{"id":28636,"date":"2024-03-28T04:32:29","date_gmt":"2024-03-28T04:32:29","guid":{"rendered":"https:\/\/fipmed.co\/molnupiravir-as-a-third-antiviral-drug-for-treatment-of-fip\/"},"modified":"2024-03-28T04:32:29","modified_gmt":"2024-03-28T04:32:29","slug":"molnupiravir-as-a-third-antiviral-drug-for-treatment-of-fip","status":"publish","type":"page","link":"https:\/\/fipmed.co\/sk\/molnupiravir-as-a-third-antiviral-drug-for-treatment-of-fip\/","title":{"rendered":"Molnupiravir ako tret\u00ed antivirotikum na lie\u010dbu FIP"},"content":{"rendered":"

Mnoh\u00ed majitelia ma\u010diek s FIP zva\u017euj\u00fa pri lie\u010dbe svojej ma\u010dky pou\u017eitie molnupiraviru aj GS441524.
\nPravdou je, \u017ee obe mo\u017enosti lie\u010dby s\u00fa \u00fa\u010dinn\u00e9 pri lie\u010dbe FIP a zabra\u0148uj\u00fa replik\u00e1cii v\u00edrusu.
\nMolnupiravir je v\u0161ak vysoko cytotoxick\u00fd, \u010do z neho rob\u00ed ve\u013emi d\u00e1nsky liek na v\u00fdber, najm\u00e4 ak potrebujete svoju ma\u010dku lie\u010di\u0165 12 t\u00fd\u017ed\u0148ov, vystavova\u0165 ju tak dlho vysoko toxick\u00e9mu lieku sa neodpor\u00fa\u010da. <\/span><\/span><\/p>\n

Ni\u017e\u0161ie je uveden\u00e1 spr\u00e1va „Molnupiravir ako tret\u00ed antiv\u00edrusov\u00fd liek na lie\u010dbu FIP“ od Dr. <\/span><\/span>Nielsa C. Pedersena DVM, PhD. na <\/span><\/i>20. okt\u00f3bra 2021 <\/span><\/i> <\/strong><\/p>\n

 <\/p>\n

Beta-d-N4-hydroxycytid\u00edn, pro-lie\u010divo molnupiraviru <\/span>, je mal\u00e1 molekula (nukleozid), ktor\u00e1 bola sk\u00faman\u00e1 koncom 70. rokov v b\u00fdvalom Sovietskom zv\u00e4ze ako s\u00fa\u010das\u0165 v\u00fdskumu biologick\u00fdch zbran\u00ed [2].
\nZbrane proti chorob\u00e1m, ako s\u00fa kiahne, boli celosvetovou obavou, ale nebezpe\u010denstvo pou\u017eitia v\u00edrusu kiahn\u00ed na tento \u00fa\u010del bolo pr\u00edli\u0161 ve\u013ek\u00e9.
\nKiahne boli vo svete vyhuben\u00e9, prakticky v\u0161etky z\u00e1soby zni\u010den\u00e9 a \u010fal\u0161\u00ed v\u00fdskum bol zak\u00e1zan\u00fd.
\nTo viedlo USA aj Sovietsky zv\u00e4z k v\u00fdskumu in\u00fdch RNA v\u00edrusov ako biologick\u00fdch zbran\u00ed a antivirot\u00edk na obranu proti nim.
\nV\u00edrus venezuelskej encefalomyelit\u00eddy kon\u00ed (VEEV) bol jedn\u00fdm z prv\u00fdch v\u00edrusov, o ktor\u00fdch sa v\u00e1\u017ene uva\u017eovalo ako o biologickej zbrani [3].
\nVEEV sa pren\u00e1\u0161a na \u010dloveka u\u0161tipnut\u00edm kom\u00e1rom a sp\u00f4sobuje vysok\u00fa hor\u00fa\u010dku, bolesti hlavy a encefalit\u00eddu a opuch, ktor\u00fd m\u00f4\u017ee by\u0165 smrte\u013en\u00fd.
\nZistilo sa, \u017ee beta-d-N4-hydroxycytid\u00edn inhibuje nielen replik\u00e1ciu VEEV, ale aj \u0161irok\u00fa \u0161k\u00e1lu alfav\u00edrusov vr\u00e1tane eboly, chikungunya, v\u00edrusu chr\u00edpky, norov\u00edrusu, v\u00edrusu hna\u010dky hov\u00e4dzieho dobytka, v\u00edrusu hepatit\u00eddy C a respira\u010dn\u00e9ho syncyci\u00e1lneho v\u00edrusu. [3-8].
\nNajstar\u0161ia spr\u00e1va o inhibi\u010dnom \u00fa\u010dinku beta-d-N4-hydroxycytid\u00ednuna <\/span>\u013eudsk\u00fd koronav\u00edrus NL63 poch\u00e1dza z roku 2006 [9].
\nNed\u00e1vne \u0161t\u00fadie potvrdili jeho inhibi\u010dn\u00fd \u00fa\u010dinok na \u0161irok\u00fa \u0161k\u00e1lu \u013eudsk\u00fdch a zvierac\u00edch koronav\u00edrusov [8]. <\/span><\/p>\n

D\u00f4le\u017eit\u00e1 \u010das\u0165 nov\u0161ej hist\u00f3rie beta-d-N4-hydroxycytid\u00ednu poch\u00e1dza z Emoryho in\u0161tit\u00fatu pre v\u00fdvoj liekov (EIDD) [1] a jeho experiment\u00e1lne ozna\u010denie bolo EIDD-1931.
\nV\u00fdznamn\u00fa finan\u010dn\u00fa podporu \u0161t\u00fadi\u00e1m antivirot\u00edk proti alfav\u00edrusom na in\u0161tit\u00faci\u00e1ch, ako je Emory, poskytla vl\u00e1da USA u\u017e v roku 2004, pri\u010dom zna\u010dn\u00fa finan\u010dn\u00fa podporu m\u00e1 aj s\u00fa\u010dasn\u00e1 [10].
\nAgent\u00fara pre zni\u017eovanie obrann\u00fdch hrozieb poskytla in\u0161titucion\u00e1lnu podporu v roku 2014 s cie\u013eom n\u00e1js\u0165 antiv\u00edrusov\u00fa zl\u00fa\u010deninu proti VEEV a in\u00fdm alfakorav\u00edrusom.
\n„N4-hydroxycytid\u00edn a deriv\u00e1ty a s nimi s\u00favisiace antiv\u00edrusov\u00e9 pou\u017eitia“ boli v roku 2016 zahrnut\u00e9 do patentovej prihl\u00e1\u0161ky USA 2016\/106050 A1 [11].
\n\u010eal\u0161ie finan\u010dn\u00e9 prostriedky pri\u0161li v roku 2019 z N\u00e1rodn\u00e9ho in\u0161tit\u00fatu pre alergie a infekcie na partnersk\u00fd v\u00fdskum esterifikovan\u00e9ho prolie\u010diva beta-d-N4-hydroxycytid\u00ednu (EIDD-2801) na lie\u010dbu chr\u00edpky [10].
\nDeklarovan\u00fdm z\u00e1merom chemick\u00fdch \u00faprav lieku EIDD-2801 bolo zv\u00fd\u0161i\u0165 jeho peror\u00e1lnu biologick\u00fa dostupnos\u0165, \u010do by v kone\u010dnom d\u00f4sledku umo\u017enilo beta-d-N4-hydroxycytid\u00ednu <\/span><\/span>sa pod\u00e1vaj\u00fa vo forme tabliet a nie injekci\u00ed.
\nV rokoch 2019\/2020 do\u0161lo k zmene d\u00f4razu v\u00fdskumu z chr\u00edpky na SARS-II CoV [2].
\nKomercializ\u00e1cia EIDD-2801 bola zveren\u00e1 pobo\u010dke Emory s n\u00e1zvom Ridgeway Biotherapeutics, ktor\u00e1 potom spolupracovala so spolo\u010dnos\u0165ou Merck na zd\u013ahavom a n\u00e1kladnom schva\u013eovacom procese FDA.
\nS\u00fa\u010dasn\u00e1 verzia EIDD-2081 ur\u010den\u00e1 na testovanie v ter\u00e9ne dostala n\u00e1zov Molnupiravir. <\/span><\/p>\n

Beta-d-N4-hydroxycytid\u00edn, \u00fa\u010dinn\u00e1 l\u00e1tka molnupiraviru <\/span>, existuje v dvoch form\u00e1ch ako tautom\u00e9ry.
\nV jednej forme napodob\u0148uje cytid\u00edn s jedinou v\u00e4zbou medzi uhl\u00edkom a skupinou N-OH.
\nVo svojej druhej forme, ktor\u00e1 napodob\u0148uje urid\u00edn, m\u00e1 oxim s dvojitou v\u00e4zbou medzi uhl\u00edkom a skupinou N-OH.
\nV pr\u00edtomnosti beta-d-N4-hydroxycytid\u00ednu ho v\u00edrusov\u00e1 RNA-dependentn\u00e1 RNA polymer\u00e1za \u010d\u00edta ako urid\u00edn namiesto cytid\u00ednu a namiesto guanoz\u00ednu vklad\u00e1 adenoz\u00edn.
\nPrep\u00ednanie medzi formami sp\u00f4sobuje nes\u00falad po\u010das transkripcie, \u010do vedie k po\u010detn\u00fdm mut\u00e1ci\u00e1m vo v\u00edrusovom gen\u00f3me a k zastaveniu v\u00edrusovej replik\u00e1cie [8]. <\/span><\/p>\n

Spolo\u010dnos\u0165 Merck ur\u00fdchlila postup spolo\u010dnosti Molnupiravir na podmiene\u010dn\u00e9 a \u00fapln\u00e9 schv\u00e1lenie zo strany FDA.
\nVo vyhl\u00e1sen\u00ed spolo\u010dnosti Merck sa uv\u00e1dza toto: [12] – „V o\u010dak\u00e1van\u00ed v\u00fdsledkov <\/i>2 <\/span><\/p>\n

od spolo\u010dnosti MOVe-OUT, Merck vyr\u00e1ba molnupiravir s rizikom. Spolo\u010dnos\u0165 Merck o\u010dak\u00e1va, \u017ee do konca roka 2021 vyrob\u00ed 10 mili\u00f3nov lie\u010debn\u00fdch d\u00e1vok, pri\u010dom \u010fal\u0161ie d\u00e1vky by sa mali vyrobi\u0165 v roku 2022. ……. . Spolo\u010dnos\u0165 Merck sa zaviazala poskytn\u00fa\u0165 v\u010dasn\u00fd pr\u00edstup k lieku Molnupiravir na celom svete, ak bude povolen\u00fd alebo schv\u00e1len\u00fd, a pl\u00e1nuje zavies\u0165 odstup\u0148ovan\u00fd pr\u00edstup k cen\u00e1m na z\u00e1klade krit\u00e9ri\u00ed pr\u00edjmov kraj\u00edn Svetovej banky, aby sa zoh\u013eadnila relat\u00edvna schopnos\u0165 kraj\u00edn financova\u0165 svoju reakciu v oblasti zdravotn\u00edctva na pand\u00e9miu. …… . V r\u00e1mci svojho z\u00e1v\u00e4zku zabezpe\u010di\u0165 \u0161irok\u00fd glob\u00e1lny pr\u00edstup spolo\u010dnos\u0165 Merck predt\u00fdm ozn\u00e1mila, \u017ee uzavrela nev\u00fdhradn\u00e9 dobrovo\u013en\u00e9 licen\u010dn\u00e9 zmluvy na molnupiravir so zaveden\u00fdmi v\u00fdrobcami gener\u00edk s cie\u013eom ur\u00fdchli\u0165 dostupnos\u0165 molnupiraviru vo viac ako 100 krajin\u00e1ch s n\u00edzkymi a stredn\u00fdmi pr\u00edjmami (LMIC) po schv\u00e1len\u00ed alebo mimoriadnom povolen\u00ed miestnymi regula\u010dn\u00fdmi org\u00e1nmi.“ <\/i>Je nepravdepodobn\u00e9, \u017ee by sa t\u00e1to „ve\u013ekorysos\u0165“ vz\u0165ahovala aj na pou\u017e\u00edvanie zvierat. <\/span><\/p>\n

Lieky na potla\u010denie p\u00f4vodcu s\u00fa\u010dasnej pand\u00e9mie Covid-19 boli v posledn\u00fdch dvoch rokoch r\u00fdchlo testovan\u00e9 v praxi a jeden z nich, Remdesivir, bol v rekordne kr\u00e1tkom \u010dase schv\u00e1len\u00fd pre hospitalizovan\u00fdch pacientov.
\nMolnupiravir bol v priebehu minul\u00e9ho roka posunut\u00fd k podmiene\u010dn\u00e9mu schv\u00e1leniu ako peror\u00e1lny liek na dom\u00e1cu lie\u010dbu v\u010dasn\u00e9ho \u0161t\u00e1dia infekcie [12].
\n\u00da\u010dinn\u00e9 antikoronav\u00edrusov\u00e9 zl\u00fa\u010deniny v\u0161ak boli vyvinut\u00e9 u\u017e sk\u00f4r na in\u00e9 be\u017en\u00e9 a ve\u013emi roz\u0161\u00edren\u00e9 ochorenie ma\u010diek, ma\u010daciu infek\u010dn\u00fa peritonit\u00eddu (FIP).
\nMedzi tieto lieky patr\u00ed inhib\u00edtor prote\u00e1zy (GC376) [13] a inhib\u00edtor RNA dependentnej RNA polymer\u00e1zy (GS-441524), ktor\u00fd je akt\u00edvnou \u010das\u0165ou lieku Remdesivir [14].
\n\u00daspech lie\u010dby FIP antiv\u00edrusov\u00fdmi liekmi podnietil ned\u00e1vnu \u0161t\u00fadiu EIDD-1931 aj EIDD-2801 na ich schopnos\u0165 inhibova\u0165 FIPV v tkanivovej kult\u00fare [15].
\n\u00da\u010dinn\u00e1 koncentr\u00e1cia 50 % (EC50) pre EIDD-1931 proti FIPV je 0,09 uM, EIDD-2801 0,4 uM a GS-441524 0,66 Um [15]. Percento cytotoxicity pri 100 uM je pre tieto zl\u00fa\u010deniny 2,8, 3,8 a 0.
\nPreto s\u00fa EIDD-1931 a -2801 o nie\u010do viac inhibi\u010dn\u00e9 vo\u010di v\u00edrusom, ale aj cytotoxickej\u0161ie ako GS-441524. <\/strong> Tieto laborat\u00f3rne \u0161t\u00fadie nazna\u010duj\u00fa, \u017ee EIDD-1931 aj EIDD-2801 s\u00fa tie\u017e vynikaj\u00facimi kandid\u00e1tmi na lie\u010dbu FIP. <\/span><\/p>\n

Hoci s\u00fa EIDD-1931 a EIDD-2801 ve\u013ek\u00fdm pr\u00eds\u013eubom pre lie\u010dbu FIP, existuje nieko\u013eko prek\u00e1\u017eok, ktor\u00e9 sp\u00f4sobuj\u00fa, \u017ee leg\u00e1lne pou\u017eitie t\u00fdchto zl\u00fa\u010den\u00edn je v doh\u013eadnej dobe nepravdepodobn\u00e9.
\nGS-441524, akt\u00edvna forma Remdesiviru, patentovan\u00e1 spolo\u010dnos\u0165ou Gilead Sciences, bola sk\u00faman\u00e1 na pou\u017eitie u ma\u010diek s FIP kr\u00e1tko pred vypuknut\u00edm pand\u00e9mie Covid-19.
\nPreto to bolo potenci\u00e1lne pou\u017eitie Remdesiviru proti v\u00edrusu Ebola a nie proti koronav\u00edrusom podobn\u00fdm SARS, ktor\u00e9 podnietilo v\u00fdskum FIP [14].
\nHoci sa tieto \u0161t\u00fadie uskuto\u010dnili v spolupr\u00e1ci s vedcami zo spolo\u010dnosti Gilead Science, spolo\u010dnos\u0165 odmietla pr\u00e1va na zvierat\u00e1 pre GS-441524, ke\u010f sa uk\u00e1zalo, \u017ee pre Covid-19 existuje ove\u013ea v\u00e4\u010d\u0161\u00ed trh u \u013eud\u00ed [16].
\nPodobne moje pokusy o v\u00fdskum EIDD-1931 a EIDD-2801 pre FIP u ma\u010diek, ktor\u00e9 som v posledn\u00fdch 2 – 3 rokoch adresoval spolo\u010dnostiam Emory, Ridgeback Biotherapeutics a veterin\u00e1rnej div\u00edzii spolo\u010dnosti Merck, zostali bez odpovede alebo boli zamietnut\u00e9, nepochybne z podobn\u00fdch d\u00f4vodov, pre ktor\u00e9 spolo\u010dnos\u0165 Gilead odmietla udeli\u0165 pr\u00e1va na zvierat\u00e1 pre GS-441524.
\nVe\u013ek\u00e1 celosvetov\u00e1 potreba lie\u010dby FIP v\u0161ak r\u00fdchlo podporila neschv\u00e1len\u00fd trh pre GS-441524 z \u010c\u00edny.
\nRovnak\u00e1 potreba lie\u010dby FIP ned\u00e1vno podnietila z\u00e1ujem o molnupiravir ako lie\u010dbu FIP, tie\u017e z \u010c\u00edny. <\/span><\/p>\n

Situ\u00e1cia s liekmi EIDD-1931 a EIDD-2801\/Molnupiravir a GS-441524 a Remdesivir vyvol\u00e1va ot\u00e1zku, pre\u010do sa niektor\u00e9 lieky na \u00fa\u010dely uvedenia na trh menia na prolie\u010div\u00e1 [17]. Remdesivir bol \u00fadajne esterifikovan\u00fd s cie\u013eom zv\u00fd\u0161i\u0165 antiv\u00edrusov\u00fa aktivitu, hoci \u0161t\u00fadie na ma\u010dk\u00e1ch uk\u00e1zali, \u017ee GS-441524 a Remdesivir mali podobn\u00fa inhibi\u010dn\u00fa aktivitu vo\u010di v\u00edrusom v tkanivov\u00fdch kult\u00farach [18]. Zistilo sa v\u0161ak, \u017ee Remdesivir sa peror\u00e1lnou cestou zle vstreb\u00e1va, a preto bol podmiene\u010dne schv\u00e1len\u00fd len na injek\u010dn\u00e9 pod\u00e1vanie. EIDD-2801 bol vytvoren\u00fd na zlep\u0161enie peror\u00e1lnej absorpcie EIDD-1931, hoci predch\u00e1dzaj\u00faci v\u00fdskum nazna\u010dil, \u017ee EIDD-1931 sa dobre absorbuje peror\u00e1lne bez esterifik\u00e1cie [6]. Mot\u00edvy komercializ\u00e1cie lieku Remdesivir namiesto lieku GS-441524 na pou\u017eitie u \u013eud\u00ed boli vedecky spochybnen\u00e9, ke\u010f\u017ee sa zd\u00e1, \u017ee druh\u00fd menovan\u00fd je vo viacer\u00fdch oh\u013eadoch lep\u0161\u00ed bez \u010fal\u0161\u00edch \u00faprav [17]. Pre\u010do bol EIDD-2801 navrhnut\u00fd na komercializ\u00e1ciu, ke\u010f EIDD-1931 by bol lacnej\u0161\u00ed, 4-kr\u00e1t viac inhibuje v\u00edrusy a je o tretinu menej toxick\u00fd ako EIDD-2801 [15]? Sila patentov\u00fdch pr\u00e1v a d\u013a\u017eka trvania patentu m\u00f4\u017eu by\u0165 pri tomto rozhodovan\u00ed presved\u010divej\u0161\u00edmi faktormi [16, 17, 19]. <\/span><\/p>\n

Jedn\u00fdm z probl\u00e9mov pri lie\u010dbe FIP u ma\u010diek je bari\u00e9ra medzi krvou a okom a krvou a mozgom, ktor\u00e1 m\u00e1 ve\u013ek\u00fd v\u00fdznam, ke\u010f choroba postihne o\u010di a\/alebo mozog [13, 14, 20].
\nTento probl\u00e9m sa pri lie\u010dbe o\u010dn\u00fdch a neurologick\u00fdch foriem FIP pomocou GS-441524 z ve\u013ekej \u010dasti prekonal postupn\u00fdm zvy\u0161ovan\u00edm d\u00e1vky s cie\u013eom zv\u00fd\u0161i\u0165 hladinu v krvi, a t\u00fdm aj koncentr\u00e1ciu lie\u010diva vo vodnom moku a\/alebo v mozgu [20]. GC376, jedno z najsilnej\u0161\u00edch antivirot\u00edk proti v\u00edrusu FIP v kult\u00fare [17], nie je \u00fa\u010dinn\u00e9 proti o\u010dnej a neurologickej forme FIP<\/strong>, preto\u017ee sa do t\u00fdchto miest nedok\u00e1\u017ee dosta\u0165 dostatok lie\u010diva ani pri nieko\u013ekon\u00e1sobnom zv\u00fd\u0161en\u00ed d\u00e1vky [14].
\nNa\u0161\u0165astie sa zd\u00e1, \u017ee EIDD-1931 m\u00f4\u017ee dosiahnu\u0165 \u00fa\u010dinn\u00e9 hladiny v mozgu, ako nazna\u010duj\u00fa \u0161t\u00fadie na ko\u0148och s infekciou VEEV [3].
\nRezistencia na liek je \u010fal\u0161\u00edm probl\u00e9mom, ktor\u00fd sa v s\u00fa\u010dasnosti pozoruje u niektor\u00fdch ma\u010diek lie\u010den\u00fdch liekom GS-441524, najm\u00e4 u jedincov s neurologickou formou FIP.
\nDlh\u00e9 trvanie lie\u010dby a \u0165a\u017ekosti pri prenikan\u00ed dostato\u010dn\u00e9ho mno\u017estva lie\u010diva do mozgu podporuj\u00fa vznik rezistencie na lie\u010divo. <\/span><\/p>\n

Kr\u00e1tkodob\u00fd a dlhodob\u00fd toxick\u00fd \u00fa\u010dinok kandid\u00e1tskeho lieku na testovan\u00fa osobu alebo zviera je mimoriadne d\u00f4le\u017eit\u00fd.
\nGS-441524 m\u00e1 ni\u017e\u0161iu toxicitu ako GC376, EIDD-1931 a EIDD-2801 v bunkov\u00fdch kult\u00farach [15].
\nNajd\u00f4le\u017eitej\u0161ia je v\u0161ak toxicita, ktor\u00e1 sa vyskytuje in vivo <\/i>. GC376 patr\u00ed medzi lieky s najv\u00e4\u010d\u0161ou zn\u00e1mou inhib\u00edciou koronav\u00edrusov [15], ale pri pod\u00e1van\u00ed mlad\u00fdm ma\u010diatkam spomal\u00ed rast dospel\u00e9ho chrupu [13].<\/strong> Po\u010das takmer troch rokov pou\u017e\u00edvania lieku GS-441524 v ter\u00e9ne nebola pozorovan\u00e1 \u017eiadna z\u00e1va\u017en\u00e1 toxicita, \u010do odr\u00e1\u017ea \u00fapln\u00fa absenciu cytotoxick\u00fdch \u00fa\u010dinkov in vitro pri koncentr\u00e1ci\u00e1ch a\u017e 400 uM [18]. EIDD-1931 a EIDd-2801 v\u0161ak vykazuj\u00fa v\u00fdznamn\u00fa cytoxicitu pri 100 uM <\/strong> [15].
\nTherefore, it is the ability of EIDD-1931 to create fatal mutations in RNA has been of greatest concern for some time [8, 21, 22].
\nThis has been a big reason why it has been slow to be applied to disease.
\nHowever, the current recommended treatment of Covid-19 with Molnupiravir is for only 5 days at the early stage of treatment [10].
\nHowever, the recommended treatment with GS-441524 for FIP is 12 weeks [14], allowing much greater time for toxicity to manifest itself.
\nTherefore, it will be important to carefully observe cats on EIDD-1931 or EIDD-2801 treatment for both short- and long-term effects. <\/span><\/p>\n

V\u0161etky doteraj\u0161ie antiv\u00edrusov\u00e9 lieky viedli k vzniku rezistencie na lieky prostredn\u00edctvom mut\u00e1ci\u00ed vo v\u00edrusovom gen\u00f3me.
\nHoci sa zd\u00e1, \u017ee remdesivir je menej n\u00e1chyln\u00fd na tak\u00e9to mut\u00e1cie ako in\u00e9 lieky pou\u017e\u00edvan\u00e9 pri v\u00edrusov\u00fdch ochoreniach, ako je HIV\/AIDS, rezistencia na lieky je dobre zdokumentovan\u00e1 [23-25].
\nRezistencia na GS-441524 u ma\u010diek lie\u010den\u00fdch na FIP sa pozorovala \u010dastej\u0161ie, najm\u00e4 u ma\u010diek s neurologickou FIP, kde je \u0165a\u017e\u0161ie dosta\u0165 dostato\u010dn\u00e9 mno\u017estvo lieku do mozgu [13, 14, 20].
\nRezistencia na GS-441524 u ma\u010diek je pravdepodobne v\u00e4\u010d\u0161\u00edm probl\u00e9mom aj preto, \u017ee ma\u010dky s FIP sa \u010dasto lie\u010dia 12 t\u00fd\u017ed\u0148ov alebo dlh\u0161ie, zatia\u013e \u010do remdesivir (a molupiravir) sa odpor\u00fa\u010da pod\u00e1va\u0165 len p\u00e4\u0165 dn\u00ed po\u010das po\u010diato\u010dn\u00e9ho vir\u00e9mie Covid-19 [16].
\nProbl\u00e9m rezistencie na lieky sa pri lie\u010dbe HIV\/AIDS \u00fa\u010dinne rie\u0161il s\u00fa\u010dasn\u00fdm pou\u017e\u00edvan\u00edm kokteilu r\u00f4znych liekov s r\u00f4znymi profilmi rezistencie.
\nMutanty rezistentn\u00e9 vo\u010di jedn\u00e9mu lieku bud\u00fa okam\u017eite inhibovan\u00e9 ostatn\u00fdmi liekmi, \u010d\u00edm sa zabr\u00e1ni ich pozit\u00edvnej selekcii vzh\u013eadom na lie\u010dbu.
\nInhib\u00edcia rezistencie je obzvl\u00e1\u0161\u0165 siln\u00e1, ke\u010f dva lieky \u00fato\u010dia na r\u00f4zne prote\u00edny zapojen\u00e9 do replik\u00e1cie v\u00edrusu.
\nNapr\u00edklad GC376 je inhib\u00edtor prote\u00e1zy [13], zatia\u013e \u010do GS-441524 p\u00f4sob\u00ed na RNA dependentn\u00fa RNA replik\u00e1zu [18].
\nLiek GC376 sa v\u0161ak cez hematoencefalick\u00fa bari\u00e9ru nevstreb\u00e1va tak dobre.
\nHoci sa e\u0161te nevykonalo dostato\u010dn\u00e9 mno\u017estvo pr\u00e1c, zd\u00e1 sa, \u017ee medzi GS-441524 a molnupiravirom nebude existova\u0165 skr\u00ed\u017een\u00e1 rezistencia, ale je rovnako \u00fa\u010dinn\u00fd ako GS-441524 pri prechode cez hematoencefalick\u00fa bari\u00e9ru [3].
\nV\u010faka t\u00fdmto skuto\u010dnostiam by bol molnupiravir (alebo 5-hyroxycytid\u00edn) d\u00f4le\u017eit\u00fdm doplnkom bud\u00facej lie\u010dby FIP. <\/p>\n

Ako sa o\u010dak\u00e1valo, molnupiravir bol ned\u00e1vno testovan\u00fd u ma\u010diek s FIP minim\u00e1lne jedn\u00fdm \u010d\u00ednskym predajcom lieku GS-441524 a predbe\u017en\u00e9 v\u00fdsledky boli uveden\u00e9 na webovej str\u00e1nke FIP Warriors CZ\/SK [26]. Ter\u00e9nna \u0161t\u00fadia pozost\u00e1vala z 286 ma\u010diek s r\u00f4znymi formami prirodzene sa vyskytuj\u00facej FIP, ktor\u00e9 boli pozorovan\u00e9 na klinik\u00e1ch pre spolo\u010densk\u00e9 zvierat\u00e1 v USA, Spojenom kr\u00e1\u013eovstve, Taliansku, Nemecku, Franc\u00fazsku, Japonsku, Rumunsku, Turecku a \u010c\u00edne. Medzi 286 ma\u010dkami, ktor\u00e9 sa z\u00fa\u010dastnili na sk\u00fa\u0161ke, nedo\u0161lo k \u017eiadnemu \u00famrtiu, vr\u00e1tane siedmich ma\u010diek s o\u010dnou (n=2) a neurologickou (n=5) FIP. Dvadsa\u0165osem z t\u00fdchto ma\u010diek bolo vylie\u010den\u00fdch po 4 – 6 t\u00fd\u017ed\u0148och lie\u010dby a 258 po 8 t\u00fd\u017ed\u0148och. V\u0161etky lie\u010den\u00e9 ma\u010dky zostali zdrav\u00e9 o 3 – 5 mesiacov nesk\u00f4r, \u010do je obdobie, po\u010das ktor\u00e9ho by sa u ma\u010diek, ktor\u00e9 neboli \u00faspe\u0161ne vylie\u010den\u00e9, o\u010dak\u00e1vali recid\u00edvy .
\nT <\/span>jeho \u00fadaje poskytuj\u00fa presved\u010div\u00e9 d\u00f4kazy o bezpe\u010dnosti a \u00fa\u010dinnosti molnupiraviru pre ma\u010dky s r\u00f4znymi formami FIP.
\nD\u00fafame v\u0161ak, \u017ee t\u00e1to ter\u00e9nna \u0161t\u00fadia bude nap\u00edsan\u00e1 vo forme rukopisu, predlo\u017een\u00e1 na odborn\u00e9 pos\u00fadenie a publikovan\u00e1.
\nNapriek tomu sa teraz pred\u00e1va majite\u013eom ma\u010diek s FIP.
\nMinim\u00e1lne jeden \u010fal\u0161\u00ed ve\u013ek\u00fd predajca lieku GS-441524 m\u00e1 tie\u017e z\u00e1ujem o pou\u017e\u00edvanie molnupiraviru na FIP, \u010do nazna\u010duje dopyt po \u010fal\u0161ej lie\u010dbe ma\u010diek s FIP antivirotikami. <\/span><\/span><\/p>\n

Bezpe\u010dn\u00e9 a \u00fa\u010dinn\u00e9 d\u00e1vkovanie molnupiraviru u ma\u010diek s FIP nebolo publikovan\u00e9.
\nNajmenej jeden predajca z \u010c\u00edny v\u0161ak poskytol niektor\u00e9 farmakokinetick\u00e9 \u00fadaje a \u00fadaje z ter\u00e9nnych testov o molnuparivire u ma\u010diek s prirodzene sa vyskytuj\u00facou FIP vo svojom reklamnom let\u00e1ku na v\u00fdrobok s n\u00e1zvom Hero-2081 [26].
\nTieto inform\u00e1cie v\u0161ak jasne neuv\u00e1dzaj\u00fa mno\u017estvo molnupiraviru v jednej z ich „50 mg tabliet“ a skuto\u010dn\u00fd d\u00e1vkovac\u00ed interval (q12h alebo q24h?).
\nNa\u0161\u0165astie odhadovan\u00fa po\u010diato\u010dn\u00fa d\u00e1vku molnupiraviru u ma\u010diek s FIP mo\u017eno z\u00edska\u0165 z publikovan\u00fdch \u0161t\u00fadi\u00ed bunkov\u00fdch kult\u00far in-vitro EIDD-1931 a EIDD-2801 [15] a laborat\u00f3rnych a ter\u00e9nnych \u0161t\u00fadi\u00ed GS-441524 [14,18].
\nMolnupiravir (EIDD-2801) m\u00e1 EC50 0,4 uM\/ul proti FIPV v bunkovej kult\u00fare, zatia\u013e \u010do EC50 GS-441524 je pribli\u017ene 1,0 uM\/ul [18].
\nOba maj\u00fa podobn\u00fa peror\u00e1lnu absorpciu pribli\u017ene 40 – 50 %, tak\u017ee \u00fa\u010dinn\u00e1 subkut\u00e1nna (SC) d\u00e1vka molnupiraviru by bola pribli\u017ene polovica odpor\u00fa\u010danej za\u010diato\u010dnej d\u00e1vky 4 mg\/kg SC q24h pre GS-441524 [14], alebo 2 mg\/kg SC q24h.
\n Peror\u00e1lna <\/i>(PO) d\u00e1vka by sa zdvojn\u00e1sobila, aby sa zoh\u013eadnila menej \u00fa\u010dinn\u00e1 peror\u00e1lna absorpcia na d\u00e1vku 4 mg\/kg PO q24h.
\nOdhadovan\u00e1 za\u010diato\u010dn\u00e1 peror\u00e1lna d\u00e1vka molnupiraviru u ma\u010diek s FIP sa m\u00f4\u017ee vypo\u010d\u00edta\u0165 aj z dostupn\u00fdch \u00fadajov o lie\u010dbe Covid-19.
\nPacientom lie\u010den\u00fdm liekom Covid-19 sa pod\u00e1va 200 mg molnupiraviru PO q12h po\u010das 5 dn\u00ed.
\nT\u00e1to d\u00e1vka bola samozrejme vypo\u010d\u00edtan\u00e1 na z\u00e1klade farmakokinetickej \u0161t\u00fadie vykonanej na \u013eu\u010foch, a ak priemern\u00fd \u010dlovek v\u00e1\u017ei 60 – 80 kg (70 kg), \u00fa\u010dinn\u00e1 inhibi\u010dn\u00e1 d\u00e1vka je ~ 3,0 mg\/kg PO q12h.
\nMa\u010dka m\u00e1 baz\u00e1lnu r\u00fdchlos\u0165 metabolizmu 1,5-kr\u00e1t vy\u0161\u0161iu ako \u010dlovek a za predpokladu rovnakej peror\u00e1lnej absorpcie u \u013eud\u00ed aj ma\u010diek by minim\u00e1lna d\u00e1vka pre ma\u010dky pod\u013ea tohto v\u00fdpo\u010dtu bola 4,5 mg\/kg PO q12 hod.
\nZa predpokladu, \u017ee molnupiravir prech\u00e1dza cez hematoencefalick\u00fa a hematoencefalick\u00fa bari\u00e9ru s rovnakou \u00fa\u010dinnos\u0165ou ako GS-441524 [3,18], d\u00e1vka by sa mala zv\u00fd\u0161i\u0165 ~ 1,5 a ~ 2,0-kr\u00e1t, aby sa umo\u017enil primeran\u00fd prienik do vodn\u00e9ho moku a mozgovomiechov\u00e9ho moku pre ma\u010dky s o\u010dnou (~ 8 mg\/kg PO, q12 h) alebo neurologickou FIP (~ 10 mg\/kg PO, q12 h).
\nD\u013a\u017eka lie\u010dby by mala by\u0165 10 – 12 t\u00fd\u017ed\u0148ov a monitorovanie odpovede na lie\u010dbu rovnak\u00e9 ako pri GS-441524 [14, 20].
\nTieto odpor\u00fa\u010dania s\u00fa zalo\u017een\u00e9 na predpokladoch z publikovan\u00fdch inform\u00e1ci\u00ed a bude potrebn\u00e9 z\u00edska\u0165 viac sk\u00fasenost\u00ed s molnupiravirom v ter\u00e9ne.
\nJe ot\u00e1zne, \u010di sa Molnupiravir uk\u00e1\u017ee ako bezpe\u010dnej\u0161\u00ed a \u00fa\u010dinnej\u0161\u00ed ako GS-441524 pri lie\u010dbe FIP, ale tret\u00ed antivirotikum by sa mohlo uk\u00e1za\u0165 ako ve\u013emi u\u017eito\u010dn\u00e9 pri prevencii rezistencie na GS-441524 (ako koktail antivirot\u00edk s r\u00f4znymi profilmi rezistencie) alebo pri lie\u010dbe ma\u010diek, ktor\u00e9 u\u017e nereaguj\u00fa dobre na GS-441524.
\nVe\u013ekou nezn\u00e1mou je, \u010di bude molnupiravir bez dlhodob\u00fdch toxick\u00fdch \u00fa\u010dinkov, ke\u010f\u017ee \u00fa\u010dinn\u00e1 l\u00e1tka, N4-hydroxycytid\u00edn, je mimoriadne siln\u00fd mutag\u00e9n [21] a doba lie\u010dby FIP je ove\u013ea dlh\u0161ia ako pri Covide-19 a pravdepodobnos\u0165 ved\u013eaj\u0161\u00edch \u00fa\u010dinkov v\u00e4\u010d\u0161ia. <\/span><\/p>\n

Je po\u013eutovaniahodn\u00e9, \u017ee EIDD-1931 (N4-hydroxycytid\u00edn), \u00fa\u010dinn\u00e1 zlo\u017eka molnupiraviru, sa pri lie\u010dbe ma\u010diek s FIP neberie do \u00favahy viac ako molnupiravir.
\nEIDD-1931 je 4-kr\u00e1t viac inhib\u00edtorom v\u00edrusu ako Molnupiravir (EC50 0,09 oproti 0,4 uM) a percento cytotoxicity je o nie\u010do ni\u017e\u0161ie (2,3 % oproti 3,8 % pri 100 uM), resp. [15].
\nN4-hydroxycytid\u00edn sa tie\u017e \u00fa\u010dinne absorbuje peror\u00e1lnou cestou [3], \u010do sa pri v\u00fdvoji lieku EIDD-2801 (molnupiravir) bagatelizovalo. Tento scen\u00e1r je toto\u017en\u00fd so scen\u00e1rom GS-441524 a Remdesiviru, pri\u010dom druh\u00fd menovan\u00fd bol vybran\u00fd na komercializ\u00e1ciu, hoci s\u00fa\u010dasn\u00fd v\u00fdskum nazna\u010duje, \u017ee prv\u00fd menovan\u00fd by bol najlep\u0161\u00edm kandid\u00e1tom [17]. <\/span><\/span> <\/p>\n

Odkazy <\/span><\/b><\/p>\n

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[26] FIP Warriors CZ\/SK – EIDD-2801 <\/span>(Molnupiravir) <\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Mnoh\u00ed majitelia ma\u010diek s FIP zva\u017euj\u00fa pri lie\u010dbe svojej ma\u010dky pou\u017eitie molnupiraviru aj GS441524. Pravdou je, \u017ee obe mo\u017enosti lie\u010dby s\u00fa \u00fa\u010dinn\u00e9 pri lie\u010dbe FIP a zabra\u0148uj\u00fa replik\u00e1cii v\u00edrusu. Molnupiravir je v\u0161ak vysoko cytotoxick\u00fd, \u010do z neho rob\u00ed ve\u013emi d\u00e1nsky liek na v\u00fdber, najm\u00e4 ak potrebujete svoju ma\u010dku lie\u010di\u0165 12 t\u00fd\u017ed\u0148ov, vystavova\u0165 ju tak dlho […]<\/p>\n","protected":false},"author":1,"featured_media":28637,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_glsr_average":0,"_glsr_ranking":0,"_glsr_reviews":0,"footnotes":""},"categories":[1169],"tags":[],"_links":{"self":[{"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/pages\/28636"}],"collection":[{"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/comments?post=28636"}],"version-history":[{"count":0,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/pages\/28636\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/media\/28637"}],"wp:attachment":[{"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/media?parent=28636"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/categories?post=28636"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/fipmed.co\/sk\/wp-json\/wp\/v2\/tags?post=28636"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}