Los ntawm Cocer Peptides 
2 months ago
Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
Raws li qhov tshwm sim ntawm cov kab mob metabolic xws li rog dhau, rog, thiab ntshav qab zib tseem nce ntxiv thoob ntiaj teb, kev tshawb nrhiav cov tshuaj kho tau zoo dua tau dhau los ua cov ncauj lus kub hauv kev kho mob. Mazdutide, raws li tus tshiab dual receptor agonist, tuaj yeem ua rau tib lub sijhawm qhib GLP-1 receptor thiab glucagon receptor, thiab xav tias yuav ua lub luag haujlwm tshwj xeeb hauv kev poob phaus thiab tswj ntshav qab zib, muab sijhawm tshiab rau kev kho mob ntawm cov kab mob metabolic.
Daim duab 1 Cov qauv tshuaj ntawm Mazdutide.
Txheej txheem cej luam ntawm Mazdutide
Mazdutide yog GLP-1 / glucagon dual receptor agonist, tshuaj tshiab rau kev kho cov kab mob metabolic. Ob peb xyoos dhau los, kev txhim kho tshuaj tsom rau cov kab mob metabolic tau txuas ntxiv mus. GLP-1 receptor agonists thiab glucagon receptor agonists tau pom qee yam kev kho mob thaum siv ib leeg, tab sis lawv kuj muaj lawv tus kheej cov kev txwv. Txhawm rau nrhiav kev kho mob zoo tshaj plaws, cov kws tshawb fawb tau tsom mus rau kev tsim cov tshuaj uas tuaj yeem ua rau ntau lub hom phiaj ib txhij, ua rau kev tsim Mazdutide. Nws txoj kev txhim kho tau dhau los ua cov kev tshawb fawb ua ntej thiab kev sim ntau theem, maj mam lees paub nws txoj kev nyab xeeb thiab kev ua tau zoo.
Mechanism ntawm Action
(1) Ua kom cov GLP-1 Receptor
Kev tswj cov ntshav qabzib homeostasis: GLP-1 yog peptide hormone secreted los ntawm txoj hnyuv L hlwb. Tom qab ua kom lub GLP-1 receptor, Mazdutide tswj cov ntshav qabzib los ntawm ntau txoj hauv kev. Nws txhawb kev tsim cov tshuaj insulin los ntawm pancreatic β hlwb, txhim kho kev nkag siab ntawm insulin, yog li ua kom cov piam thaj nce ntxiv thiab siv, thiab txo cov ntshav qabzib. Nws inhibits glucagon secretion los ntawm pancreatic α hlwb thiab txo cov piam thaj hauv siab, ua kom cov ntshav qabzib ruaj khov ntxiv.
Kev ncua lub plab zom mov: Mazdutide activates GLP-1 receptor, ua rau lub plab zom mov kom qeeb plab hnyuv. Qhov no prolongs cov zaub mov khaws cia hauv plab, ua kom satiety thiab txo cov zaub mov kom tsawg, yog li pab tswj qhov hnyav.
Kev tswj kev noj qab haus huv: Tom qab GLP-1 receptor activation, cov teeb liab raug xa mus rau hauv nruab nrab lub paj hlwb, ua haujlwm ntawm lub chaw noj zaub mov hypothalamic los tswj kev tso tawm ntawm kev noj qab haus huv ntsig txog neuropeptides, xws li txo qis neuropeptide Y (NPY) qhia thiab nce proopiomelanocortin (POMC) kev qhia, yog li kev noj qab haus huv.
(2) Ua kom cov glucagon receptors
Txhawb kev siv hluav taws xob: Thaum lub glucagon receptor yog qhib los ntawm Mazdutide, nws txhawb kev rog rog thiab fatty acid oxidation, nce kev siv zog. Tsis tas li ntawd, nws txhawb nqa kev qhia ntawm uncoupling protein 1 (UCP1), txhawb nqa thermogenesis hauv cov ntaub so ntswg adipose, ntxiv dag zog rau lub cev lub zog metabolism thiab pab kom poob phaus.
Kev tswj cov piam thaj metabolism: Ua kom cov glucagon receptors txhawb lub siab glycogenolysis thiab gluconeogenesis. Txawm li cas los xij, nyob rau hauv kev cuam tshuam ntawm Mazdutide, qhov kev txhawb nqa no tsis tsuas yog nce cov ntshav qabzib tab sis hloov ua tiav cov ntshav qabzib cov cai los ntawm kev sib koom ua ke nrog GLP-1 receptor activation teebmeem. Thaum cov ntshav qabzib siab siab, cov nyhuv hypoglycemic mediated los ntawm GLP-1 receptor activation predominates; Thaum cov ntshav qabzib qis qis, cov nyhuv hyperglycemic sib kho los ntawm glucagon receptor activation tiv thaiv hypoglycemia.
(3) Synergistic Mechanism
Mazdutide ib txhij ua haujlwm ob leeg GLP-1 receptors thiab glucagon receptors. Cov kev taw qhia txoj hauv kev qhib los ntawm ob lub receptors ua haujlwm sib koom ua ke los ua kom muaj txiaj ntsig ntau dua thiab muaj zog metabolic tswj cov nyhuv. Nyob rau hauv cov nqe lus ntawm kev poob phaus, GLP-1 receptor activation txo lub zog kom tsawg los ntawm suppressing qab los noj mov thiab ncua lub plab khoob, thaum glucagon receptor activation txhawb zog kev siv nyiaj. Lub synergistic kev txiav txim ntawm ob qho tib si receptors zoo dua ua tiav qhov hnyav txo. Hais txog kev tswj ntshav qabzib, cov teebmeem ntawm ob qho tib si receptor activations ntxiv rau ib leeg kom tswj cov ntshav qabzib nyob rau hauv qhov qub thiab zam dhau qhov hloov pauv ntau dhau.
3. Cov teebmeem ntawm lub cev
(1) Poob qhov hnyav
Cov pov thawj kho mob: Ntau qhov kev sim tshuaj ntsuam xyuas tau pom tias Mazdutide muaj qhov cuam tshuam loj heev. Hauv cov kev tshawb fawb tsom rau cov neeg laus rog rog lossis rog rog hauv , 24 lub lis piam ntawm kev kho Mazdutide (nrog rau qhov siab tshaj plaws ntawm 6 mg) ua rau qhov hnyav poob ntawm 6.7% -11.3%, thaum pab pawg placebo ntsib qhov hnyav nce 1.0%. Ntawm cov pab pawg sib txawv, Mazdutide ntawm 4.5 mg thiab 6 mg tau qhia ntau qhov kev poob phaus, nrog kev kho mob sib txawv piv rau cov placebo xws li -7.7% txog -12.3% (P <0.0001). Hauv kev tshuaj xyuas thiab kev tshuaj ntsuam xyuas meta uas suav nrog 680 tus neeg koom, Mazdutide tau pom tias muaj txiaj ntsig zoo dua li cov placebo hauv kev txo qhov hnyav, nrog qhov sib txawv (MD) ntawm -6.22% (95% kev ntseeg siab luv [CI]: -8.02% rau -4.41%).
Daim duab 2 Lub cev hnyav qhov ua tau zoo kawg nkaus. Ib Feem pua ntawm cov hauv paus hauv lub cev qhov hnyav ntawm lub lim tiam 24. b Qhov feem pua ntawm kev hloov pauv ntawm lub hauv paus hauv lub cev hnyav dhau sijhawm.
(2) Glycemic Regulation Effects
Kev cuam tshuam rau cov neeg mob ntshav qab zib hom 2: Rau cov neeg mob ntshav qab zib hom 2, Mazdutide txo qis hemoglobin A1c (HbA1c) thiab ceev cov ntshav qabzib. Hauv kev sib piv randomized, ob-dig muag, placebo-tswj Theem 2 kev soj ntsuam kuaj mob, cov neeg mob ntshav qab zib hom 2 uas tau txais kev kho mob Mazdutide (ntawm qhov siab tshaj plaws ntawm 6 mg) rau 20 lub lis piam, pom qhov hloov pauv nruab nrab ntawm HbA1c txij li -1.41% mus rau -1.67%, thaum cov placebo pab pawg muaj qhov sib txawv ntawm 3%. cov placebo (P <0.0001). Cov neeg mob kuj tau txais kev poob qis hauv lub cev hnyav, nrog qhov feem pua ntawm cov kev hloov pauv uas qhia txog kev sib raug zoo ntawm koob tshuaj, nce mus txog -7.1%.
Cov txiaj ntsig zoo hauv kev tswj ntshav qabzib: Mazdutide tsis tsuas yog txo qis cov ntshav qabzib tab sis kuj tseem txhim kho cov ntshav qabzib hloov pauv thiab txo qhov kev pheej hmoo ntawm cov xwm txheej hypoglycemic. Piv nrog rau cov tshuaj antidiabetic ib txwm siv, nws ob lub receptor agonist mechanism ntawm kev ua tiav ua tiav ntau dua thiab kev tswj hwm cov ntshav qabzib, yog li txhim kho cov neeg mob lub neej zoo thiab kev cia siab ntev.
(3) Kev cuam tshuam rau cov hlab plawv thiab cov kab mob metabolic
Kev tswj ntshav siab: Mazdutide txo cov ntshav siab systolic thiab diastolic. Kev tshuaj xyuas thiab kev tshuaj ntsuam meta pom tau tias piv nrog cov placebo, Mazdutide txo cov ntshav siab systolic los ntawm qhov sib txawv nruab nrab (MD) ntawm -7.57 mmHg (95% CI: -11.17 txog -3.98 mmHg); rau kev txo cov ntshav siab diastolic, MD yog -2.98 mmHg (95% CI: -5.74 txog -0.22 mmHg). Qhov no yuav raug ntaus nqi rau Mazdutide ntau lub tswv yim, suav nrog kev txhim kho vascular endothelial muaj nuj nqi, txo qis peripheral vascular tsis kam, thiab tswj dej-sodium tshuav nyiaj li cas.
Kev tswj lipid: Mazdutide zoo tswj cov lipid profile. Nws txo tag nrho cov cholesterol (MD = -16.82%, 95% CI: -24.52 rau -9.13%), triglycerides (MD = -43.29%, 95% CI: -61.57 rau -25.01%), thiab low-density lipoprotein (MD = -17.07%) - 9. theem, thaum tseem ua rau muaj kev tswj hwm ntawm cov lipoprotein ntau ntom ntom (MD = -7.54%, 95% CI: -11.26 txog -3.83%). Cov teebmeem no pab txo qis kev pheej hmoo ntawm cov kab mob plawv thiab muaj kev tiv thaiv kab mob plawv.
(4) Cov teebmeem ntawm hyperuricemia
Tsiaj cov pov thawj: Nyob rau hauv ib tug hyperuricemia (HUA) nas qauv kawm, subcutaneous txhaj ntawm 0.05 mg / kg thiab 0.075 mg / kg ntawm Mazdutide (txhua 3 hnub) txo cov ntshav uric acid (SUA) qib hauv nas. Piv nrog rau pawg HUA, SUA thiab ntshav creatinine (SCr) qib tau txo qis hauv Maz-MD thiab Maz-HD pawg, thiab cov qib urinary protein (U-Pro) kuj tseem txo qis hauv Maz-MD pawg. Tsis tas li ntawd, Mazdutide txhim kho lub raum histopathological hloov hauv HUA nas.
Daim duab 3 a: Kev hloov pauv feem pua ntawm cov hauv paus hauv lub cev hnyav dhau sijhawm. b: Tus nqi ntawm cov neeg koom mus txog qhov hnyav poob lub hom phiaj.
Kev tshawb nrhiav kev thov
(1) Kev Tshawb Fawb Txog Kev Kho Mob
Cov Kev Ntsuas Thaum Ntxov: Thaum Ntxov Theem 1 qhov kev sim tshuaj ntsuam xyuas feem ntau tau soj ntsuam kev nyab xeeb, kev zam, thiab kev ua haujlwm ua ntej ntawm Mazdutide. Hauv kev sib tw, kev tswj hwm cov placebo, ntau qhov koob tshuaj nce qib Phase 1b sim, cov neeg laus uas rog dhau lossis rog tau muab ntau koob tshuaj Mazdutide (txog 10 mg). Cov txiaj ntsig tau pom tias Mazdutide tau txais txiaj ntsig zoo nyob rau hauv qhov koob tshuaj no, tsis muaj qhov tshwm sim tsis zoo tshwm sim, thiab pom qhov poob ceeb thawj tseem ceeb.
Theem 2 kev sim tshuaj ntsuam xyuas: Theem 2 qhov kev sim tshuaj ntsuam xyuas ntxiv tau lees paub qhov ua tau zoo thiab kev nyab xeeb ntawm Mazdutide hauv ntau haiv neeg. Hauv Phase 2 sim tsom rau Suav cov neeg mob ntshav qab zib hom 2, Mazdutide tau pom cov txiaj ntsig tseem ceeb hauv kev txo HbA1c thiab lub cev hnyav, nrog kev nyab xeeb piv rau cov placebo pawg. Cov kev phiv tshwm sim feem ntau yog mob me mus rau nruab nrab ntawm plab hnyuv, xws li raws plab thiab xeev siab. Hauv Theem 2 sim tsom rau cov neeg laus rog rog lossis rog rog, 24 lub lis piam ntawm kev kho Mazdutide (txog 6 mg) tau pom tias muaj txiaj ntsig zoo thiab kev nyab xeeb.
(2) Kev Tshawb Fawb Sib Piv nrog Lwm Cov Tshuaj
Kev sib piv nrog GLP-1 receptor agonists: Piv rau ib txwm siv GLP-1 receptor agonists, Mazdutide tuaj yeem muaj kev cuam tshuam ntau dua ntawm kev poob phaus thiab kev tswj ntshav qabzib vim nws ob txoj kev ua haujlwm ntawm GLP-1 receptors thiab glucagon receptors. Hauv qee qhov kev tshawb fawb, Mazdutide tau ua tiav qhov hnyav dua li qee qhov GLP-1 receptor agonists nyob rau tib lub sijhawm kho thiab ua kom pom kev ruaj ntseg zoo dua hauv kev tswj ntshav qabzib.
Kev sib piv nrog lwm cov tshuaj tiv thaiv kab mob: Piv nrog rau cov tshuaj tiv thaiv kab mob hauv qhov ncauj, Mazdutide tsis tsuas yog txo cov ntshav qabzib tab sis kuj muaj txiaj ntsig ntxiv xws li kev poob phaus thiab txhim kho cov kab mob plawv metabolic.
Xaus
Raws li GLP-1 / glucagon dual receptor agonist, Mazdutide ua tiav kev tswj hwm ntawm lub zog metabolism, ntshav qabzib, ntshav siab, thiab cov ntshav lipids los ntawm kev ua kom muaj ob qho tseem ceeb hauv kev tswj hwm cov metabolism, ua kom pom ntau dua thiab muaj zog kho cov teebmeem ntau dua li ib leeg receptor agonists. Mazdutide tuav cov lus cog tseg tseem ceeb rau ntau yam kab mob metabolic, suav nrog kev rog rog, ntshav qab zib hom 2, thiab hyperuricemia.
Qhov chaw
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[2] Nalisa DL, Cuboia N, Dyab E, et al. Kev ua tau zoo thiab kev nyab xeeb ntawm Mazdutide ntawm kev poob phaus ntawm cov neeg mob ntshav qab zib thiab cov neeg mob uas tsis yog ntshav qab zib: kev tshuaj xyuas thiab kev tshuaj xyuas meta-kev soj ntsuam ntawm randomized tswj kev sim [J]. Frontiers hauv Endocrinology, 2024, 15. https://api.semanticscholar.org/CorpusID:267984513.
[3] Ji L, Jiang H, Chen Z, et al. Ib theem 2 randomized tswj kev sim ntawm mazdutide hauv Suav cov neeg rog rog lossis cov neeg laus uas rog rog [J]. Nature Communications, 2023,14(1):8289.DOI:10.1038/s41467-023-44067-4.
[4] Jiang H, Zhang Y, REN Y S. 77-LB: A Novel Glucagon-Like Peptide-1 (GLP-1R) thiab Glucagon (GCGR) Receptor Dual Agonist, Mazdutide (IBI362), Attenuates Hyperuricemia hauv Hyperuricemic Rats [J]. Diabetes, 2023. https://api.semanticscholar.org/CorpusID:259452040
[5] Ji L, Gao L, Jiang H, et al. Kev nyab xeeb thiab kev ua tau zoo ntawm GLP-1 thiab glucagon receptor dual agonist mazdutide (IBI362) 9 mg thiab 10 mg hauv Suav cov neeg laus uas rog dhau lossis rog: Ib qho randomised, placebo-tswj, ntau-ascending-dose theem 1b sim [J]. Eclinicalmedicine, 2022,54:101691.DOI:10.1016/j.eclinm.2022.101691.
Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
