Posachedwapa, British Journal of Clinical Pharmacology inafalitsa malangizo oyamba azachipatala omwe adapangidwa ndi UK Centre of Excellence for Regulatory Science and Innovation in Pharmacogenomics (CERSI PGx), otchedwa “CYP2C19 genotype testing for clopidogrel: Malangizo omwe adapangidwa ndi UK Centre of Excellence for regulatory science and innovation in pharmacogenomics (CERSI PGx)”. Chikalatachi chikuyang'ana kwambiri kufunika kwa CYP2C19 genotyping mu chithandizo chotsogolera clopidogrel.
Zokhudza CERSI PGx
CERSI PGx ndi imodzi mwa malo asanu ndi awiri ochirikizidwa ndi boma la UK omwe adakhazikitsidwa mu Januwale 2025. Motsogozedwa ndi University of Liverpool, imathandizidwa ndi Innovate UK, Medical Research Council (MRC), Medicines and Healthcare products Regulatory Agency (MHRA), ndi Office for Life Sciences (OLS). Cholinga cha malowa ndi kufulumizitsa kuphatikizana kotetezeka komanso kogwira mtima kwa pharmacogenomics (PGx) mu National Health Service (NHS) pothana ndi zopinga zazikulu zogwiritsira ntchito. Malangizo awa ndi malangizo oyamba azachipatala omwe adaperekedwa kuyambira pomwe CERSI PGx idakhazikitsidwa.
Chifukwa Chake CYP2C19 Ndi Yofunika pa Clopidogrel
CYP2C19 ndi membala wofunikira wa banja la ma enzyme a cytochrome P450, omwe amachititsa kuti kagayidwe kachakudya kayambe kugwira ntchito kapena kuletsa mankhwala ambiri. Kuchuluka kwa majini mu CYP2C19 kumabweretsa kusiyana kwakukulu pakati pa anthu pa kagayidwe kachakudya ka mankhwala, zomwe zimakhudza mphamvu ndi chitetezo.
Clopidogrel ndi mankhwala oletsa magazi m'mitsempha omwe amagwiritsidwa ntchito kwambiri poletsa zochitika za thrombosis mu matenda a mitsempha ya mtima, sitiroko ya ischemic, matenda a mitsempha ya m'mitsempha, ndi fibrillation ya atrial. Monga mankhwala othandizira, clopidogrel imafuna kuyambitsa kagayidwe kachakudya ndi CYP2C19. Malangizowa amagawa anthu m'magulu a metabolizers omwe amagwira ntchito mwachangu kwambiri, mwachangu, mwachibadwa, pakati, komanso moyipa kutengera mtundu wa CYP2C19. Onyamula ma alleles omwe amataya ntchito (monga CYP2C192 ndi *3*) - omwe amagwira ntchito pakati komanso moyipa kwambiri - sangathe kuyambitsa bwino clopidogrel, zomwe zimapangitsa kuti magazi asakwanitse kuletsa magazi m'mitsempha komanso chiopsezo chowonjezeka cha thrombosis.
Kuchuluka kwa CYP2C192 allele ndi pafupifupi 15% mwa anthu aku Europe, 30% mwa anthu aku South Asia, komanso kufika pa 60% mwa anthu aku Oceania.
Malangizo Ofunika: Kuyesa kwa CYP2C19 kwa Clopidogrel
Malangizowo amanena kuti, mosasamala kanthu za chizindikiro, odwala onse omwe akuganiziridwa kuti alandire clopidogrel ayenera kulandira chithandizo.CYP2C19kupanga majini.Kutengera ndi zotsatira zake, chithandizo cha antiplatelet chiyenera kukhala chabwino:
-Mankhwala ochepetsa mphamvu ya metabolismAyenera kupewa clopidogrel ndipo azigwiritsa ntchito mankhwala ena omwe samadalira kagayidwe ka CYP2C19, monga ticagrelor kapena prasugrel.
-Mankhwala ochepetsa mphamvu ya metabolismayeneranso kuganizira njira zina kapena njira zina zosinthira m'malo mongowonjezera mlingo wa clopidogrel.
Ku UK, clopidogrel imavomerezedwa kuti igwiritsidwe ntchito popewa zochitika za atherothrombotic, pa chiopsezo chapakati mpaka chachikulu cha ischemic attack (TIA) kapena sitiroko yofatsa ya ischemic, komanso popewa zochitika za atherothrombotic ndi thromboembolic mu atrial fibrillation.
Kupitilira Clopidogrel: Mankhwala Ena Omwe Kuyesa Kubadwa kwa CYP2C19 Ndi Kofunika Kwambiri
Kufunika kwa CYP2C19 genotyping kumapitirira clopidogrel. Monga enzyme yaikulu yogwiritsira ntchito mankhwala, CYP2C19 imagwiranso ntchito yofunika kwambiri pa kagayidwe ka voriconazole, mankhwala angapo oletsa kuvutika maganizo, ndi zoletsa ma proton pump (PPIs). Malangizo ambiri apadziko lonse lapansi ndi adziko lonse amalimbikitsa kuti mankhwalawa azigwiritsidwa ntchito payekhapayekha pogwiritsa ntchito genotype.
1. Mankhwala Oletsa Kuvutika Maganizo (SSRIs)
Mankhwala oletsa kubwerezabwereza kwa serotonin (SSRIs) – monga sertraline, citalopram, ndi escitalopram – ndi omwe amayambitsa kuvutika maganizo ndipo amasinthidwa kwambiri ndi CYP2C19. Ntchito ya enzyme ya CYP2C19 imatsimikizira mwachindunji kuchuluka kwa mankhwala awa m'magazi. Mankhwala ochepetsa mphamvu ya mankhwala amachepa ndi 30%–60%, zomwe zimapangitsa kuti akumane ndi zotsatirapo zoyipa monga kutalikitsa nthawi ya QT komanso kupumula. Mankhwala ochepetsa mphamvu ya mankhwala nthawi zambiri amakhala ndi kuchuluka kwa mankhwala m'magazi, zomwe zimapangitsa kuti chithandizo chichedwe komanso chiopsezo chowonjezeka cha kusiya kugwiritsa ntchito mankhwala.
Buku la 2023 Clinical Pharmacogenetics Implementation Consortium (CPIC) limati anthu omwe ali ndi vuto la metaboliser ochepa omwe amatenga citalopram kapena escitalopram ali ndi chiopsezo chachikulu cha kutalikitsa QT ndipo amalimbikitsa kuchepetsa mlingo ndi 50%. Buku la 2021 Dutch Pharmacogenetics Working Group (DPWG) limalangiza kuti anthu omwe ali ndi vuto la metaboliser ochepa ayenera kulandira mlingo waukulu wa escitalopram wochepetsedwa ndi 50%, ndipo anthu omwe ali ndi vuto la metaboliser ochepa kwambiri ayenera kupewa escitalopram konse. Pa sertraline, DPWG imalimbikitsa mlingo wa tsiku ndi tsiku wosapitirira 75 mg mwa anthu omwe ali ndi vuto la metaboliser ochepa.
Chofunika kwambiri, chikalata chofalitsidwa posachedwapa cha akatswiri aku China chogwirizana pa mayeso a Pharmacogenomic mu Psychiatry (2025) - chopangidwa ndi Precision Medicine Collaboration Group of the Chinese Society of Psychiatry - chikuphatikizapo malangizo okhudza kupanga majini a CYP2C19. Chikalata chogwirizana chikuwonetsa kuti malangizo osintha mlingo kuchokera ku malangizo apadziko lonse lapansi monga CPIC ndi DPWG a ma enzymes ogwiritsira ntchito mankhwala (kuphatikizapo CYP2C19) akhoza kutchulidwa kwa anthu aku China. Chifukwa chake, kupanga majini a CYP2C19 musanayambe chithandizo cha SSRI (monga escitalopram) kumathandiza kukonza mlingo kapena kusintha mankhwala ena omwe CYP2C19 sinasinthe, motero kupeza chithandizo cholondola, kusintha kuchuluka kwa mayankho, ndikuchepetsa zochitika zoyipa.
2. Zoletsa Pump ya Proton (PPI)
Mankhwala oletsa kupopera kwa proton - kuphatikizapo omeprazole, lansoprazole, ndi pantoprazole - amagwiritsidwa ntchito kwambiri pa matenda okhudzana ndi asidi monga matenda a reflux a m'mimba ndi zilonda zam'mimba. Kagayidwe kawo ka thupi kamadaliranso kwambiri CYP2C19. Odwala omwe ali ndi majini osiyanasiyana a CYP2C19 amasonyeza kusiyana kwakukulu poyankha ma PPI. Anthu omwe ali ndi ma alleles otayika (*2, *3) ali ndi kuchuluka kwakukulu kwa mankhwala, zomwe zingapangitse kuti asidi achepetsedwe komanso zimawonjezera chiopsezo cha zotsatirapo zoyipa. Mosiyana ndi zimenezi, mankhwala abwinobwino amakhala ndi kuchuluka kochepa kwa plasma ndipo amatha kukhala ndi asidi wofooka, ngakhale kuti kusiyana pakati pa munthu ndi munthu kumakhala kwakukulu.
Malangizo a CPIC a 2020 a PPIs amalimbikitsa kuti anthu omwe amamwa omeprazole kapena mankhwala ena ofanana nawo azigwiritsa ntchito mankhwalawa mofulumira kwambiri, zomwe zimapangitsa kuti plasma ikhale yochepa komanso kuti asidi asagwire bwino ntchito. Mwa odwalawa, mlingo uyenera kuwonjezeredwa ndipo njira yochizira imayang'aniridwa. Kwa anthu omwe amamwa mankhwala molakwika, kuchotsa mankhwala kumakhala pang'onopang'ono ndipo plasma imakhala yochuluka; ngakhale kuti mphamvu yake ingakhale yabwinoko, chiopsezo cha poizoni wa mankhwala chimawonjezeka. Kuchepetsa mlingo ndi kuyang'anira momwe mankhwalawa amayankhidwira ndi zinthu zoyenera kuziganizira. Chifukwa chake, kwa odwala omwe akuyamba chithandizo cha PPI kapena omwe akukumana ndi vuto la kuyankha kapena zotsatirapo zoyipa, CYP2C19 genotyping ikulimbikitsidwa kuti itsogolere mlingo wosankhidwa payekha, kukulitsa mphamvu yake, ndikuchepetsa zochitika zoyipa.
3. Voriconazole
Voriconazole ndi mankhwala opha mabakiteriya osiyanasiyana omwe amagwiritsidwa ntchito pochiza matenda akuluakulu a bowa monga aspergillosis. Ili ndi njira yochepetsera chithandizo: kuchuluka kwambiri kwa plasma kumawonjezera chiopsezo cha poizoni wa chiwindi ndi kusokonezeka kwa maso, pomwe kuchuluka kochepa kumapangitsa kuti chithandizo chilephereke. Kagayidwe ka voriconazole kamachitika makamaka chifukwa cha CYP2C19, ndipo ma genetic polymorphisms amakhudza kwambiri kuchuluka kwake m'magazi.
CPIC idasindikiza malangizo apadera okhudza CYP2C19 ndi voriconazole mu 2016. Imati ma metaboliser a ultrapid achepetsa kuchuluka kwa voriconazole mumtsuko ndipo nthawi zambiri amalephera kufika pamlingo wofunikira wochiritsira. Ma metaboliser osauka ali ndi kuchuluka kwa through ndipo chiopsezo chowonjezeka cha zotsatira zoyipa chimawonjezeka. Malangizo a CPIC amapereka malangizo enieni okhudza mlingo kutengera mtundu wa genotype. Mwachitsanzo, ma metaboliser akuluakulu a ultrapid ayenera kulandira mankhwala ena oyamba omwe sadalira kagayidwe ka CYP2C19, monga isavuconazole, liposomal amphotericin B, kapena posaconazole. Chifukwa chake, CYP2C19 genotyping isanayambe chithandizo cha voriconazole imalola kumwa mankhwala payekhapayekha ndikuchepetsa kuchuluka kwa zochitika zoyipa zokhudzana ndi mankhwala.
Kufunika kwa Zachipatala: Kupanga Mankhwala Kukhala Odalirika Kwambiri
Malangizo omwe atulutsidwa kumene akuikanso CYP2C19 genotyping patsogolo pa mankhwala olondola. Komabe, ndikofunikira kuzindikira kuti kugwiritsa ntchito CYP2C19 genotyping kuchipatala kumapitirira clopidogrel - kuyambira voriconazole (antifungal) ndi SSRIs (antidepressants) mpaka zoletsa za proton pump kuti asidi achepetsedwe. CYP2C19 genotype imagwira ntchito ngati "compass" yothandizira mankhwala.
Pamene mankhwala olondola akulandiridwa kwambiri, malangizo ambiri ovomerezeka akuwonjezera kupanga majini a CYP2C19 mu njira zochiritsira zachizolowezi. Kwa odwala, kudziwa mtundu wawo wa majini a CYP2C19 kumawathandiza kumvetsetsa momwe mankhwalawo amayankhira payekhapayekha komanso kumawathandiza kupanga zisankho zofanana ndi dokotala wawo kuti apange dongosolo loyenera la chithandizo. Kwa asing'anga, kuphatikiza zotsatira zenizeni za majini mu zisankho zolembera odwala ndi njira yamphamvu yowonjezerera ubwino wa chithandizo ndikuwonetsetsa kuti odwala ali otetezeka.
Macro & Micro-Test'sYankho la CYP2C19 Genotyping
Macro & Micro Test imapereka zida zoyesera majini za CYP2C19 kutengera njira yowongolera yosinthira ma amplification refractory (ARMS) yophatikizidwa ndi ma probe a Taqman okhala ndi zinthu zotsatirazi:
-Kuphunzira kwathunthu kwa allele- kuzindikiraCYP2C192, *3, ndi *17popanda kusowa mitundu yofunika.
-Kulamulira khalidwe kolimba- imaphatikizapo zowongolera zoyipa/zabwino, zowongolera zamkati, ndi enzyme ya UDG yowongolera khalidwe la magawo anayi kuti zitsimikizire zotsatira zolondola.
-Kutulutsa kokha- imagwirizana ndi chotulutsira nucleic acid cha Macro & Micro-Test chomwe chimagwira ntchito yokha, zomwe zimapangitsa kuti ntchito igwire bwino ntchito.
-Kugwirizana kwakukulu- imagwira ntchito ndi zida za PCR zomwe zikupezeka pamsika, kuphatikizapo ABI 7500 Hongshi SLAN 96P.
-Kutanthauzira zotsatira zokha- pulogalamu yowunikira yodzipereka (pa ABI 7500, SLAN 96P, ndi zina zotero) imalola kutanthauzira zotsatira zokha, zomwe zimawonjezera magwiridwe antchito.
-POCT yokonzeka yokha- HWTS AIO800 Yodziyimira Yokha Yopangira Nucleic Acid Amplification Analyzer imalola ntchito ya "chitsanzo kulowa, zotsatira".
Ndi kupita patsogolo kosalekeza kwa pharmacogenomics, CYP2C19 genotyping ikuyembekezeka kupindulitsa odwala ambiri, kusintha mankhwala olondola kuchokera ku lingaliro kupita ku machitidwe azachipatala wamba. Malangizo a CERSI PGx omwe angofalitsidwa kumene akulimbitsa gawo lofunika kwambiri la mayeso a CYP2C19 osati kokha pa clopidogrel komanso pamndandanda wokulirakulira wa mankhwala, kuphatikiza mankhwala oletsa kupsinjika maganizo, zoletsa za proton pump, ndi voriconazole. Kuti zithandizire kukhazikitsidwa kwa mankhwala otsogozedwa ndi genotype, mayankho odalirika komanso osavuta kugwiritsa ntchito ndi ofunikira. Pulogalamu yoyesera ya pharmacogenomic ya Macro & Micro-Test, yokhala ndi kufalikira kwa allele kwathunthu, kuwongolera bwino khalidwe, ndi nsanja zokonzekera zokha, cholinga chake ndi kuthandiza opereka chithandizo chamankhwala pakukhazikitsa mankhwala olondola komanso kuteteza thanzi la odwala.
Zogulitsa Zofanana:
Maumboni:
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2.Lee CR, Luzum JA, Sangkuhl K, ndi ena. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022. doi:10.1002/cpt.25261.
3. National Institute for Health and Care Excellence (NICE). Kuyesa kwa majini a CYP2C19 kuti kutsogolere kugwiritsa ntchito clopidogrel pambuyo pa sitiroko ya ischemic kapena kuukira kwa ischemic kwakanthawi. Malangizo ozindikira matenda DG59. Lofalitsidwa: 31 Julayi 2024.
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7.Bousman CA, Stevenson JM, Ramsey LB, ndi ena. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, ndi HTR2A Genotypes ndi Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68. doi:10.1002/cpt.2903.
8.Brouwer JMJL, Nijenhuis M, Soree B, ndi ena. Dutch Pharmacogenetics Working Group (DPWG) malangizo okhudza kuyanjana kwa majini ndi mankhwala pakati pa CYP2C19 ndi CYP2D6 ndi SSRIs. Eur J Hum Genet. 2021. doi:10.1038/s41431-021-00894-2.
Nthawi yotumizira: Epulo-22-2026