Ngaba i-Merck's Molnupiravir kunye nePfizer's Paxlovid, aMachiza amabini amatsha achasene ne-COVID-19 aKhawulezisa ukuphela kobhubhane?

I-Molnupiravir, i-oral yokuqala yehlabathi iziyobisi (eyamkelwe yi-MHRA, e-UK) ngokuchasene ne-COVID-19 kunye namachiza azayo anje nge-Paxlovid kunye nogonyo oluzinzileyo lunyuse ithemba lokuba ubhubhani we-COVID-19 unokuphela kwakamsinyane ukubuyisela ubomi kwimeko yesiqhelo. I-Molnupiravir (I-Lagevrio) lichiza elibanzi elisebenza ngokuchasene nenkitha yee-coronavirus eziquka ii-VOCs (iintlobo zenkxalabo) ngenxa yendlela yokusebenza kwayo. Iinzuzo ezinkulu zala mayeza omlomo kukuba zinciphisa iindleko zokunyamekela kakhulu esibhedlele (njengoko zinokuthi zithathwe ngomlomo kwiindawo ezingekho esibhedlele), ngaloo ndlela zinciphisa umthwalo kwinkqubo yokhathalelo lwempilo kunye nezibonelelo, ukuyeka ukuqhubeka kwekliniki yesifo kubunzima ukuba zithathwe ngexesha (kwisithuba seentsuku ezintlanu ukuqala kwesifo) kunye nokuthintela ukufa, kwaye zisebenza ngokuchasene neendidi ezininzi zekoronavirus, kubandakanywa ii-VOCs. 

Ubhubhani we-COVID-19 ubulale abantu abangaphezu kwezigidi ezi-5 ukusukela ngoMatshi ka-2020, ngamatyala angaphezulu kwezigidi ezingama-252 kwihlabathi liphela kwaye sele efumene umthwalo ongazange ubonwe ngaphambili kwezezimali noqoqosho.  

Intshayelelo yogunyaziso olungxamisekileyo lwezitofu zokugonya oludityaniswe nephulo elikhulu lokugonya linciphise ngokubonakalayo ukusweleka ukuya malunga ne-10% yento ebibonwa ngamaxesha aphambi kogonyo. Nangona kunjalo, ubhubhane awubonakali ngathi usondele esiphelweni njengoko kubonakala kwidatha ekhankanywe kwiTheyibhile yoku-I.  

Ngapha koko, amazwe aliqela okwangoku, abonakala ekwindawo yesithathu. Amatyala e-COVID-19 kulo lonke elaseYurophu sele eqalisile ukufikelela kumanqanaba erekhodi, esenza lo mmandla ube ngubhubhani wobhubhane. Kwiiveki ezimbalwa ezidlulileyo, iYurophu kunye noMbindi we-Asiya zibone ukonyuka kwe-6% kunye ne-12% yonyuka ngokulandelelana, kwinani lamatyala e-COVID-19. Kule nyanga iphelileyo, lo mmandla uye wajongana nokunyuka okungaphezulu kwe-55% kumatyala amatsha e-COVID-19 ebalelwa kuma-59% azo zonke iimeko kwihlabathi jikelele kunye ne-48% yokusweleka okuxeliweyo.¹ Imeko kumazwe akuMbindi naseMpuma Yurophu afana neRomania, Bulgaria, Ukraine njl. njl  

Imeko e-USA isekude ukuba yanelise. E-China, kukho iingxelo zemithombo yeendaba zokubiyelwa kwe-Beijing njengesilumkiso malunga nokuqhambuka kwamaphondo aliqela elizweni. Nangona inqanaba lokugonya eliphunyeziweyo, ukuba ezi zikhokelo zangoku zikho naziphi na iimpawu, kubonakala ngathi akukho siqinisekiso, ukuba yonke imimandla yehlabathi ayiyi kubona imeko efana nale siyibonayo eYurophu nakuMbindi Asia ngoku, kwixesha elizayo elibonakalayo. 

Ngale mvelaphi, izibhengezo zakutsha nje zeziphumo ezikhuthazayo zolingo lwezonyango lweepilisi ezimbini ezintsha ze-antiviral (i-Merck's Molnupiravir kunye ne-Pfizer's Paxlovid) ngokuchasene ne-COVID-19 kunye nokwamkelwa okukhawulezileyo kwe-Molnupiravir e-UK kuzuza ukubaluleka njengomgca wesibini ofumaneka ngomlomo. yokhuseleko (emva kokugonywa) kumatyala asandul 'ukuxilongwa ngokuchasene nokuqhubela phambili kweempawu zesifo, ngokuthintela iimfuno zokulaliswa esibhedlele okanye nokufa.  

Iindlela zangoku zokujongana nobhubhane  

IiCoronaviruses zibonisa amazinga aphezulu ngokumangalisayo eempazamo ngexesha lokuphindaphinda (ngenxa yokungabikho kokuvavanywa kwemisebenzi ye-nuclease yeepolymerase zazo) ezihlala zingalungiswanga kwaye ziqokelelana ukuze zisebenze njengomthombo wokwahluka. Ugqithiso olungakumbi, iimpazamo eziphindaphindwayo kunye nokwanda kotshintsho kwigenome, okukhokelela ekuveleni kwezinto ezintsha ezahlukeneyo. Kungoko, izithintelo zentlalo zokunciphisa usulelo kubalulekile kuthintelo lwamatyala amatsha kunye nokuthintela ukuvela kwezinto ezintsha ezahlukeneyo. Ukuza kuthi ga ngoku, ukugonywa kubonise isithembiso esikhulu ekuthinteleni iimpawu zesifo kunye nokuqhubela phambili ngokukrakra, okudinga ukulaliswa esibhedlele. Kumazwe anamazinga aphezulu ogonyo umz., e-UK, amazinga okusweleka asezantsi ukuya malunga ne-10% yezinto ebezibonwa kumaza angaphambili. Ukanti, uninzi lwabantu lufuna ukulaliswa esibhedlele.  

Kwiimeko ezinobuthathaka ukuya kumaqatha, iindlela ezahlukeneyo ziye zazanywa. Iimeko ezinzima ngokuphakathi zifuna inkxaso ye-oxygen, ngelixa iimeko ezinzima zifuna intubation ngokhathalelo olunzulu. I-Dexamethasone ifunyaniswa inexabiso eliphezulu kakhulu kwiimeko ezinzima zokulaliswa esibhedlele. I-antiviral, i-remdesivir ibonakala isebenza kodwa iyabiza, kwaye kungoko ayinakwenzeka ukuba ibe lunyango oluneendleko eziphezulu ze-COVID-19.².  

Ii-Antivirals ze-COVID-19 ziwela kumaqela amathathu (jonga inqaku elingu-1 kwiTheyibhile II ngasentla). Iqela lokuqala liqulathe amachiza afana ne-Umifenovir (ngoku esetyenziswa kunyango lomkhuhlane eRashiya nase China) inqanda ukungena kwentsholongwane kwiiseli zomntu ngelixa iqela lesibini libandakanya iintsholongwane zeRNA inhibitors ezifana neRemdesivir, Favipiravir kunye neMolnupiravir zisebenza njenge analogue ye-nucleoside ekhuphisanayo. kubangela ukuguqulwa kwezinto ezininzi ezingenangqondo (i-RNA mutagenesis), ngaloo ndlela iphazamisa ukuphindaphinda kwentsholongwane. Iqela lesithathu leleentsholongwane ze-protease inhibitors ezifana ne-lopinavir/ritonavir, PF-07321332, kunye ne-PF-07304814 ezivimba i-enzayim yentsholongwane ye-protease ngokwenza oko ikhubaze iintsholongwane zenze iintsholongwane ezintsha, ngaloo ndlela yehlisa umthamo wentsholongwane.  

Ngaphandle kweziqendu ezininzi zangaphambili zendyikityha yomkhuhlane kunye nokuqhambuka ezibini zekoronavirus (ukuqhambuka kuka-2003 e-China okubangelwa kukuqhambuka kwe-SARS-CoV kunye ne-MERS ka-2012), lichiza elinye kuphela le-antiviral (Remdesivir) eliye labona ukukhanya kwemini kwaye linokuba lelinye. uncedo kwindyikityha yangoku, nangona yaphuhliswa ekuqaleni ukunyanga iHepatitis C kunye ne-Ebola. I-Remdesivir ibiluncedo ekunyangeni abaguli be-COVID-19 abaneempawu eziqatha kwiindawo zasesibhedlele, kodwa kubiza kakhulu kwaye ke ayinikezeli ngonyango olufikelelekayo ngexabiso eliphantsi. 

Isidingo seyure ngamachiza anokuthintela ukuqhubeka kwezonyango kumatyala amatsha e-COVID-19 ukusuka ekubeni kungabikho zimpawu ukuya kumbi ukuya phakathi okanye kuqatha, ngaloo ndlela kuncitshiswa isidingo sokulaliswa esibhedlele kunye nokuthintela ukusweleka okunxulumene ne-COVID.  

I-Molnupiravir kunye ne-PF-07321332, amachiza amabini achasene nentsholongwane egazini abonisa isithembiso ekunqandeni ukuqhubeka kwekliniki kwiimeko ezingabonakaliyo okanye ezibuthathaka.  

IiCoronavirus zisebenzisa i-RNA exhomekeke kwi-RNA polymerase (RdRp) ukuphindaphinda kunye nokushicilelwa kwe-RNA genome yabo eyenza i-RdRp ibe yeyona nto ibalulekileyo ekujoliswe kuyo kumachiza e-antiviral ngokuchasene ne-coronavirus.⁴.  

I-Molnupiravir, inhibitor ye-viral RNA polymerase, i-nucleoside analogue ekhuphisanayo kwi-viral RNA exhomekeke kwi-RNA polymerase, ebangela ukuguqulwa kwezinto ezininzi ezingenangqondo kubangela i-RNA mutagenesis. Yonyusa ukuphindaphindwa kweentsholongwane ze-RNA kwaye iphazamise ukuphindaphinda kwe-SARS-CoV-2. Ithintela ukuphindaphinda kwentsholongwane ngendlela eyaziwa ngokuba yi-'lethal mutagenesis'. I-Molnupiravir iphazamisa ukuthembeka kwe-SARS-CoV-2 genome replication kwaye inqande ukwanda kwentsholongwane ngokukhuthaza ukuqokelelana kwempazamo kwinkqubo ebizwa ngokuba 'yintlekele yempazamo'. ^4,5.  

I-Molnupiravir, ephuhliswe yi-Ridgeback therapeutics kunye ne-MSD (Merck) njengegama lokurhweba i-Lagevrio, imveliso ye-ß-D-N4-hydroxycytidine kwaye ibonakaliswe ukunciphisa ukuphindaphinda kwentsholongwane ka-100,000 kwiimpuku ezenziwe ukuba zibe nezicubu zemiphunga yomntu.⁶. Kwimeko yeeferrets, i-molnupiravir ayinciphisi nje kuphela iimpawu, kodwa ikhokelele ekosulelekeni yintsholongwane iqanda kwiiyure ezingama-24.⁶. I-Molnupiravir yanyanyezelwa kakuhle ngaphandle kweziganeko ezimbi kakhulu kwi-randomized, double-blind-blind, placebo-controlled, First-in-Human study eyenzelwe ukuvavanya ukhuseleko, ukunyamezela, kunye ne-pharmacokinetics yechiza, emva kokulawulwa komlomo kumavolontiya anempilo ngokupheleleyo. kwizifundo ezili-130^7,8. Kwinqanaba lesi-2/3 lolingo lwezonyango, iLagevrio yafunyaniswa isebenza kakuhle ekunciphiseni umngcipheko wokulaliswa esibhedlele okanye ukubhubha kwabantu abadala abangalaliswanga esibhedlele abanobuthathaka ukuya kwimodareyitha ye-COVID-19 ngama-50%.⁹. ILagevrio lichiza lokuqala elivunyiweyo lehlabathi elichasene nentsholongwane egazini elinokuthi lithathwe ngomlomo kunokuba lifakwe emithanjeni. Oku kubalulekile njengoko kunokulawulwa kwindawo engeyoyasesibhedlele, phambi kokuba i-COVID-19 iqhubele phambili ukuya kwinqanaba eliqatha. Kufuneka ithathwe ngokukhawuleza emva kovavanyo lwe-COVID-19 kwaye kwisithuba seentsuku ezintlanu zokuqala kweempawu. Nangona kunjalo, ayinakuthathwa njengento ethatha indawo yogonyo, kungoko iphulo lokugonya kufuneka liqhubeke. 

I-Paxlovid (PF-07321332) kwelinye icala, isebenza ngendlela yokuthintela i-viral protease SARS-CoV-2-3CL protease, i-enzyme ekufuneka iphindaphindwe yi-coronavirus. Isetyenziswa nokuba yodwa okanye kudityaniswe nedosi ephantsi ye-ritonavir.  

I-Ritonavir yi-HIV protease inhibitor, idla ngokusetyenziswa kunye nezinye ii-protease inhibitors njengenxalenye yonyango lwe-antiretroviral olusebenza kakhulu kwi-HIV, njengoko ithintela ukumetabolzeka kwesibindi kwiqabane lechiza.  

Ngokusekwe kuhlalutyo lwethutyana lweSigaba sesi-2/3 se-EPIC-HR (uVavanyo lwe-Protease Inhibition ye-COVID-19 kwizigulana ezikuMngcipheko oPhezulu)¹⁰ Uphononongo olungacwangciswanga, oluyimfama oluphindwe kabini lwabaguli abangalaliswanga esibhedlele abane-COVID-19, abasemngciphekweni omkhulu wokuqhubela phambili kwisigulo esiqatha, uPaxlovid ubonise ukuncipha kwe-89% kumngcipheko wokulaliswa esibhedlele okanye ukufa okunxulumene ne-COVID-19 xa kuthelekiswa ne-placebo kwizigulana. unyango phakathi kweentsuku ezintathu zokuqala kweempawu. Iziganeko ezimbi ezinxulumene ne-Paxlovid zazithelekiseka nezo ze-placebo kwaye zincinci kakhulu. 

Olunye uncedo lwePaxlovid kukuba ibonise umsebenzi onamandla we-antiviral in vitro ngokuchasene nokujikeleza okwahluka kwenkxalabo (VOCs), kunye nezinye ii-coronavirus ezaziwayo. I-Paxlovid ke inokubanakho ukusetyenziswa njengonyango kwiindidi ezininzi zosulelo lwe-coronavirus.  

Akuzukuthatha xesha lide ngaphambi kokuba sibone imvume yePaxlovid kunye nearhente yonyango kumlo ochasene ne-COVID-19. 

Ngelixa i-Molnupiravir iyi-nucleoside analogue ephazamisana nokuphindaphindwa kwe-RNA yentsholongwane, i-Paxlovid sisithinteli se-3CL protease, i-enzyme efunekayo kuphindaphindo lwe-coronavirus. 

Imibuzo ephambili ephakanyisiweyo kuwo omabini la mayeza omlomo achasene nentsholongwane iya kujikeleza ukusebenza kwawo, ukhuseleko, nokuba aya kusebenza na ngokuchasene nezinto ezikhoyo nezizayo, uphuhliso lokunganyangeki kula machiza kunye nokufikeleleka kwawo kumazwe ahlwempuzekileyo.¹¹. Ngelixa zombini i-Molnupiravir kunye ne-Paxlovid ziqhuba kakuhle kwiimpendulo zemibuzo emithathu yokuqala, kuya kubaluleka ukuhlalutya abantu abangaphenduliyo nakweliphi na lachiza ukuthintela ukuxhathiswa yintsholongwane kunye nokubeka iliso kubantu abane-immune system ebuthathaka kwaye balawulwa ezi. amayeza onyango lwe-COVID-19. Ngaphandle kokunganyangeki kwentsholongwane, ukufikeleleka kwala machiza kumazwe ehlabathi lesithathu kuya kubangela isoyikiso esikhulu sokunciphisa ubhubhane njengoko la mazwe esenokungakwazi ukufikelela okufanayo, umzekelo, unyango lweMolnupiravir luxabisa i-USD 700 yesigulana ngasinye ngelixa elo likaPaxlovid lihlala linjalo. ingabonwa kodwa inokuba kwipaki enye yebhola. Omnye umceli mngeni unokuthi amazwe atyebileyo natyebileyo anokuqalisa ukugcina iidosi kubantu bawo, enze ukufikelela kube nzima kubo bonke. Nokuba umntu wenza ukuba iyeza (i-molnupiravir) lifumaneke kumazwe ahlwempuzekileyo, basenokungabi nawo amandla okuxilonga ukunyanga abaguli nge-molnupiravir kwangethuba lokugula kwabo, xa unyango lunokusebenza kakhulu.¹². 

Nangona kunjalo, la mayeza mabini achasene nentsholongwane yentsholongwane abonakala enamandla amakhulu kunyango lwe-COVID-19 kwaye anokunceda ukukhawulezisa ukuphela kobhubhane kwakamsinya, eshiya i-COVID-19 njengesifo esineziphumo ezincinci. 

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

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Iingxelo:  

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8. I-ClinicalTrial.gov 2021. I-Randomized, i-Double-Blind, i-Placebo-Controlled, i-First-in-Human Study eyenzelwe ukuHlola uKhuseleko, ukunyamezela, kunye ne-Pharmacokinetics ye-EIDD-2801 elandela uLawulo loMlomo kumaVolontiya aphilileyo. Umxhasi: Ridgeback Biotherapeutics, LP. Isazisi seClinicalTrials.gov: NCT04392219. Iyafumaneka kwi-intanethi https://clinicaltrials.gov/ct2/show/NCT04392219?term=NCT04392219&draw=2&rank=1 Ifikeleleke nge-20 ka-Epreli 2021. 

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