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Gefitinib

  1. Isishwankathelo seGefitinib
  2. Inkqubo yeGefitinib yesenzo
  3. Ukusetyenziswa kweGefitinib kwihlabathi
  4. Iziphumo ebezingalindelekanga zeGefitinib
  5. Ukugcinwa kweGefitinib
  6. Ukufumana ngakumbi: "Umbulali womhlaza wemiphunga" Gefitinib

 

Gefitinib isishwankathelo

Igama leekhemikhali le-gefitinib yi-4-Quinazolinamine N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [3- (4-morpholinyl) propoxy]. IGefitinib ine-molecular formula C22H24ClFN4O3 , ubunzima beemolekyuli ezinxulumene nee-dalton ezingama-446.9 kwaye yimpuphu emhlophe. IGefitinib sisiseko sasimahla. Imolekyuli ine-pKas ye-5.4 kunye ne-7.2. I-Gefitinib inokuchazwa njenganyibilikayo kancinci kwi-pH 1, kodwa inyibilikisiwe ngaphezulu kwe-pH 7, kunye nokunyibilika kuncipha ngokuqatha phakathi kwe-pH 4 kunye ne-pH 6. Kwizinyibilikisi ezingezizo ezamanzi, i-gefitinib inyibilika ngokukhululekileyo kwi-glacial acetic acid kunye ne-dimethyl sulfoxide, inyibilike kwi-pyridine, inyibilika kancinci kwi-tetrahydrofuran, kwaye inyibilike kancinci kwi-methanol, i-ethanol (99.5%), i-ethyl acetate, i-propan-2-ol kunye ne-acetonitrile.

Iitafile zeGefitinib ziyafumaneka njengamacwecwe amdaka ngombala agqunywe ngefilimu, aqukethe i-250 mg ye sifile powder, yolawulo lomlomo. Izithako ezingasebenziyo zecwecwe lecwecwe lamacwecwe e-IRESSA zii-lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate kunye nemagnesium stearate. Ipeyinti yecwecwe yenziwe ngehypromellose, i-polyethylene glycol 300, i-titanium dioxide, i-red ferric oxide kunye ne-oxide ye-ferric emthubi.

 

Ulwazi lobuGcisa:

igama Gefitinib
Igama eliqhelekileyo N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine
Inani leCAS 184475-35-2
Iintetho ezifanayo ZD 1839
I-Molecular Formula Ikhowudi yemali ye-C22H24ClFN4O3
Ubukhulu beFormula 446.9
Ukungcola ≥98%
UkuQulunqa I-crystalline eqinile
Umzimba I-DMF: 20 mg / ml
I-DMSO: 20 mg / ml
I-DMSO: I-PBS (pH7.2) (1: 1): 0.5 mg / ml
I-Ethanol: 0.3 mg / ml
SMILES COC1=CC2=C(C(NC3=CC=C(F)C(Cl)=C3)=NC=N2)C=C1OCCCN4CCOCC4
InChi Code InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
Isitshixo se-InChi XGALLCVXEZPNRQ-UHFFFAOYSA-N
yoGcino -20 ° C

 

I-Gefitinib isetyenziselwa ukunyanga umhlaza wamaphaphu ongekho mncinci osasazeke kwamanye amalungu omzimba wabantu abaneentlobo ezithile zamathumba. UGefitinib ukwiklasi yamayeza abizwa ngokuba yi-kinase inhibitors. Isebenza ngokuthintela isenzo sento ethile evela ngokwendalo enokufuneka ukunceda umhlaza iiseli ziyanda.

I-AASraw ngumenzi wobugcisa weGefitinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

Gefitinib Inkqubo yesenzo

IGefitinib sisithinteli se-epidermal ukukhula factor receptor (EGFR) tyrosine kinase ebopha indawo ebopha i-adenosine triphosphate (ATP) ye-enzyme. I-EGFR ihlala iboniswa ukuba icinezelwe kakhulu kwiiseli ezithile ze-carcinoma, ezinje ngemiphunga kunye nebele iiseli zomhlaza. Ukunyanzeliswa kwe-Overexpression kukhokelela ekuphuculeni ukusebenza kwe-anti-apoptotic umqondiso wokuhanjiswa kwe-Ras, emva koko kukhokelela ekusasazeni kweeseli zomhlaza kunye nokwanda kweseli okungalawulwayo. IGefitinib sisithinteli sokuqala sokukhetha i-EGFR tyrosine kinase ekwabizwa ngokuba yi-Her1 okanye i-ErbB-1. Ngokuthintela i-EGFR tyrosine kinase, i-Cascade eshukumayo esezantsi nayo iyathintelwa, ekhokelela ekwandeni kwesifo esibi.

 

Gefitinib Sebenzisa kwiLizwe

IGefitinib ngoku ithengiswa kumazwe angaphezu kwama-64. IGefitinib yamkelwa yaza yathengiswa ukusuka ngoJulayi 2002 eJapan, isenza ilizwe lokuqala ukungenisa iziyobisi elizweni.

The I-FDA ivume i-gefitinib Ngo-Meyi ka-2003 yomhlaza wamaphaphu ongekho mncinci (i-NSCLC) Yavunywa njenge-monotherapy kunyango lwezigulana ezine-NSCLC yangaphakathi okanye ye-metastatic emva kokungaphumeleli kokubini okusekwe kwiplatinam kunye ne-docetaxel chemotherapies, njengonyango lodidi lwesithathu.

NgoJuni 2005 i-FDA yarhoxisa imvume yokusetyenziswa kwizigulana ezitsha ngenxa yokungabikho kobungqina bokuba yandisa ubomi.

EYurophu i-gefitinib ibonakalisiwe ukusukela ngo-2009 kwi-NSCLC ephambili kuyo yonke imigca yonyango kwizigulana ezigcina utshintsho lwe-EGFR. Le ilebheli yanikwa emva kokuba i-gefitinib iboniswe njengonyango lodidi lokuqala ukuphucula ngokubonakalayo ukuqhubekeka ngaphandle kokuqhubela phambili ngokuchasene nolawulo lweplatinam kwizigulana ezigcina olo tshintsho. I-IPASS ibe yeyokuqala kwizigaba ezine zezilingo zokuqinisekisa ukuphakama kwe-gefitinib kwesi sigulana.

Kwinkoliso yamanye amazwe apho i-gefitinib ithengiswa khona ngoku ivunyiwe kwizigulana ezine-NSCLC ehambileyo eyayifumene ubuncinci i-chemotherapy. Nangona kunjalo, izicelo zokwandisa ilebheli yazo njengonyango lodidi lokuqala kwizigulana ezigcina utshintsho lwe-EGFR okwangoku zenziwa ngokusekwe kubungqina benzululwazi yakutshanje. [Ucaphulo luyafuneka] Nge-Agasti ka-2012 iNew Zealand iye yamkela i-gefitinib njengonyango lodidi lokuqala kwizigulana Utshintsho lwe-EGFR lokungazi kakuhle indawo ekuhlaleni okanye kwimastastatic, engenakuphikiswa yeNSCLC. Oku kuxhaswa esidlangalaleni kwikota yokuqala yeenyanga ezi-4 kunye nokuhlaziywa ukuba akukho nkqubela phambili NgoJulayi 13, 2015, i-FDA yamkele i-gefitinib njengonyango lodidi lokuqala lwe-NSCLC.

Gefitinib

Iziphumo ebezingalindelekanga ze Gefitinib

Izinto ezibalulekileyo ekufuneka uzikhumbule malunga neziphumo ebezingalindelekanga zegefitinib:

Uninzi lwabantu alunazo zonke iziphumo ebezingalindelekanga ezidwelisiweyo.

Iziphumo ebezingalindelekanga zihlala ziqikelelwa ngokuqala kwazo kunye nobude bazo.

Iziphumo ebezingalindelekanga zihlala zibuyela umva kwaye ziya kumka emva kokuba unyango lugqityiwe.

Kukho iindlela ezininzi zokunceda ukunciphisa okanye ukuthintela iziphumo ebezingalindelekanga.

Akukho buhlobo phakathi kobukho okanye ubuzaza beziphumo ebezingalindelekanga kunye nokusebenza kweyeza.

 

Iziphumo zilandelayo zixhaphakile (zenzeka ngaphezulu kwe-30%) kwizigulana ezithatha i-gefitinib:

♦ Urhudo

Impendulo yolusu (irhashalala, amabala)

I-AASraw ngumenzi wobugcisa weGefitinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

Ezi ziphumo zingalindelekanga (ezenzeka malunga ne-10-29%) yezigulana ezifumana i-gefitinib:

Ause Isicaphucaphu

♦ Ukuhlanza

Ching Ukurhawuzelela

♦ Ukungatyi kakuhle

Ukucaphuka kwamehlo

 

Amatyala anqabileyo (malunga ne-1%) yesiphumo esibi sesifo semiphunga (inyumoniya, okanye ukudumba kwemiphunga ngaphandle kosulelo). Xa le mpembelelo yecala yenzekile, yayihlala ihamba nobunzima bokuphefumla ngokukhohlela okanye umkhuhlane ophantsi ofuna ukulaliswa esibhedlele. I-1/3 yamatyala ikhokelele ekufeni. Ukuba ngesiquphe ukuphefumla okufutshane, ukukhohlela kunye / okanye umkhuhlane kwenzeka ngelixa uthatha i-gefitinib, yazisa ukhathalelo lwempilo yakho.

Ukuphakama kwiimvavanyo zomsebenzi wesibindi (i-transaminase, i-bilirubin, kunye ne-alkaline phosphatase) kuye kwabonwa kwizigulana ezanyangwa nge-gefitinib. Ezi ziphakamileyo bezingahambi kunye naziphi na iimpawu zetyhefu yesibindi. Nangona kunjalo, ugqirha wakho wokhathalelo lwempilo unokujonga uvavanyo lwegazi ukubeka esweni ukusebenza kwesibindi rhoqo, ngelixa uthatha i-gefitinib.

Ayizizo zonke iziphumo ebezingalindelekanga ezidweliswe apha ngasentla. Ezinye ezinqabileyo (ezenzeka ngaphantsi kwe-10% yezigulana) azidweliswanga apha. Nangona kunjalo, kuya kufuneka usoloko umazisa umboneleli wakho wezempilo ukuba ufumana naziphi na iimpawu ezingaqhelekanga.

 

Gefitinib yoGcino

Gcina i-gefitinib kwisitya engene ngayo, ivaliwe ngokuqinileyo, kwaye ayifumaneki ebantwaneni. Yigcine kubushushu begumbi kwaye kude nobushushu obuninzi kunye nokufuma (hayi kwigumbi lokuhlambela).

I-gefitinib engafunekiyo kufuneka ilahlwe ngeendlela ezizodwa zokuqinisekisa ukuba izilwanyana zasekhaya, abantwana kunye nabanye abantu abanakuzisebenzisa. Nangona kunjalo, akufuneki uyigungxule le gefitinib phantsi kwendlu yangasese. Endaweni yoko, eyona ndlela yokulahla i-gefitinib yakho yinkqubo yokubuyisa amayeza. Thetha kumachiza wakho okanye unxibelelane nesebe lakho lenkunkuma / lokurisayikilisha ukuze ufunde malunga neenkqubo zokubuyisa kwindawo ohlala kuyo. Bona i Ukulahlwa ngokuKhuselekileyo kweeMithi kwiwebhusayithi ye-FDA ngolwazi oluthe kratya ukuba awunakho ukufikelela kwinkqubo yokubuyela umva.

Kubalulekile ukugcina onke amayeza angabonakaliyo kunye nokufikelela kubantwana njengezikhonkwane ezininzi (ezifana neepilisi zeveki zeeveki kunye nezokwamahla, i-creams, i-patches, kunye ne-inhalers) abaxhomeki abantwana kunye nabantwana abancinci bangabavula ngokulula. Ukukhusela abantwana abancinci besetyhefu, soloko uvale iifake zokuphepha kwaye ubeke ngokukhawuleza loo mayeza kwindawo ekhuselekileyo - enye ephakanyisiwe kwaye ingabikho emehlweni abo kwaye ifinyelele.

Gefitinib

Ukufumana ngakumbi: "Umbulali womhlaza wemiphunga" Gefitinib

I-Gefitinib yonyango ekujolise kulo inoveli ethintela umsebenzi we-tyrosine kinase we-epidermal yokukhula kwe-receptor factor ngokukhuphisana ngokuvimba indawo ebopha i-ATP. Kwizifundo zangaphambi kokubeleka i-gefitinib ibonakalise umsebenzi onamandla kwiimodeli ezininzi zethumba, kubandakanya imigca yeseli yomhlaza wamaphaphu kunye ne-xenografts. Izifundo ezibini ezingahleliwe zeSigaba II (IDEAL 1 kunye ne-IDEAL 2) kumhlaza wesifo somhlaza wamaphaphu osele wenziwe kwangaphambili uxele inqanaba lokuphendula lisondela kwi-20% kwizigulana ezikumgca wesibini kunye ne -10% kwabo batyholwa ngeerejimeni ezimbini okanye nangaphezulu zeechemotherapy. Ukusinda okuphakathi kwezi zifundo zibini kuye kwinyanga ezi-6-8. Njengonyango lokuqala, i-gefitinib ihlolwe ngokudibanisa neerejimeni ezimbini ezahlukeneyo zekhemotherapy kwizifundo ezibini ezikhulu ezingenamsebenzi (INTACT 1 kunye ne-INTACT 2). Zombini ezi zifundo zoyisakele ukubonisa ukuphucuka kokusinda kwisigulana esipheleleyo> sezigulana ezili-1000 kwisifundo ngasinye. Amanye amanqaku okuphela (umzekelo, ixesha lokuqhubela phambili kunye nenqanaba lokuphendula) nawo awaphuculwanga ngokongezwa kwe-gefitinib. Izifundo ezongeziweyo zibonisiwe ukuvavanya indima enokubakho ye-gefitinib kulondolozo lwezigulana ezifumene ichemotherapy okanye ichemoradiotherapy. Izifundo eziphanda nge-gefitinib njenge-monotherapy yodidi lokuqala nayo iyafuneka.

Uninzi lwezigulana ezineseli engeyiyo encinci umhlaza wemiphunga (NSCLC) ekugqibeleni ikhule isifo se-metastatic okanye isifo esingafumanekiyo kunyango lwasekhaya kuphela kwaye banokuba ngabagqatswa kunyango lwenkqubo. Nangona i-chemotherapy inokuphucula ukusinda kwizigulana ezinesifo esihambele phambili, inzuzo kuphela ziinyanga ezi-∼2 ngaphezulu kokhathalelo olulungileyo, kwaye oku kuyindleko yemiphumo emibi. Ukukhangela iiarhente ezintsha ubuncinci ezisebenzayo njenge-chemotherapy kodwa ezinganyamezelwa ngcono kubaluleke kakhulu. Inani leearhente zamanoveli ezisebenza ngokuthe ngqo ngokuchasene neethagethi ezikhethiweyo ezikhoyo umhlaza Iiseli, ezinje nge-epidermal grow factor receptor (EGFR), ziyavavanywa kwi-NSCLC ephambili. Ukuza kuthi ga ngoku, ikakhulu abaguli abane-NSCLC ehambileyo bavavanyiwe, kodwa kukho into elungileyo ukuphanda uninzi lwezi arhente kuseto lwezifo zangaphambili, apho ezinye izinto ekujolise kuzo kwimfuza sele zikhona.

I-EGFR ibonakaliswe kakhulu kwizidumbu eziqinileyo, kubandakanya iNSCLC. I-EGFR ibonakaliswe kakhulu kuninzi (∼80%) lung squamous cell carcinomas, kwaye malunga nesiqingatha sayo yonke i-lung adenocarcinomas kunye ne-cell-carcinomas enkulu. Ukwenza kusebenze i-EGFR kwiiseli ezinomhlaza kubonisiwe ukukhuthaza iinkqubo ezibandakanyekayo ekwandeni kweseli, i-angiogenesis, ukuhlasela, kunye ne-metastasis, kunye nokuthintela i-apoptosis. I-EGFR (erbB1 okanye i-HER1) lilungu losapho lwe-erbB receptor, ekwabandakanya i-erbB2 (HER2), erbB3 (HER3), kunye ne-erbB4 (HER4). Yidemembrane yeglycoprotein equlathe i-extracellular ligand-binding domain, indawo yedluliso, kunye ne-intracellular signal-transducing domain kunye nomsebenzi we-tyrosine kinase. Emva kokubopha kwe-ligand ye-physiological ligand enjenge-epidermal growth factor, i-EGFR iyancipha ngomnye umonomer we-EGFR okanye elinye ilungu losapho lwe-erbB. Oku kukhokelela ekusebenziseni i-tyrosine kinase, i-autophosphorylation ye-tyrosine, kunye nokuqaliswa kokusayina i-cascades ethi ekugqibeleni ikhokelele kwiimpendulo ezahlukeneyo ezisezantsi njengokukhula kweseli. Ngaphaya koko, ukubonakaliswa kwe-EGFR kwizidumbu kunxulunyaniswe nempendulo engalunganga kunyango, ukukhula kokunganyangeki ngamachiza e-cytotoxic, ukuqhubela phambili kwesifo kunye nokusinda okungalunganga. Ezinye iindlela zokunyusa umqondiso we-EGFR onokuthi ubandakanyeke ekwandeni kweseli yesisu kubandakanya ukonyuka kwamanqanaba e-ligand yangaphandle, i-heterodimerization ye-EGFR, kunye nokutshintsha kwe-EGFR. Eyona ndlela ixhaphakileyo yokutshintsha kwe-EGFR kumathumba yi-EGFRvIII, efumaneka kwiipesenti ezingama-39 zamatyala e-NSCLC. I-EGFRvIII ithwala ukususwa kuguquko ukusuka kwi-amino acid 6 ukuya kwi-273 kwindawo engaphandle yokubopha kunye nokubonisa imisebenzi ye-tyrosine kinase ezimeleyo ekubophelelweni kwe-ligand yangaphandle.

I-AASraw ngumenzi wobugcisa weGefitinib.

Nceda ucofe apha ngolwazi locaphulo: Unxibelelwano nathi

 

isingqiniso

[1] URukazenkov Y, Thetha G, uMarshall G, et al. Ukukhula kwe-Epidermal factor receptor tyrosine kinase inhibitors: ezifanayo kodwa zahlukile? Iziyobisi ze-Anticancer 2009; 20: 856-866.

[2] I-Woodburn, JR, kunye ne-receptor yokukhula kwe-epidermal factor kunye nokuthintelwa kwayo kunyango lomhlaza. IPhemacol Ther 1999; 82: 241-250.

[3] Iqela eliDibeneyo leCancer Lung Collaborative Group. I-Chemotherapy kumhlaza womhlaza wamaphaphu ongekho mncinci: uhlalutyo lweemeta kusetyenziswa idatha ehlaziyiweyo kwizigulana ezizezinye ezivela kuvavanyo lweeklinikhi ezingama-52. BMJ 1995; 311: 899-909.

[4] UDouillard JY, uKim ES, uHirsh V, et al. I-Gefitinib (i-IRESSA) xa ithelekiswa ne-docetaxel kwizigulana ezinomhlaza wamaphaphu wesifo somhlaza esingaphambi kokunyangwa nge-chemotherapy esekwe kwiplatinam: isifundo esingahleliwe, esivulekileyo selebheli yesigaba sesithathu (INZALO). UJ Thoracic Oncol 2007; 2: PRS-02 ukuya ku-XNUMX

[5] UFukuoka M, Wu Y, Thongprasert S, et al. Uhlalutyo lwe-Biomarker ukusuka kwisigaba se-III, i-randomised, ilebhile evulekileyo, isifundo somgca wokuqala we-gefitinib (G) xa kuthelekiswa ne-carboplatin / paclitaxel (C / P) kwizigulana ezikhethiweyo zeklinikhi (pts) ezinomhlaza wesifo somhlaza wamaphaphu ongekho mncinci (NSCLC) kwi I-Asiya (IPASS). J Ikliniki yase-Oncol 2009; 27 Nyusa. 15: 8006–.

[6] I-Reck MA inyathelo eliphambili kunyango lomntu ngamnye lomhlaza wemiphunga kunye negefitinib: ulingo lwe-IPASS nangaphaya. Ingcali Rev Anticancer Ther 2010; 10: 955-965.

[7] I-Barker, Izifundo ze-AJ ezikhokelela ekuchongeni i-ZD1839 (IRESSA): ngomlomo esebenzayo, ekhethiweyo yokukhula kwe-epidermal factor receptor tyrosine kinase inhibitor ejolise kunyango lomhlaza. Bioorg. IMed. Chem. Ileta. 11, 1911-1914 (2001).

[8] Wakeling, AE okqhubekayo. I-ZD1839 (Iressa): isithintelo somlomo sokukhula kwento ebonakalayo ebonisa amandla onyango lomhlaza. Umhlaza Res. 62, 5749-5754 (2002).

[9] I-Yarden, Y. kunye neSliwkowski, MX Ukungaxhonyi inethiwekhi yomqondiso ye-ErbB. Indalo uMfu. Iseli yeBiol. 2, 127-137 (2001).

[10] Cersosimo, RJ Umhlaza wemiphunga: uphononongo. Ndingu. J. Impilo Syst. Ikhemesti. 59, 611-642 (2002).

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