Merck's Molnupiravir thiab Pfizer's Paxlovid, Ob Qhov Tshuaj Tiv Thaiv Kab Mob Tshiab Tawm tsam COVID-19 puas tuaj yeem cuam tshuam qhov kawg ntawm kev sib kis?

Molnupiravir, lub ntiaj teb thawj qhov ncauj tshuaj (kev pom zoo los ntawm MHRA, UK) tiv thaiv COVID-19 nrog rau cov tshuaj tom ntej xws li Paxlovid thiab kev txhaj tshuaj tiv thaiv tau ua rau muaj kev cia siab tias COVID-19 kev kis thoob qhov txhia chaw yuav xaus sai sai ua rau lub neej rov qab mus rau qhov qub. Molnupiravir (Lagevrio) yog cov tshuaj dav dav siv tau los tiv thaiv tus tswv ntawm tus mob coronaviruses suav nrog VOCs (variants ntawm kev txhawj xeeb) vim nws cov txheej txheem ntawm kev ua. Qhov zoo ntawm cov tshuaj no qhov ncauj yog tias lawv txo tus nqi ntawm kev saib xyuas mob hnyav hauv tsev kho mob (raws li lawv tuaj yeem noj hauv qhov ncauj tsis nyob hauv tsev kho mob), yog li txo lub nra ntawm kev saib xyuas kev noj qab haus huv thiab cov peev txheej, nres kev kho mob ntawm cov kab mob mus rau qhov hnyav yog tias noj raws sijhawm (hauv tsib hnub ntawm qhov pib muaj kab mob) thiab tiv thaiv kev tuag, thiab muaj txiaj ntsig zoo tiv thaiv ntau yam kab mob coronaviruses, suav nrog VOCs. 

Tus kab mob COVID-19 tau tshaj tawm txog 5 lab tus tib neeg txij li lub Peb Hlis 2020, nrog ntau dua 252 lab tus neeg mob thoob ntiaj teb thiab ua rau muaj kev cuam tshuam nyiaj txiag thiab nyiaj txiag tsis tau muaj dua.  

Kev taw qhia txog kev tso cai thaum muaj xwm txheej ceev ntawm cov tshuaj tiv thaiv ua ke nrog kev txhaj tshuaj tiv thaiv loj heev tau txo qis cov neeg tuag mus txog li 10% ntawm qhov tau pom thaum lub sijhawm txhaj tshuaj tiv thaiv ua ntej. Txawm li cas los xij, tus kab mob kis thoob qhov txhia chaw tsis zoo li yuav nyob ze qhov kawg raws li pom tseeb los ntawm cov ntaub ntawv hais hauv Table I.  

Qhov tseeb, ntau lub teb chaws tam sim no, zoo li nyob rau hauv throes ntawm peb nthwv dej. COVID-19 cov neeg mob thoob plaws Tebchaws Europe tau pib nce mus txog qib sau tseg, ua rau thaj av ntawd yog qhov tseem ceeb ntawm kev sib kis. Ob peb lub lis piam dhau los, Tebchaws Europe thiab Central Asia tau pom 6% nce ntxiv thiab 12% nce ntxiv, raws li tus lej ntawm COVID-19. Nyob rau lub hli tas los, thaj av tau ntsib ntau dua 55% nce ntxiv ntawm COVID-19 cov neeg mob tshiab suav txog 59% ntawm txhua kis thoob ntiaj teb thiab 48% ntawm cov neeg tuag tau tshaj tawm.¹ Qhov xwm txheej hauv Central thiab Eastern European lub teb chaws xws li Romania, Bulgaria, Ukraine thiab lwm yam yog qhov nyuaj ntxiv vim muaj kev txhaj tshuaj tiv thaiv qis dua piv rau Western Europe.  

Qhov xwm txheej hauv Tebchaws Meskas yog deb ntawm qhov txaus siab. Hauv Suav teb, muaj xov xwm tshaj tawm ntawm lub nplhaib-fencing ntawm Beijing raws li kev ceev faj tiv thaiv kev sib kis hauv ntau lub xeev hauv lub tebchaws. Txawm hais tias theem ntawm kev txhaj tshuaj tiav, yog tias cov kev hloov pauv tam sim no yog qhov qhia tau, tsis zoo li tsis muaj kev lees paub, tias lwm thaj tsam ntawm lub ntiaj teb yuav tsis pom qhov xwm txheej zoo ib yam li peb pom hauv Tebchaws Europe thiab Central Asia tam sim no, nyob rau yav tom ntej ze ze. 

Nrog rau cov keeb kwm yav dhau los no, cov lus tshaj tawm tsis ntev los no ntawm kev txhawb nqa cov txiaj ntsig ntawm kev sim tshuaj rau ob hom tshuaj tiv thaiv kab mob tshiab (Merck's Molnupiravir thiab Pfizer's Paxlovid) tiv thaiv COVID-19 thiab kev pom zoo sai sai ntawm Molnupiravir hauv UK tau txais qhov tseem ceeb raws li kab lus tshiab thib ob. ntawm kev tiv thaiv (tom qab txhaj tshuaj tiv thaiv) rau cov neeg mob tsis ntev los no tau kuaj pom tus kab mob cov tsos mob, yog li tiv thaiv kev xav tau ntawm kev mus pw hauv tsev kho mob lossis kev tuag.  

Txoj hauv kev tam sim no los daws qhov kev sib kis  

Coronaviruses tso tawm cov txiaj ntsig zoo heev ntawm kev ua yuam kev thaum lub sijhawm rov ua dua (vim tsis muaj kev ua pov thawj nuclease ntawm lawv cov polymerases) uas tseem tsis raug kho thiab sib sau ua ke los ua qhov sib txawv. Ntau qhov kev sib kis, ntau qhov kev hloov pauv tsis raug thiab ntau qhov kev hloov pauv hauv cov genome, ua rau kev hloov pauv ntawm cov hloov pauv tshiab. Yog li, kev txwv kev sib raug zoo los txwv kev sib kis yog qhov tseem ceeb rau kev tiv thaiv cov xwm txheej tshiab nrog rau kev tiv thaiv kev hloov pauv ntawm cov hloov pauv tshiab. Txog tam sim no, kev txhaj tshuaj tiv thaiv tau pom cov lus cog tseg zoo hauv kev tiv thaiv cov tsos mob ntawm tus kab mob thiab kev loj hlob mus rau qhov hnyav, yuav tsum tau pw hauv tsev kho mob. Hauv cov teb chaws uas muaj kev txhaj tshuaj tiv thaiv siab xws li UK, cov neeg tuag tau nqis mus txog li 10% ntawm qhov tau pom thaum lub sijhawm ua ntej nthwv dej. Txawm li cas los xij, muaj coob tus neeg zoo xav tau mus pw hauv tsev kho mob.  

Rau qhov mob me me mus rau qhov hnyav, ntau txoj hauv kev tau sim. Cov mob hnyav hnyav yuav tsum tau txais kev txhawb nqa oxygen, thaum cov mob hnyav yuav tsum tau siv tshuaj tua kab mob nrog kev saib xyuas hnyav. Dexamethasone tau pom tias muaj txiaj ntsig zoo tshaj plaws hauv cov mob hnyav hauv tsev kho mob. Cov tshuaj tiv thaiv kab mob, remdesivir zoo li ua tau zoo tab sis raug nqi, thiab yog li tsis zoo li yuav kho tus nqi zoo rau COVID-19.².  

Cov tshuaj tiv thaiv kab mob rau COVID-19 poob rau hauv peb pawg (saib cov ntsiab lus 1 hauv Table II saum toj no). Thawj pab pawg muaj cov tshuaj xws li Umifenovir (tam sim no siv rau kev kho mob khaub thuas hauv Russia thiab Tuam Tshoj) inhibit qhov nkag ntawm tus kab mob mus rau hauv tib neeg lub hlwb thaum cov pab pawg thib ob suav nrog cov kab mob RNA inhibitors xws li Remdesivir, Favipiravir thiab Molnupiravir ua raws li kev sib tw nucleoside analogue rau ua rau ntau yam tsis hnov ​​​​tsw hloov pauv (RNA mutagenesis), yog li cuam tshuam nrog cov kab mob sib kis. Cov pab pawg thib peb yog cov kab mob viral protease inhibitors xws li lopinavir / ritonavir, PF-07321332, thiab PF-07304814 uas thaiv cov kab mob protease enzyme uas cuam tshuam cov kab mob los ua cov kab mob tshiab, yog li txo cov kab mob kis.  

Txawm hais tias ob peb lub sijhawm dhau los ntawm kev kis mob khaub thuas thiab ob qhov kev kis tus kabmob coronavirus tsis ntev los no (2003 qhov tshwm sim hauv Suav teb suav nrog SARS-CoV thiab MERS tshwm sim xyoo 2012), tsuas yog ib qho tshuaj tiv thaiv kab mob (Remdesivir) tau pom lub teeb ntawm hnub thiab tuaj yeem yog qee qhov. pab nyob rau hauv kev sib kis tam sim no, txawm tias nws yog thawj zaug tsim los kho kab mob siab C thiab Ebola. Remdesivir tau pab kho cov neeg mob COVID-19 uas muaj cov tsos mob hnyav hauv tsev kho mob, tab sis yog tus nqi kim heev thiab yog li ntawd tsis ua rau kev kho tus nqi pheej yig. 

Qhov xav tau ntawm ib teev yog cov tshuaj uas tuaj yeem txwv kev kho mob ntawm cov mob tshiab ntawm COVID-19 los ntawm tsis muaj tsos mob mus rau me me mus rau nruab nrab lossis hnyav, yog li txo qis kev xav tau mus pw hauv tsev kho mob thiab tiv thaiv COVID cuam tshuam txog kev tuag.  

Molnupiravir thiab PF-07321332, ob cov tshuaj tiv thaiv kab mob qhia tau cog lus tias yuav tsum txwv tsis pub kev kho mob ntawm cov mob asymptomatic lossis mob me.  

Coronaviruses siv RNA-dependent RNA polymerase (RdRp) rau kev rov ua dua thiab hloov pauv ntawm lawv cov RNA genome uas ua rau RdRp yog lub hom phiaj tseem ceeb rau cov tshuaj tiv thaiv kab mob coronaviruses.⁴.  

Molnupiravir, tus inhibitor ntawm tus kab mob RNA polymerase, kev sib tw nucleoside analogue hauv cov kab mob RNA nyob ntawm RNA polymerase, ua rau muaj ntau yam kev hloov pauv tsis zoo induces RNA mutagenesis. Nws nce qhov zaus ntawm tus kab mob RNA hloov pauv thiab cuam tshuam SARS-CoV-2 replication. Nws inhibits viral replication los ntawm ib tug mechanism hu ua 'lethal mutagenesis'. Molnupiravir cuam tshuam qhov kev ncaj ncees ntawm SARS-CoV-2 genome replication thiab tiv thaiv kev kis kab mob los ntawm kev txhawb nqa kev ua yuam kev hauv cov txheej txheem hu ua 'yuam kev puas tsuaj' ^4,5.  

Molnupiravir, tsim los ntawm Ridgeback therapeutics thiab MSD (Merck) ua lag luam lub npe Lagevrio, yog ib tug prodrug ntawm ß-D-N4-hydroxycytidine thiab tau pom tias yuav txo tau tus kab mob replication 100,000-fold nyob rau hauv nas engineered kom muaj tib neeg lub ntsws ntaub so ntswg.⁶. Nyob rau hauv cov ntaub ntawv ntawm ferrets, molnupiravir tsis tsuas yog txo cov tsos mob, tab sis kuj coj mus rau xoom kab mob kis nyob rau hauv 24 teev.⁶. Molnupiravir tau txais txiaj ntsig zoo yam tsis muaj qhov tshwm sim tsis zoo nyob rau hauv ib qho randomized, ob-dig muag, tshuaj placebo-tswj, Thawj-hauv-Human txoj kev tshawb fawb tsim los ntsuas kev nyab xeeb, kam rau ua, thiab pharmacokinetics ntawm cov tshuaj, tom qab kev tswj hwm qhov ncauj rau cov neeg ua haujlwm noj qab haus huv hauv tag nrho. ntawm 130 yam^7,8. Hauv theem 2/3 kev sim tshuaj, Lagevrio tau pom tias yuav ua tau zoo los txo qhov kev pheej hmoo ntawm kev mus pw hauv tsev kho mob lossis kev tuag rau cov neeg laus uas tsis muaj tsev kho mob uas muaj kev pheej hmoo me me mus rau nruab nrab COVID-19 los ntawm 50%⁹. Lagevrio yog li lub ntiaj teb thawj zaug pom zoo tshuaj tiv thaiv kab mob uas tuaj yeem noj hauv qhov ncauj es tsis yog txhaj tshuaj. Qhov no yog qhov tseem ceeb vim nws tuaj yeem tswj hwm hauv qhov chaw tsis yog tsev kho mob, ua ntej COVID-19 tau nce mus rau theem hnyav. Nws yuav tsum tau noj sai li sai tau tom qab qhov kev kuaj pom zoo COVID-19 thiab hauv tsib hnub ntawm cov tsos mob pib. Txawm li cas los xij, nws tsis tuaj yeem suav tias yog qhov hloov pauv rau kev txhaj tshuaj, yog li kev txhaj tshuaj tiv thaiv yuav tsum txuas ntxiv mus. 

Paxlovid (PF-07321332) ntawm qhov tod tes, ua los ntawm txoj kev inhibition ntawm tus kab mob protease SARS-CoV-2-3CL protease, ib qho enzyme uas tus mob coronavirus xav tau rov ua dua. Nws yog siv ib leeg lossis ua ke nrog cov tshuaj ritonavir tsawg.  

Ritonavir yog tus kab mob HIV protease inhibitor, feem ntau yog siv nrog lwm cov protease inhibitors raws li ib feem ntawm cov tshuaj tiv thaiv kab mob HIV, vim nws inhibits hepatic metabolism ntawm tus khub tshuaj.  

Raws li kev soj ntsuam ib ntus ntawm Theem 2/3 EPIC-HR (Kev Ntsuam Xyuas ntawm Protease Inhibition rau COVID-19 nyob rau hauv Cov Neeg Mob Risk Siab)¹⁰ randomized, ob-dig muag txoj kev tshawb fawb ntawm cov neeg laus uas tsis nyob hauv tsev kho mob nrog COVID-19, uas muaj kev pheej hmoo siab ntawm kev mob hnyav, Paxlovid tau pom tias yuav txo tau 89% ntawm kev pheej hmoo ntawm kev mus pw hauv tsev kho mob lossis kev tuag piv rau cov placebo hauv cov neeg mob. kho tsis pub dhau peb hnub ntawm qhov tshwm sim tshwm sim. Cov xwm txheej tsis zoo cuam tshuam nrog Paxlovid tau muab piv rau cov placebo thiab mob hnyav heev. 

Lwm qhov kom zoo dua ntawm Paxlovid yog tias nws tau pom muaj zog tiv thaiv kab mob hauv vitro ua haujlwm tawm tsam kev sib txawv ntawm kev txhawj xeeb (VOCs), nrog rau lwm cov kab mob coronaviruses. Paxlovid yog li muaj peev xwm siv tau los ua kev kho mob rau ntau hom kab mob coronavirus.  

Nws yuav tsis ntev ua ntej peb pom kev pom zoo ntawm Paxlovid nrog rau tus kws kho mob hauv kev tawm tsam COVID-19. 

Thaum Molnupiravir yog ib qho nucleoside analogue uas cuam tshuam nrog tus kab mob RNA replication, Paxlovid yog ib qho inhibitor ntawm 3CL protease, ib qho enzyme xav tau rau tus mob coronavirus replication. 

Cov lus nug tseem ceeb uas tau tsa rau ob lub qhov ncauj tshuaj tiv thaiv kab mob no yuav tig mus ncig lawv cov kev ua tau zoo, kev nyab xeeb, txawm tias lawv yuav ua haujlwm tawm tsam cov kev hloov pauv uas twb muaj lawm thiab yav tom ntej, kev txhim kho kev tiv thaiv rau cov tshuaj no thiab lawv nkag mus rau cov teb chaws txom nyem.¹¹. Thaum ob qho tib si Molnupiravir thiab Paxlovid fare zoo nyob rau hauv cov lus teb rau thawj peb lo lus nug, nws yuav yog ib qho tseem ceeb rau kev soj ntsuam cov neeg uas tsis teb rau ib yam ntawm cov tshuaj los txiav txim tus kab mob no tiv thaiv kab mob thiab tseem saib xyuas cov neeg muaj lub cev tsis muaj zog tiv thaiv kab mob thiab tau txais cov tshuaj no. tshuaj kho mob COVID-19. Sib nrug los ntawm kev tiv thaiv kab mob, kev nkag tau ntawm cov tshuaj no mus rau lub ntiaj teb thib peb yuav ua rau muaj kev hem thawj loj los txo tus kab mob kis thoob qhov txhia chaw vim cov teb chaws no yuav tsis muaj peev xwm them taus ib yam, xws li Molnupiravir kho tus nqi USD 700 rau ib tus neeg mob thaum Paxlovid tseem nyob. pom tab sis tej zaum yuav nyob rau hauv tib lub chaw ua si pob. Lwm qhov kev sib tw tuaj yeem hais tias cov tebchaws nplua nuj thiab muaj txiaj ntsig tuaj yeem pib khaws cov koob tshuaj rau lawv tus kheej, ua rau kev nkag mus nyuaj rau txhua tus. Txawm hais tias ib qho ua rau cov tshuaj (molnupiravir) muaj rau cov tebchaws txom nyem, lawv yuav tsis muaj peev xwm kuaj xyuas cov neeg mob uas muaj molnupiravir thaum ntxov ntawm lawv qhov mob, thaum kho tau zoo tshaj plaws.¹². 

Txawm li cas los xij, ob qho tshuaj tiv thaiv kab mob tshiab no zoo li muaj peev xwm loj hauv kev kho mob ntawm COVID-19 thiab tuaj yeem pab ua kom qhov kawg ntawm kev sib kis sai sai, tawm hauv COVID-19 yog ib qho kab mob sib kis nrog me me. 

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DOI: https://doi.org/10.29198/scieu/2111151 

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