Gimeracil CAS 103766-25-2

(1) Kev kho mob plab hnyuv
Kev mob plab hnyuv: Raws li cov ntsiab lus tseem ceeb ntawm Tegio capsule (TS-1), gemostat ua ke nrog tegafur thiab ateiracile yog siv los kho thawj kab mob qog noj ntshav siab. Qhov kev sim JCOG9912 tau pom tias lub sijhawm muaj sia nyob nruab nrab ntawm pawg Tegio yog 12.5 lub hlis, uas zoo dua li 10.1 lub hlis ntawm pawg 5-FU monotherapy.
Kev mob qog nqaij hlav hauv plab: Raws li DPD modulator hauv FOLFOXIRI kev tswj hwm, ua ke nrog irinotecan thiab oxaliplatin, theem III kev tshawb fawb tau pom tias lub hom phiaj teb tus nqi (ORR) ntawm 65%, uas yog 18% siab dua li cov kev cai ib txwm muaj.

(2) Kev siv cov qog nqaij hlav pancreatic
Hauv kev sib xyaw ua ke ntawm gemcitabine thiab tigio (GS txoj kev kho), gemcitabine txhim kho cov nyhuv synergistic los ntawm kev tswj kom muaj txiaj ntsig zoo ntawm 5-FU. Txoj kev tshawb fawb Japanese GEST tau lees paub tias 1-xyoo kev ciaj sia ntawm tus mob qog noj ntshav hauv zos tau nce los ntawm 42% mus rau 63%.
(3) Tshawb nrhiav lwm cov qog nqaij hlav
Hauv theem II kev sim tshuaj kho mob qog noj ntshav mis thiab tsis yog -mob qog nqaij hlav qog noj ntshav, gemcitabine ua ke nrog capecitabine tau pom tus kab mob tswj hwm tus lej (DCR) ntawm 72%, tshwj xeeb tshaj yog rau cov neeg mob uas muaj DPD kev ua haujlwm siab.

(1) Kev sib koom tes tsim ntawm Tigio capsules
Tigafur (FT): Raws li ib tug prodrug ntawm 5-FU, nws yog hloov mus rau hauv ib tug active ingredient nyob rau hauv qhov kev txiav txim ntawm daim siab microsomal CYP2A6.
Oxo: faib nyob rau hauv cov hnyuv mucosa, xaiv inhibits orotate phosphoribosyltransferase (OPRT) thiab txo cov hnyuv toxicity.
Jimost: Tswj ntshav plasma 5-FU concentration los ntawm DPD inhibition, ua tiav qhov sib npaug ntawm kev ua tau zoo thiab tshuaj lom nrog peb qhov piv txwv molar ntawm 1: 0.4: 1.

(2) Piv txwv ntawm Combination Chemotherapy Protocol
S-1+Cisplatin (SP regimen): Hauv neoadjuvant chemotherapy rau gastric cancer, ORR nce mus txog 58% thiab cov kab mob ua tiav cov lus teb (pCR) yog 12%, zoo dua li ECF txoj cai.
S-1+paclitaxel: Rau HER2 tsis zoo mob qog noj ntshav, qhov nruab nrab ntawm kev muaj sia nyob tsis muaj sia nyob (PFS) qhia hauv theem I / II kev tshawb fawb yog 6.8 lub hlis, uas zoo dua li 4.2 lub hlis ntawm paclitaxel monotherapy.
(3) Cov tswv yim muab tshuaj rau tus kheej
Kev kwv yees ua haujlwm enzyme los ntawm kev kuaj pom DPD gene polymorphism (xws li 2A / 2A hom) hauv cov neeg mob, thiab qhia txog kev hloov kho ntawm Giemster ntau npaum li cas. Qhov kev sim UMIN000002345 tau pom tias qhov tshwm sim ntawm qib III-IV toxicity nyob rau hauv pawg genotype poob ntawm 42% mus rau 23%.

Kev kho mob ntawm cov laus cov qog
Rau cov neeg mob hnub nyoog 75 xyoo lossis tshaj saud, koob tshuaj Tegio raug hloov kho rau 40mg / m ² kev twv, thiab Gimostat them nyiaj rau cov metabolism qeeb los ntawm kev ncua sij hawm ua haujlwm ntawm 5-FU. Txoj kev tshawb fawb JGCOG1213 tau lees paub tias qhov ua tau zoo ntawm qhov kev tswj hwm no yog sib npaug rau cov qauv koob tshuaj hauv cov neeg laus uas muaj mob qog noj ntshav siab, tab sis qhov tshwm sim ntawm neutropenia raug txo los ntawm 15%.

Daim Ntawv Thov Kev Hloov Kho Kev Kho Mob
Hauv daim siab metastasis ntawm mob qog nqaij hlav hauv plab, kev sib xyaw ntawm Tegio thiab Bevacizumab yog siv los ua cov tshuaj kho mob txhais lus, thaum Gismost txhawb cov qog regression los ntawm kev tswj cov tshuaj. Kev tshawb nrhiav rov qab tau pom tias R0 resection tus nqi nce los ntawm 18% mus rau 34%.
Tus nqi ntawm palliative care
Rau kev mob qog noj ntshav siab, Tegio tuaj yeem txhim kho kev nqhis dej kom zoo thiab ua kom lub neej zoo (EORTC QLQ-OES18) los ntawm 27 cov ntsiab lus, uas zoo dua rau kev kho kom zoo.

Tshiab prodrug tsim template
Txhim kho dual functional prodrug molecules los ntawm kev siv DPD inhibitory zog ntawmGimeracil. Piv txwv li, los ntawm kev txuas Giemster nrog topoisomerase inhibitors los ntawm cleavable linkers, qog microenvironment teb cov tshuaj tso tawm tuaj yeem ua tiav.
Nano tshuaj xa system
Co loading Gimostat thiab 5-FU mus rau mesoporous silica nanoparticles (MSN) txhim kho qog lub hom phiaj los ntawm EPR nyhuv. Cov kev sim tsiaj tau pom tias cov tshuaj concentration ntawm cov qog nqaij hlav nce 6.8 npaug, thiab qhov ntsuas cardiotoxic troponin I qib qis dua 45%.

Tshawb nrhiav kev tiv thaiv kab mob sib xyaw ua ke
Jimost txhim kho M1 polarization ntawm cov qog txuam nrog macrophages (TAMs) los ntawm kev ncua sij hawm ua haujlwm ntawm 5-FU, thiab thaum ua ke nrog PD-1 inhibitors, nws tuaj yeem nce cytotoxic T lymphocyte infiltration. Tus qauv preclinical tau pom tias cov qog loj hlob inhibition ntawm cov pab pawg ua ke mus txog 78%, uas yog 42% siab dua li ntawm pawg kws kho mob monotherapy.

Antiviral tshawb fawb
Kev sim hauv vitro tau pom tias gemostat muaj qhov cuam tshuam rau tus kab mob Zika (ZIKV) NS5 polymerase, nrog ib nrab qhov siab tshaj plaws inhibitory concentration (IC50) ntawm 12.7 μ M, thiab qhia tau hais tias muaj kev sib koom ua ke ntawm cov tshuaj tiv thaiv kab mob thaum ua ke nrog sofosbuvir.
Tshawb nrhiav kev ua haujlwm antibacterial
Rau cov tshuaj -tiv taus Staphylococcus aureus, Gimostat siv tshuaj tua kab mob los ntawm inhibiting dihydropteroate synthase (DHPS), nrog rau MIC tus nqi ntawm 64 μ g / mL. Txawm hais tias siab dua qhov kev soj ntsuam cov tshuaj concentration, nws muab lub hom phiaj tshiab rau kev ua kom zoo dua qub.

Kev tshawb fawb txog cov kab mob neurodegenerative
Cov kev tshawb fawb ua ntej tau pom tias gemostat tuaj yeem hla cov ntshav- lub paj hlwb teeb meem thiab txhim kho kev txawj ntse hauv Alzheimer tus kab mob qauv nas los ntawm kev tswj cov thymine metabolism. Cov txheej txheem tshwj xeeb tseem tab tom tshawb nrhiav.

Perioperative kho mob plab hnyuv (JCOG1301 sim)
Tshuaj: Ceio 80mg/m² bid d1-14+Cisplatin 60mg/m² d8q3w x 3 cycles
Qhov tshwm sim: R0 resection tus nqi yog 83%, 3-xyoo DFS tus nqi yog 62%, thiab piv nrog cov pab pawg kws kho mob tom qab phais, nws nce 11%
Kev tswj tshuaj lom: Los ntawm kev kho qhov ntau npaum li cas ntawm Giemster, hematological toxicity ntawm qib III lossis siab dua tau txo los ntawm 52% mus rau 38%
Kev hloov pauv kev kho rau daim siab metastasis ntawm mob qog noj ntshav (OPUS txoj kev tshawb fawb)
Kev daws: FOLFOXIRI (irinotecan + oxaliplatin + fluorouracil) + gemcitabine 9mg twv

Qhov tshwm sim: Lub hom phiaj teb tus nqi (ORR) ntawm daim siab metastases yog 69%, R0 resection tus nqi yog 34%, thiab nruab nrab OS yog 33 lub hlis

Innovation point: Jimos tus neeg sawv cev txuas ntxiv lub sijhawm ua haujlwm ntawm 5-FU rau 48 teev, txhim kho nws cov txiaj ntsig zoo nrog oxaliplatin

Kev kho neoadjuvant rau kev mob qog noj ntshav pancreatic (PREOPANC-1 sim)
Scheme: Gemcitabine 1000mg/m² d1,8,15+Tegio 30mg/m² bid d1-28 q4w × 3 cycles
Qhov tshwm sim: R0 resection tus nqi yog 42%, uas yog 18% siab dua cov pab pawg phais yooj yim, thiab qhov nruab nrab OS tau ntev los ntawm 6.3 lub hlis.
Mechanism: Gemcitabine txhim kho DNA kev puas tsuaj ntawm gemcitabine los ntawm kev tswj cov concentration ntawm 5-FU hauv cov qog nqaij hlav

Kev hloov kho koob tshuaj
Lub raum tsis txaus: Thaum creatinine tshem tawm tsawg dua 50mL / min, koob tshuaj Tegio txo ​​qis los ntawm 20%
Lub siab ua haujlwm tsis zoo: Tus menyuam Pugh chav kawm B cov neeg mob uas muaj 35% nce hauv Gimostat AUC yuav tsum tau saib xyuas ze
Kev tiv thaiv toxicity thiab tswj cov tswv yim

Hematological toxicity: Prophylactic tswj ntawm G-CSF (PEG rhG CSF 6mg d2) tuaj yeem txo qhov tshwm sim ntawm qib IV neutropenia ntawm 32% mus rau 8%
Cov tshuaj tiv thaiv kab mob hauv plab: Ua ke nrog triple antiemetic regimen ntawm aripipitan, qhov tshwm sim ntawm CINV poob ntawm 68% mus rau 41%
Cov tshuaj sib cuam tshuam
CYP2A6 inhibitors (xws li ciprofloxacin): nce kev hloov pauv ntawm tegafur thiab yuav tsum tau saib xyuas ntawm 5-FU ntsig txog toxicity
Fluorouracil enhancers (xws li methotrexate): tej zaum yuav ua rau mob mucosal o, thiab kev tswj hwm yuav tsum tau kho.

Kev loj hlob ntawm biomarkers
Tsim cov khoom siv tshawb nrhiav sai rau DPD kev ua ub no, raws li qhov piv ntawm uracil / dihydrouracil hauv cov neeg mob tso zis los coj cov tshuaj kho tus kheej. Tam sim no, cov khoom tsim qauv tau nkag mus rau theem kev sim tshuaj.
ntse tshuaj xa system
Tsim cov pH rhiab heev nanoparticles thiab siv pH gradient ntawm cov qog microenvironment kom ua tiav cov txheej txheem tso tawm ntawm gemcitabine ntawm qhov chaw qog. Tsiaj thwmsim tau pom cov qog/plasma tshuaj concentration piv ntawm 12: 1.

Daim ntawv thov ntawm Synthetic Biology
Tsim DPD tsis muaj qog cell kab los ntawm kev kho cov noob caj noob ces thiab kawm txog cov nyhuv adjuvant ntawmGimeracilhauv kev txhim kho CAR-T cell therapy. Cov kev sim hauv vitro tau pom tias muaj 2.3-fold nce hauv cov qog tua cov nyhuv.