Molnupiravir hmoov

Molnupiravir belongs rau nucleoside analogue, thiab nws cov qauv tshuaj lom neeg zoo ib yam li cov nucleosides ntuj xav tau rau tus kab mob RNA replication, xws li cytidine triphosphate (CTP). Qhov zoo sib xws no tso cai rau nws "yuam kev" raws li ib txwm substrate los ntawm tus kab mob RNA nyob ntawm RNA polymerase (RdRp) thiab koom ua ke rau hauv cov kab mob RNA tshiab.

Daim ntawv nquag ntawm Molnupiravir ( - D-N4-hydroxycytidine triphosphate, NHC-TP), thaum hloov CTP hauv kab mob RNA strands, ua rau muaj kev hloov pauv ntawm ob txoj hauv kev:
Direct mutagenesis: NHC-TP tuaj yeem tsim cov hauv paus tsis ruaj khov nrog adenosine (A) lossis guanosine (G), uas ua rau kev nkag mus rau hauv cov hauv paus tsis raug nyob rau tom ntej ntawm kev rov ua dua (xws li A → G lossis G → A hloov).

Indirect mutagenesis: NHC-TP kev koom ua ke tuaj yeem hloov pauv qhov sib txawv hauv zos ntawm RNA strands, ua rau RdRp "slippage" thiab ua rau hauv paus ntxig lossis tshem tawm (indels).

Mutation accumulation effect: single integration may only cause individual mutations, but viral RNA replication is extremely fast (COVID-19 can produce about 10 ¹² viral particles every day), resulting in exponential accumulation of mutations in the virus population. When the mutation rate exceeds the virus tolerance threshold (usually requiring a mutation frequency of>1%), tus kab mob genome yuav plam kev ua haujlwm zoo, tsis tuaj yeem tsim cov proteins uas muaj txiaj ntsig zoo lossis ua kom tiav, thiab thaum kawg raug tshem tawm los ntawm lub cev tiv thaiv kab mob.

Lub hom phiaj ntawm Molnupiravir (RdRp) tau txais txiaj ntsig zoo hauv cov kab mob RNA, thiab nws cov txheej txheem mutagenic tsis nyob ntawm tus kab mob tshwj xeeb cov qauv protein. Yog li, nws muaj peev xwm ua haujlwm tawm tsam ntau yam kab mob RNA, suav nrog:
Coronavirus family: SARS-CoV-2 (original strain and Alpha, Beta, Delta, Omicron and other variants) SARS-CoV, MERS-CoV.
Orthomyxoviridae: influenza A virus (IAV), influenza B virus (IBV).
Paramyxoviridae: respiratory syncytial virus (RSV), kab mob qhua pias.
Cov kab mob RNA me me: Norovirus, poliovirus.

Raws li kev pom zoo los ntawm Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb (WHO) thiab cov koom haum tswj hwm tshuaj hauv tebchaws (xws li FDA, EMA), cov lus qhia rau Molnupiravir yog:
Cov pej xeem: cov neeg laus uas muaj tus kab mob me me mus rau nruab nrab ntawm COVID-19 (Ntau dua lossis sib npaug li 18 xyoo).
Risk stratification: Yuav tsum muaj siab - cov yam tseem ceeb rau kev loj hlob mus rau kev mob hnyav, suav nrog:

Hnub nyoog Ntau dua lossis sib npaug li 60 xyoo;
Tsis tau txhaj tshuaj tiv thaiv COVID-19 lossis kev tiv thaiv kab mob tsis txaus;
Cov kab mob hauv paus (xws li rog rog, ntshav qab zib mellitus, mob plawv thiab mob ntsws, kab mob raum ntev, tiv thaiv kab mob);
Kev xeeb tub lig (qhov hnyav ntawm qhov zoo thiab qhov tsis zoo, feem ntau yog contraindicated).
Lub Sijhawm Lub Sijhawm: Pib kho tsis pub dhau 5 hnub tom qab cov tsos mob tshwm sim ua kom lub sijhawm ntev ntawm lub qhov rais rau inhibiting tus kab mob sib kis.

Cov kev sim tseem ceeb (MOVe OUT): 1433 yam tsis tau txhaj tshuaj tiv thaiv siab - cov neeg mob uas tsis nyob hauv tsev kho mob pheej hmoo raug muab tso rau hauv pawg Molnupiravir (800 mg, ob zaug ib hnub, 5 hnub) lossis pab pawg placebo.
Thawj qhov kawg (kev kho mob lossis kev tuag hauv 28 hnub) qhov tshwm sim: Molnupiravir pawg: 7.3% (28/385); Cov pab pawg placebo: 10.1% (37/365); Relative Risk Reduction (RRR): 28% (95% CI: 2% -48%).

Secondary endpoint: Rate of viral load poob: Hnub 5, tus kab mob kis hauv lubMolnupiravir hmoovpab pawg poob los ntawm kwv yees li 0.3 teev ₁₀ daim ntawv / mL piv rau cov hauv paus (p=0.02); Lub sij hawm kho cov tsos mob: qhov nruab nrab luv luv los ntawm 1 hnub (10 hnub vs 11 hnub, p=0.07).

Cov kev sim tsiaj tau pom tias Molnupiravir tuaj yeem txo qhov kev pheej hmoo ntawm kev kis tus kab mob hauv cov neeg nyob ze, tab sis tib neeg cov ntaub ntawv tshawb fawb tau txwv thiab tam sim no tsis pom zoo ua cov tshuaj tiv thaiv niaj hnub.

Molnupiravir tuaj yeem siv los ua lwm txoj hauv kev rau cov tshuaj tiv thaiv kab mob los yog Paxlovid rau cov neeg mob uas muaj B cell lossis T cell ua haujlwm tsis zoo (xws li cov neeg mob AIDS thiab tom qab siv tshuaj tua kab mob ntawm cov qog ntshav), tab sis nws yog ib qho tsim nyog los saib xyuas qhov rov qab ntawm cov kab mob kis.

Tsiaj thwmsim tau pom tias koob tshuaj ntau yuav ua rau fetal pob txha deformities, yog li ntawd lawv yog contraindicated thaum cev xeeb tub; Cov poj niam pub niam mis yuav tsum ncua kev pub niam mis rau 5 hnub tom qab qhov kawg ntawm kev kho mob.