Menene pharmacogenomics: cikakken jagora, kwayoyin halitta, misalai, da gwaje-gwaje

A cikin 'yan shekarun nan, magani ya canza daga tsarin da ya dace-duka-duka zuwa na musamman na musamman, kuma magunguna na ɗaya daga cikin dalilai. Wannan horo yana karatu Yadda bambance-bambancen kwayoyin halittar mu ke yin tasiri ga martani ga magunguna, tare da manufar rubuta maganin da ya dace, a daidai adadin kuma a lokacin da ya dace.

Wannan sauye-sauyen yanayi yana ba mu damar yin watsi da gwaji da kuskure a cikin tsarawa da rage mummunan halayen. Ba ƙaramin aiki ba ne: Mummunan halayen ga magunguna matsala ce ta lafiyar jama'a da kuma wani muhimmin dalili na asibiti da mace-mace. Pharmacogenomics yana ba da kayan aiki don hasashen inganci da amincin magani kafin fara shi.

Menene pharmacogenomics kuma me yasa yake da mahimmanci?

Pharmacogenomics ya haɗu da ilimin kimiyyar magani (nazarin magunguna) da kuma kwayoyin (nazarin kwayoyin halitta da aikinsu) don fahimtar yadda wasu bambance-bambancen DNA da maganganunsu ke canza martani ga jiyya. Wannan yana ba da damar daidaitawa magunguna da allurai dangane da bayanan kwayoyin halitta na kowane majiyyaci.

A aikace, wannan yana nufin ƙaura daga tsarin "girma ɗaya ya dace da kowa" zuwa madaidaicin hanya. Yawancin magunguna ba sa aiki iri ɗaya ga kowa da kowa. kuma wasu na iya haifar da mummunar guba a cikin waɗanda ke ɗauke da takamaiman bambance-bambancen. Tare da bayanan kwayoyin halitta, likitoci na iya rage haɗari da inganta sakamako.

Daga girman-daya-daidai-duk magani zuwa magani na musamman

Magungunan zamani suna bin "magungunan da suka dace, a daidai adadin, a lokacin da ya dace." Don cimma wannan, dole ne mu yi la'akari da babban bambance-bambancen tsakanin daidaikun mutane. Amsa ga kwayoyi ya dogara da kwayoyin halitta, epigenetic da abubuwan muhalli, kuma gudunmawar kowanne ya bambanta dangane da maganin.

Misalin misali shine warfarin: mafi kyawun adadin sa yana da sharadi na kwayoyin halitta (genetics).CYP2C9, VKORC1) da kuma ta wasu mabambantan kwayoyin halitta kamar shekaru, jima'i, nauyi, shan taba, ko mu'amala. Haɗa duk waɗannan sigogi Yana haɓaka tsinkayar kashi kuma yana rage mummunan al'amura.

A yau mun san hakan Fiye da kashi 90% na yawan jama'a suna ɗauke da aƙalla nau'ikan nau'ikan magunguna masu yuwuwar aiki, kuma akwai ɗaruruwan magunguna tare da la'akari da magunguna waɗanda hukumomin da suka tsara suka gane. Wannan yana ƙarfafa amfanin asibiti na haɗa kwayoyin halitta cikin rubutawa.

Neman zuwa gaba, pharmacogenomics zai zama mabuɗin don keɓance hanyoyin kwantar da hankali a yankuna kamar su cardiology, Oncology, Neurology ko pulmonology, da kuma hanzarta haɓaka sabbin ƙwayoyi, mafi aminci kuma mafi inganci.

Genes, biomarkers da hanyoyin da ke ƙayyade amsa

Yawanci ana auna canjin halitta ta hanyar biomarkers a matsayin guda nucleotide polymorphisms (SNPs). Waɗannan bambance-bambancen na iya canza metabolizing enzymes, masu karɓa, ko masu jigilar kaya, don haka gyara inganci ko aminci na wani magani.

A cikin metabolism (lokaci na I), dangin enzymes CYP450 karya saukar da babban adadin kwayoyi. Ƙididdigar sunan sa ta dogara ne akan dangi, dangi, da enzyme (misali, CYP2E1), kuma ana bayyana bambance-bambancen alloli ta amfani da tsarin "tauraro" (*1,*2,*3…). Canje-canje a cikin waɗannan kwayoyin halitta suna haifar da metabolizing phenotypes wanda ke ƙayyade matakan plasma da amsawar asibiti.

A cikin lokaci na II, glutathione S-transferases, N-acetyltransferases, ya fito fili. UGT, sulfotransferases da methyltransferases irin su TPMT ya da COMT. Bambance-bambance a cikin waɗannan enzymes suna da alaƙa da takamaiman guba. Idan an rage jinkirin kawar da kwayoyin halitta, magani tare da kunkuntar kewayon warkewa zai iya kai ga taro masu haɗari.

Maƙasudin ƙwayoyi kuma suna da mahimmanci: polymorphisms a cikin kwayoyin halitta waɗanda ke ƙididdige su masu karɓa canza aikin su ko magana da canza hankali ko haɗarin mummunan tasiri. Hakazalika, Masu sufurin ABC kamar P-gp (ABCB1 / MDR1) canza sha, rarrabawa da kawarwa, yana shafar bayyanar nama da amsawa.

A taƙaice, an bayyana martani ga magunguna ta hanyar hulɗar da ke tsakanin Pharmacokinetics (ADME) y pharmacodynamics, duka biyun sun daidaita ta kwayoyin halittar majiyyaci kuma, wani lokacin, ta hanyar kwayar cutar kwayar cutar kansa a cikin oncology.

Metabolism phenotypes: daga ultra-sauri zuwa jinkirin

Dangane da tarin aikin enzyme, ana iya rarraba mutum a matsayin matsananci-sauri, sauri, al'ada, matsakaici, ko jinkirin metabolizerWannan lakabin ba "mai kyau ko mara kyau" ba ne: dacewarsa ya dogara da miyagun ƙwayoyi kuma ko yana aiki ko samfur.

Idan mutum ya kasance mai jinkirin metabolizer na hanyar da ba ta kunna miyagun ƙwayoyi ba, za su iya tara matakan girma kuma su kasance guba. Akasin haka, idan wannan hanyar ta kunna prodrug, jinkirin metabolizer zai sami ƙarancin sinadarai mai aiki kuma. rashin lafiyar warkewa. Shi ya sa jagororin asibiti ke daidaita shawarwari dangane da magunguna da nau'in halitta.

• Ultrafast: tuba ko kawar da miyagun ƙwayoyi da sauri; na iya buƙatar mafi girma ko madadin allurai idan akwai asarar inganci.
• Matsakaici/hankali: ƙara yawan bayyanar da kwayoyi masu aiki; haɗarin abubuwan da ba su da kyau kuma suna buƙatar rage allurai ko guje wa miyagun ƙwayoyi.
• Al'ada: aikin enzyme da ake tsammani; daidaitattun allurai yawanci ana bin su, saka idanu abubuwan da ba na kwayoyin halitta ba.

Baya ga DNA, an daidaita amsa ta ƙarshe ta shekaru, jima'i, nauyi, rage cin abinci, cututtuka da kuma polypharmacy, wanda zai iya haifar da ko hana hanyoyin rayuwa da kuma canza yawan ƙwayoyi.

Yadda muke bincike: kwayoyin dan takara, GWAS, da bangarori

Akwai dabaru na yau da kullun guda biyu don gano ƙungiyoyin magungunan ƙwayoyin cuta. Na farko shine ɗan takarar nazarin halittu, mayar da hankali kan metabolism, sufuri ko manufa ta kwayoyin halitta, mafi tattalin arziki da kuma kai tsaye don inganta dangantakar genotype-phenotype.

Na biyu, da GWAS (nazarin haɗin gwiwar genome-fadi) kwatanta bayanan martabar kwayoyin halitta tsakanin ƙungiyoyi (sharuɗɗa da sarrafawa) da gano bambance-bambancen da ke da alaƙa da amsa, inganci, ko guba. Tare da faduwar farashin jeri, Wadannan binciken sun haifar da binciken a wurare masu yawa na warkewa.

A cikin dakin gwaje-gwaje na asibiti, dukkanin jerin kwayoyin halitta (WGS) shine manufa ta fasaha, amma saboda farashi a halin yanzu ana amfani da shi da farko. exome (WES) da bangarori masu niyya. Mafi kyawun panel ya haɗa da pharmacokinetic da pharmacodynamic alamomi, bambance-bambancen tare da shaidar aiki da mitar yawan jama'a masu amfani don magungunan da aka saba amfani da su.

Don daidaita aikin, akwai jagorori da tushen ilimi waɗanda ke tattarawa shaida na asibiti da shawarwarin sashi ko zaɓi na madadin bisa genotype. Waɗannan jagororin suna sauƙaƙa fassara sakamakon gwaji zuwa yanke shawara na warkewa.

Misalai na asibiti inda kwayoyin halitta ke yin bambanci

Wasu al'amuran sun kafu sosai. Misali, da clopidogrel Prodrug ne wanda bioactivation ya dogara da CYP2C19. Bambance-bambancen asarar aiki suna da alaƙa da ƙananan ƙarni na aiki metabolite da ƙarin gazawar warkewa; A cikin waɗannan lokuta, ana bada shawara don canzawa zuwa wani wakili na antiplatelet.

da fluoropyrimidine (5-FU, capecitabine) suna shafar bambance-bambance a cikin DPYD: Rage aikin enzyme yana ƙara haɗarin haɗari mai tsanani, wanda shine dalilin da ya sa jagororin da yawa ke ba da shawara gyare-gyaren kashi ko madadin a cikin masu ɗaukar haɗari masu haɗari.

Tare da opioids, sauye-sauye a cikin hanyoyin CYP na iya canza haɓakar ƙwayoyin metabolites masu aiki da haɓaka haɗarin bakin ciki na numfashi Idan metabolism yana da girma ko ƙasa da yawa dangane da miyagun ƙwayoyi. Wannan yana kwatanta yadda phenotype metabolizing ke canza ma'aunin haɗarin fa'ida.

Wani yanayin shine myopathy tare da simvastatin: Bambance-bambance a cikin masu safarar hanta (misali, SLCO1B1) yana rage yawan amfani da shi kuma yana ƙara yawan ƙwayar plasma, wanda aka danganta da shi. lalacewar tsoka kuma yana buƙatar taka tsantsan cikin zaɓi ko sashi.

Ƙungiya tsakanin wasu HLAs da mummunan halayen fata irin su Stevens-Johnson ciwo ko mai guba epidermal necrolysis, da predisposition zuwa m hyperthermia tare da magungunan kashe qwari a cikin takamaiman mahallin kwayoyin halitta.

Gwajin Pharmacogenomic: abin da yake nazari da kuma yadda ake yin shi

Za a iya yin gwaji a kan miyagu, swab ɗin baki, ko jini. Gidan gwaje-gwajen yana fitar da DNA kuma yana nazarin bambance-bambancen da ke tasiri magungunan da ke cikin ka'idodin asibiti. Sakamako baya canzawa tsawon rayuwa (genotype ɗinku ya rage), kodayake ana sabunta fassarori yayin da shaida ke tasowa.

A cikin aikin asibiti, rahotanni sun nuna kwayoyin halitta, genotypes, phenotypes (misali, matsakaici metabolizer) da shawarwari: daidaita kashi, zaɓi madadin, ko ci gaba da miyagun ƙwayoyi tare da saka idanu. Yana da mahimmanci a koyaushe a yi gyare-gyaren magani kwararre na kiwon lafiya.

Wasu dakunan gwaje-gwaje suna ba da cikakkun fa'idodi don marasa lafiya da ke jurewa maganin polypharmacy. Wannan hanyar rigakafin ta ba da damar kauce wa m takardun magani daga farkon jiyya, maimakon amsawa bayan wani abu mara kyau.

Iyakoki da ƙalubalen da har yanzu muna buƙatar shawo kan su

Shingayen sun ci gaba: rashin dakunan gwaje-gwaje masu tsada, matsayin inganci ingantattun jagororin doka/da'a da garanti, da kuma gibi a cikin ƙwararrun da aka horar da su fassara sakamako.

Wani iyakance gama gari shine lokacin amsawa: idan an yi gwaje-gwaje bayan wani abu mara kyau, sun rasa wasu ƙimar rigakafin su. Saboda haka tura don preemptive model (haɓaka genotyping) haɗawa cikin tarihin asibiti da tsarin tallafi na yanke shawara.

Ƙididdigar bayanai kuma ƙalubale ne: haɗawa, fassara da adana bayanan genomic amintattu kuma tare da low cost yana buƙatar zuba jari a cikin abubuwan more rayuwa da sarrafa bayanai.

A ƙarshe, ana buƙatar ƙarin horo na asibiti da kayan aiki masu sauƙin amfani. Shaida tana taruwa cikin sauri, amma juya ta cikin yanke shawara na asibiti shine muhimmin mataki na yin pharmacogenomic na yau da kullun.

Pharmacogenomics vs. pharmacogenetics: ba abu ɗaya bane.

La pharmacogenetics yana nufin yadda bambance-bambance a cikin takamaiman kwayoyin halitta ke shafar metabolism da amsawa ga magani. Pharmacogenomics Yana faɗaɗa mayar da hankali ga dukan kwayoyin halitta kuma, ban da canje-canje a cikin DNA, ya haɗa da sassa na maganganun kwayoyin halitta wanda ke daidaita martanin pharmacological.

A cikin wallafe-wallafen, an yi amfani da su duka biyun kalmomi na tsawon shekaru, amma haɓakar ilimin halittu ya ƙarfafa a ƙarin madaidaicin bambanci: pharmacogenetics wani sashe ne na pharmacogenetics, ba ma'anarsa ba.

Lokacin neman gwajin magunguna

Yana da amfani musamman kafin fara magunguna da babban haɗarin guba yana da alaƙa da bambance-bambancen da aka sani (misali, thiopurines da TPMT/NUDT15; fluoropyrimidines da DPYD; carbamazepine da HLA), a cikin gazawar warkewa ba tare da bayyana ko lokacin da aka shirya polypharmacy.

Hakanan yana da ma'ana a cikin marasa lafiya waɗanda ake tsammanin bayyanar cututtuka da yawa a cikin lokaci: Sakamakon kwayoyin halitta yana aiki har tsawon rayuwa kuma ana iya tuntubar shi duk lokacin da aka yi takardar sayan magani..

Don haɓaka ƙimar su, dole ne a haɗa sakamakon a cikin lantarki rikodin likita tare da faɗakarwa da dokokin yanke shawara, kuma tare da horo ga ƙungiyar kiwon lafiya.

Pharmacogenomics, aiwatarwa da kyau, yana aiki azaman ƙarin tsarin tsaro wanda ke ƙara yanke hukunci na asibiti, ilimin harhada magunguna na gargajiya da zaɓin haƙuri don jagorantar mafi kyawun zaɓi na warkewa.

Shaidu da fasaha suna ci gaba cikin sauri, kuma tare da su yiwuwar kowane mutum ya sami magani wanda ya dace da ilimin halittarsa. Tare da ƙungiyoyin da aka horar da su, ƙayyadaddun jagorori, da hadedde bayanai, Madaidaicin takardar sayan magani ba zai zama banda ba ya zama gama gari.