba izigulana ezinomngcipheko ophezulu kakhulu zazikhethwa ukuba zinikwe uthintelo.

Ababhali bezikhokelo bakuqaphele oku. Isikhokelo esihlangeneyo setyhefu kwimithambo-luvo semibutho yaseYurophu yezengcali zomhlaza nezemithambo-luvo sagqiba kwelokuba izilingo ezinamaqela othelekiso azikho, yaye imethylene blue ayinakucetyiswa ukuthintela okanye ukunyanga ngokusekelwe kubungqina obukhoyo. Ulwazi lokumisela ichiza kunye nezinye iinkqubo zamaziko zithatha indlela ethambileyo, zisithi inokucingelwa kwi-encephalopathy ephakathi okanye enzima. Zombini ezi zimvo zichaza idatha efanayo; zahluka kuphela ekubalulekeni ezikunika iingxelo zezigulana xa kungekho ndlela ingcono.

Umxholo wonyango lweengcali omele waziwe ngongengcali yomhlaza

Amanqaku amathathu asebenzayo asisiseko sesigqibo ngasinye ecaleni kwebhedi yesigulana. Okokuqala, ukusetyenziswa kwemethylene blue apha kungaphandle kosetyenziso oluvunyiweyo, inikwa ngomthambo esibhedlele, ngokuqhelekileyo i-50 mg rhoqo kwiiyure ezine ukuya kwezisibhozo de iimpawu ziphele. Ayilonyango lwasekhaya, yaye eli nqaku alisosikhokelo seedosi.

Okwesibini, imethylene blue sisithinteli se-monoamine oxidase A, esinesilumkiso esikwibhokisi ngesifo se-serotonin xa idityaniswe namachiza okudakumba asebenza kwi-serotonin kunye nezinye ii-opioid; yaye isifo se-serotonin siye sabikwa ngokukodwa ngexesha lokunyangwa kwe-encephalopathy ebangelwa yi-ifosfamide. Ikwangavumelekanga kubantu abanokusilela kwe-glucose-6-phosphate dehydrogenase ngenxa yomngcipheko wokuqhekeka kweeseli ezibomvu zegazi. Iinkcukacha zokhuseleko nokusebenzisana kwamachiza kunye nombuzo obanzi wokuba ukusetyenziswa kwemethylene blue kukhuselekile na kwisigulana esithile kufuneka ziqwalaselwe kwisigqibo ngaphambi kokuvulwa kwayo nayiphi na ibhotile yalo mchiza uluhlaza.

Okwesithathu, ukuyeka i-ifosfamide, ukunika ulwelo, ukulungisa amanqanaba ee-electrolyte nokuhlengahlengisa amachiza asetyenziswa kunye nayo, kunye nokukhupha ezinye izizathu zokudideka, kusahleli kusisiseko. Imethylene blue, apho isetyenziswa khona, yongezwa kweso siseko, ayithathi indawo yaso. Ukufunda indlela yokufunda uphononongo lwemethylene blue kuyanceda apha: buza ukuba ingxelo ibinalo na iqela lothelekiso, ukuba ubunzima be-encephalopathy babulinganiswa njani, ukuba yintoni enye eyatshintsha ngaxeshanye, nokuba ixesha lokuchacha lahlukile na kwixesha elaziwayo losuku olunye ukuya kwezintathu apho imeko idla ngokuphela ngokwayo.

Isishwankathelo

Ukusetyenziswa kwemethylene blue kwi-encephalopathy ebangelwa yi-ifosfamide kusekelwe kwindlela ehambelanayo yokusebenza kwi-mitochondria, kwiingxelo ezimbalwa zoncedo olungxamisekileyo olukhawulezayo noluchukumisa ngokwenene, nakuthotho oluninzi lwezigulana apho ezinyangiweyo nezinganyangwanga zichacha ngamaxesha afanayo. Njengonyango loncedo olungxamisekileyo lwe-encephalopathy enzima okanye ethatha ixesha elide, ezinye iingcali zomhlaza zikubona kusengqiqweni ngenxa yokunqongophala kwezinye iindlela. Njengothintelo oluqhelekileyo, ubungqina abukuxhasi. Nabani na ojongene nalo mbuzo, enoba sisigulana, ngumkhathaleli, okanye yingcali yezonyango, kufuneka awuthathe njengesigqibo sengcali esenziwa kwisigulana esilaliswe esibhedlele, ngokwemeko yaso nganye, aze akuthathe ukuchacha okukhawulezayo njengengcamango efuna ukuvavanywa kunokuba kube bubungqina obuqinisekisayo.