Non-steroidal MRA hauv Kev Kho Mob Cardiorenal Disease: Los ntawm Mechanism mus rau Kev Ntsuam Xyuas Kev Ntsuam Xyuas
Feb 08, 2023
Nrog rau cov kev kho mob uas twb muaj lawm, cov neeg mob plawv tsis ua hauj lwm thiab mob raum kab mob (CKD) tseem muaj kev pheej hmoo siab ntawm qhov tshwm sim tsis zoo thiab kev loj hlob. Steroidal mineralocorticoid receptor antagonists (MRA), xws li spironolactone thiab eplerenone, tuaj yeem txo qhov kev tuag ntawm cov neeg mob, tab sis muaj kev pheej hmoo siab ntawm cov kev mob tshwm sim, yog li daim ntawv thov kev kho mob raug txwv, tsis yog-steroidal MRA Kev tshawb fawb thiab kev loj hlob ntawm cov tshuaj muaj coj cov kev xaiv tshiab rau kev kho mob plawv thiab raum kab mob.
Nyem rau cistanche tshuaj xyuas kab mob raum
Non-steroidal MRAs muaj kev sib raug zoo thiab kev xaiv rau mineralocorticoid receptors (MRs) thiab txawv ntawm steroidal MRAs hais txog lub cev muaj zog, pharmacodynamics, thiab pharmacokinetics. Non-steroidal MRAs muaj txiaj ntsig los tiv thaiv kab mob, ua haujlwm tsis zoo, tiv thaiv kev hloov kho, thiab tiv thaiv fibrotic cuam tshuam hauv lub raum, lub plawv, thiab vasculature.
Hauv Nyij Pooj, eplerenone tau pom zoo rau kev kho mob ntshav siab tseem ceeb thiab tau kawm hauv ntshav qab zib nephropathy. Finerenone tau pom zoo rau kev kho mob raum mob raum mob ntshav qab zib hom 2. Piv nrog rau steroidal MRA, finerenone muaj txiaj ntsig zoo dua hauv inhibiting MR receptors thiab fibrosis thiab muaj kev faib tawm ntau dua hauv lub plawv thiab lub raum. Theem 3 FIGARO-DKD thiab FIDELIO-DKD kev sim tau pom tias finerenone txo cov mob raum loj thiab cov hlab plawv hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus-mob raum mob. Nonsteroidal MRAs tam sim no raug soj ntsuam hauv cov neeg mob plawv tsis ua haujlwm, thiab ua ke nrog SGLT2 inhibitors.
Mineralocorticoid receptor yog lub hom phiaj kho mob tseem ceeb hauv cov kab mob cardiorenal
Cov mineralocorticoid receptor yog ib qho ligand-activated nuclear transcription yam uas qhia nyob rau hauv lub plab hnyuv ib ntsuj av, lub plawv, hlwb, lub raum, lub cev tiv thaiv kab mob, thiab vasculature. MR muaj qhov zoo sib xws rau ntau yam endogenous steroids, suav nrog progesterone, cortisol, thiab aldosterone.
Nyob rau hauv lub raum epithelial hlwb, MR activation ua rau sodium thiab kua retention los ntawm nce epithelial sodium channel (ENaC) kev ua thiab K ntxiv excretion. Hauv lub hauv paus paj hlwb, MR tuaj yeem ua lub luag haujlwm hauv kev tswj ntshav siab; Hauv cov ntaub so ntswg adipose, MR overactivation tuaj yeem cuam tshuam nrog insulin tsis kam thiab metabolic syndrome. Nyob rau hauv lub plawv, lub raum, thiab vasculature, MR overactivation yog txuam nrog cov ntaub so ntswg remodeling, dysfunction, o, thiab fibrosis.
Muaj ib qho kev sib cuam tshuam ntawm lub plawv tsis ua hauj lwm thiab mob raum kab mob. Lub ntim ntev thiab siab dhau, ntshav tsis txaus, neurohormonal dysregulation (xws li RAAS thiab kev ua siab ntev ntawm lub paj hlwb), oxidative stress, o thiab fibrosis, thiab cov teebmeem ncaj qha ntawm uremic toxins tuaj yeem ua rau kev kho mob thiab thaum kawg plawv thiab lub raum tsis ua haujlwm. Cov txheej txheem metabolic, hemodynamic, thiab inflammatory / fibrotic txheej txheem yog tag nrho cov hom phiaj tseem ceeb rau kev kho. Ntawm lawv, MR-induced o, fibrosis, thiab kho dua tshiab yog cov hom phiaj kho mob tseem ceeb rau cov kab mob cardiorenal. Cell hom-specific MR antagonism nyob rau hauv cardiomyocytes thiab myeloid hlwb tej zaum yuav txuam nrog txo o thiab fibrosis, organ dysfunction, thiab pathological remodeling thaum txo cov kev pheej hmoo ntawm hyperkalemia txuam nrog epithelial MR inhibition.
Non-steroidal MRA rau cov kab mob cardiorenal: qhov zoo thiab kev soj ntsuam kev soj ntsuam
Thaum Lub Rau Hli 2022, finerenone tau pom zoo hauv Suav teb rau kev kho mob raum mob raum mob ntshav qab zib hom 2. Piv nrog rau eplerenone thiab spironolactone, finerenone yog xaiv ntau dua rau MR, tsis tshua muaj kev cuam tshuam rau lwm cov steroid receptors thiab ion channels, thiab accumulates ntau nyob rau hauv lub raum. Finerenone tsis tshua muaj lipophilic, ntau dua polar, thiab tsis hla cov ntshav-hlwb barrier. Finerenone tsis muaj cov metabolites nquag, ib nrab-lub neej luv luv, hyperkalemia tuaj yeem kho tau sai dua, thiab muaj kev cuam tshuam rau ntshav siab.
Preclinical thiab soj ntsuam cov ntaub ntawv qhia tias finerenone yog ib qho tseem ceeb tshuaj rau kev kho mob ntawm cardiorenal kab mob. Cov kev sim tsiaj tau pom tias, piv nrog eplerenone, finerenone txhim kho myocardial thiab lub raum hypertrophy, BNP thiab proteinuria, thiab kev qhia ntawm pro-inflammatory / pro-fibrotic noob hauv plawv thiab lub raum cov ntaub so ntswg. Theem 3 FIDELIO-DKD thiab FIGARO-DKD kev sim tau pom tias finerenone yog ob qho tib si renoprotective thiab txhim kho cov hlab plawv hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus-mob raum mob. Qhov kev sim FIDELITY (n=13,{{10}}}26) ntxiv tau lees paub qhov txiaj ntsig kho mob ntawm finerenone, nrog rau kev pheej hmoo ntawm cov hlab plawv ntawm 14 feem pua (HR 0.{{ 11}}, 95 feem pua CI: 0.78, 0.95) thiab cov txiaj ntsig ntawm lub raum ua kom muaj kev pheej hmoo txo qis ntawm 23 feem pua (HR 0.77, 95 feem pua CI: 0.67, 0.88). Finerenone tau zoo zam.
Prespecified subgroup soj ntsuam ntawm FIDELIO-DKD tau pom cov txiaj ntsig zoo ib yam rau cov kab mob plawv thiab lub raum kawg hauv cov neeg mob kho nrog finerenone, tsis hais seb cov neeg mob puas muaj lub plawv tsis ua haujlwm ntawm lub hauv paus. FIGARO-DKD pawg kev tshuaj ntsuam xyuas tau pom tias qhov kev pheej hmoo ntawm lub plawv tsis ua haujlwm tshiab tau txo qis hauv pawg finerenone (HR 0.68, 95 feem pua CI: 0.50, { {13}}.93). Cov txiaj ntsig ntawm kev tshawb nrhiav kev tshawb fawb qhia tias qhov txo qis yuav ntau dua rau cov neeg mob uas tau txais SGLT2 inhibitor ntawm qhov pib. FIDELIO-DKD preset tsom xam cov txiaj ntsig tau pom tias finerenone kuj txo qhov tshwm sim ntawm atrial fibrillation / flutter tshiab (HR 0.71, 95 feem pua CI: 0.53, 0.94).
Qhov kev sim FIND-CKD yuav tshawb xyuas cov txiaj ntsig ntawm finerenone hauv kev tiv thaiv kev mob raum hauv cov neeg mob uas tsis muaj ntshav qab zib CKD. Qhov kev sim FINEARTS-HF tau tsim los ntsuas qhov cuam tshuam ntawm finerenone ntawm qhov kawg ntawm lub plawv tsis ua hauj lwm hauv tsev kho mob thiab cov hlab plawv tuag hauv cov neeg mob plawv tsis ua hauj lwm nrog kev khaws cia ejection feem (HFpEF). Qhov kev txiav txim siab CONFIDENCE yuav ntsuas cov tshuaj finerenone ntxiv rau empagliflozin hauv cov neeg mob ntshav qab zib nrog CKD.
Nrog rau qhov txuas ntxiv ntawm cov pov thawj kho mob, tsis yog-steroidal MRA yuav tsum dhau los ua txoj kev kho mob tseem ceeb thoob plaws cov kab mob cardiorenal.
