Farmakogenetika depresija Henigsberg, Neven; Folnegović-Šmalc, Vera
Medicus (Zagreb, Croatia : 1992),
01/2004, Letnik:
13, Številka:
1_Depresija
Journal Article
Recenzirano
Odprti dostop
Farmakogenetika, a posebno farmakogenomika,
nove su znanstvene discipline čiji početni rezultati daju
nadu da će se među bolesnicima koji boluju od depresije uspjeti
prepoznati homogene skupine s ...obzirom na očekivani
terapijski odgovor i na taj način omogućiti učinkovitije liječenje
depresije.
Sasvim je jasno da je terapijski odgovor rezultat složenih genskih
učinaka, a ne samo jednoga gena. Na njega utječu ne
samo genski polimorfizmi nego i varijacije u ekspresiji gena i
posttranslacijske modifikacije proteina pod utjecajem brojnih
čimbenika kao što su doza lijeka, prehrana te interakcije s
drugim tvarima unijetim u organizam. Ne valja očekivati da bi
se samim farmakogenetičkim ili čak farmakogenomskim
istraživanjima mogla objasniti većina varijabiliteta u terapijskom
odgovoru, no ustanovljavanje uzroka čak i dijela njegova
varijabiliteta koji je pod izravnim genskim utjecajem znatno
bi pridonijelo pouzdanijoj procjeni očekivanog terapijskog
učinka i značajnije povisilo sada nizak udio bolesnika koji
povoljno odgovaraju na antidepresivnu terapiju. Veći dio varijabiliteta
terapijskog odgovora bit će moguće objasniti tek
daljnjim razvojem transkriptomskih i proteomskih istraživanja
koja su, za sada, ipak još u fazi ranog razvoja.
Farmakoterapija depresije mogla bi se opisati slabom predvidljivosti individualnog odgovora. Antidepresivi se ordiniraju po načelu slučaj ili pogreška, jer kliničkim značajkama ne uspijevamo odrediti ...koji će bolesnik odgovoriti na antidepresive ili razviti nuspojave. Čini se da je farmakogenetika put koji najviše obećava kako bi se postigao zadani cilj, individualizirana terapija. Danas se najčešće primjenjuju antidepresivi iz skupine selektivnih inhibitora ponovne pohrane serotonina (SSRI). S druge strane, najistraživanija genetska varijanta u predviđanju i individualizaciji antidepresivne terapije je polimorfizam gena za serotoninski transporter (5-HTT LPR). Cilj ovoga rada je prikazati dosadašnja istraživanja polimorfizma 5-HTT LPR i odgovora na SSRI. U radu je prikazano 35 studija u kojima se istraživala učinkovitost antidepresiva SSRI u ovisnosti o polimorfizmu 5-HTT LPR. Prikazani su i rezultati 3 meta analize koje su istraživale navedenu problematiku. Ukratko, velika većina dosadašnjih studija je pokazala da nosioci L alela imaju brži i bolji odgovor na antidepresive SSRI ako su bijelci. Navedeno potvrđuju i 2 meta analize. Studije koje su bile negativne imale su etnički miješanu populaciju, a zna se da su frekvencije alela drugačije kod različitih etničkih skupina i posljedično tome i različiti rezultati farmakogenetskih istraživanja. Za Azijate rezultati su još proturječni. Farmakogenetska analiza polimorfizma 5-HTT LPR se pokazala i ekonomski isplativa ako se uračuna rekurentni tijek bolesti. Čini se da su odgovor na antidepresive SSRI i razvoj nuspojava povezani s polimorfizmom 5-HTT LPR u bijelaca i navedena farmakogenetska analiza bi mogla biti jedna od prvih u budućoj psihijatrijskoj kliničkoj praksi.
Vrlo visok stupanj polimorfnosti, zbog interindividualne genske varijabilnosti, enzima citokroma P450 (CYP) značajno pridonosi raznolikosti u odnosima između primijenjene doze lijeka, koncentracije ...lijeka u serumu, kao i terapijskoga odgovora, ali i interakcije lijekova. Podaci o poznatim polimorfizmima CYP vrlo su važni u kliničkoj primjeni saznanja farmakogenetike tj. u samoj farmakoterapiji. Učestalost pojedinih polimorfizama može značajno varirati između različitih populacija te je bitno provesti istraživanja učestalosti u pojedinim populacijama. Do sada nema objavljenih podataka o učestalosti polimorfizama gena CYP u populaciji Kosova te je cilj ovog istraživanje bio utvrditi učestalost najvažnijih varijanti alela CYP2C9, CYP2C19 i CYP3A5 u toj populaciji. Istraživanje je obuhvatilo 234 stanovnika Kosova koji nisu u rodbinskoj vezi. U ispitanika je otkrivena učestalost alela CYP2C9*2 17,52 %, a alela CYP2C9*3 10,89 %, te je otkriveno šesnaest ispitanika (6,81 %) sporih metabolizatora CYP2C9. Što se tiče CYP2C19 enzima, učestalost alela CYP2C19*2 je 13,03 %, a za alel CYP2C19*17 učestalost je 19,01 %. Uz to, dokumentirano je 2,13 % sporih metabolizatora CYP2C19 te 4,27 % homozigotnih nositelja alela *17 (fenotip vrlo brzih metabolizatora). S obzirom na CYP3A5 enzim, zabilježena je učestalost alela *3 od 98,29 % (fenotip neekspresora), a 1,70 % ispitanika kategorizirano je kao ekspresori. Rezultati istraživanja pokazali su da je varijabilnost alela, genotipova i fenotipova u populaciji Kosova u velikoj mjeri u skladu s drugim europskim populacijama, konkretnije s populacijama jugoistočne Europe.
Farmakogenetika je vedný odbor, ktorý skúma efekt jednotlivých liekov v závislosti od genotypu. V súčasnosti sú liečebné odporúčania pre liečbu niektorých monogenénových diabetov založené na ...genetickej diagnostike. Aj v oblasti farmakogenetiky perorálnych antidiabetík boli už publikované prvé štúdie, ktoré zistili asociácie jednotlivých génových variantov s liečebnou odozvou. Odozva na deriváty sulfonylurey bola signifikantne asociovaná s variantmi KCNJ11/ABCC8, TCF7L2 a CYP2C9. Odozva na liečbu metformínom bola asociovaná s variantmi génov ATM a SLC47A1. Odozva na liečbu glitazónmi bola asociovaná s variantom génu PPARG. Terapeutická odozva na liečbu gliptínmi bola asociovaná s variantmi génov TCF7L2 a CTRB1/2. Je možné očakávať, že v blízkej budúcnosti budú farmakogenetické poznatky využívané aj pri personalizácii liečby diabetu 2. typu.
Pharmacogenetics is the study of how genes (individual genotypes) affect a person‘s response to drugs. At present, recommendations made about the treatment of some monogenic forms of diabetes are based on genetic diagnostics. The first studies in the field of pharmacogenetics of oral antidiabetics have now been published which have identified associations of individual genetic variants with response to treatment. The response to sulfonylurea derivatives was significantly associated with the variants KCNJ11/ABCC8, TCF7L2 and CYP2C9. The response to metformin treatment was associated with the genetic variants ATM and SLC47A1. The response to treatment with glitazones was associated with the genetic variant PPARG. The therapeutic response to the treatment with gliptins was associated with the genetic variants TCF7L2 and CTRB1/2. It may be expected that in the near future pharmacogenetic knowledge will also be used within personalized treatment of type 2 diabetes.
Ivan Tkáč
Osteoporóza je závažné onemocnění charakterizované vysokou morbiditou a mortalitou v důsledku atraumatických fraktur. Kromě vlivu vnějšího prostředí se v patogeneze osteoporózy uplatňují faktory ...vnitřní (hormonální nerovnováha a genetické pozadí). Článek podává přehled kandidátních genů pro osteoporózu, které klasifikuje podle metabolických okruhů regulujících minerální denzitu nebo kvalitu kosti (okruh estrogenní, RANKL/RANK/OPG, mevalonátový, okruh Wnt, geny pro kolagen a vitamin D). Zabývá se také perspektivou praktického využití farmakogenetiky (identifikace jednotlivých kandidátních genů pomocí PCR) nebo farmakogenomiky (plošné měření škály genů pomocí GWAS) při výběru optimální léčby osteoporózy. Potencionálními prediktory odpovědi na antiresorpční léčbu jsou geny pro ER, FDPS, Cyp19A1, VDR, Col 1A1 a gen pro signalizaci Wnt. Polymorfizmy genů CYP2C, ale také FDPS mohou naopak identifikovat nemocné s vysokým rizikem nežádoucí odpovědi na bisfosfonáty (osteonekróza čelisti). Limitujícím faktorem výzkumu genetiky osteoporózy je nedostatečný konsenzus výsledků asociačních studií. Vysvětlení kontroverzních výsledků lze hledat v rozdílných metodických přístupech (rozsah a homogenita souboru, etnické rozdíly nebo vazebná nerovnováha mezi geny). Klíčovým úskalím asociačních studií je nízká variabilita (7-10 %) kostních fenotypů, které souvisí se zkoumaným genem. Nicméně identifikace nových genů a ověřování jejich asociace s kostními parametry oběma metodami zůstává velkou výzvou s cílem optimalizace prevence a léčby osteoporózy.
Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In pathogenesis of osteoporosis, except environment, internal factors, such as hormonal dysbalance and genetic background, are also in play. In this review, candidate genes for osteoporosis are classified accorging to metabolic or hormonal pathways, which regulate bone mineral density/and or quality (estrogen, RANKL/RANK/OPG, mevalonate, Wnt circuit, genes for collagen and vitamin D). Authors discuss the perspectives of practical utilization of pharmacogenetics (identification of single candidate genes using PCR) or pharmacogenomics (using genome wide association studies) in choise of optimal treatment of osteoporosis. Potentional predictors of effectivity of antiresorption therapy are genes ER, FDPS, Cyp19A1, VDR, Col1A1 and gene of Wnt pathway. Moreover, polymorphisms of CYP2C gene, but also FDPS may identify patients with high risk of undesirable effects of bisphosphonates (osteonecrosis of jaw). Unfortunately, results of the most association studies has not been confirmed by other investigators. The controversial results could be explained by different methodic approches in individual studies (different sample size, homogenity of investigated groups, ethnic differences or linkage disquilibrium between genes). Key cliff of association studies is low variability (7-10 %) of bone phenotypes associated with investigated genes. Nevertheless, identification of new genes and verification their association with bone denzity and/or quality using both PCR and genome wide association studies remain to be a great challenge targeting optimal prevention and treatment of osteoporosis.
Ivana Žofková, Radoslav Omelka
Mikofenolna kiselina (MPA) pokazuje varijabilnu farmakokinetiku (PK). Metabolizira se enzimima UGT u MPA-glukuronid koji podliježe enterohepatičkoj recirkulaciji. U izlučivanje putem žuči i bubrega ...uključen je i protein multirezistencije 2 (MRP2) kodiran genom ABCC2. Ispitali smo PK MPA u stanju ravnoteže u ispitanika s bubrežnim presatkom u odnosu na genotip ABCC2 donora i primatelja, uz druge kliničke kovarijable uključujući komedikaciju s ciklosporinom ili takrolimusom. Bolesnici (n=68, muškarci=53%, dob 15-72 godine) su dobivali mikofenolat-natrij, (EC-MPS) (n= 45, 2x720 mg/dan) ili mikofenolat mofetil (MMF) (n=23, 2x500 do 2x1000 mg/dan) i svi su dobivali ciklosporin (n=43) ili takrolimus (n= 25) te kortikosteroide. Uzorak krvi se uzimao tijekom jednog intervala doziranja (12 sati) u 0, 0.5, 1, 2, 3, 8, 12 h nakon jutarnje doze. MPA je analizirana metodom HPLC. Genotipizacija ABCC2 -24C>T i 1249G>A je provedena metodom PCR u stvarnom vremenu. PK parametri (ln-transformirani) su analizirani prilagodbom generalnog linearnog modela s neovisnim parametrima za dob, spol, indeks tjelesne mase, liječenje (EC-MPS ili MMF), vrstu kalcineurinskog inhibitora te genotip donora i primatelja (-24C>T i 1249G>A). S obzirom na genotip donora ABCC2: alel -24T je neovisno povezan s nižimom Cmin (omjer geometrijskih sredina, GMR=0.61, 90% CI 0.40-0.92), nižom ostatnom koncentracijom Co (GMR=0.54, 0.35-0.83), nižom ostatnom koncentracijom C12 (GMR 0.61, 0.37-0.99) i većim oscilacijama koncentracija MPA (GMR=1.88, 1.09-3.23). S obzirom na genotip primatelja ABCC2: alel 1249A je neovisno povezan s nižom Cmin (GMR=0.55, 0.36-0.66), nižom ostatnom koncentracijom C12 (GMR=0.54, 0.32-0.90) i većim oscilacijama koncentracija MPA (GMR=1.85, 1.05-3.28). Pacijenti liječeni ciklosporinom i koji su bili nositelji alela ABCC2 1249A (niska aktivnost), imali su za 30 % niži AUC MPA u odnosu na pacijenate liječene s takrolimusom, a koji su imali genotip visoke aktivnosti, ABCC2 1249GG. Kombinacija ciklosporina i varijantnih alela ABCC2 (-24T, 1249A) bila je povezana s Cmax/AUC, povišenima za 60%, odnosno 52%. Zaključujemo da je farmakokinetika MPA pod značajnim utjecajem polimorfizama ABCC2 donora i primatelja te ciklosporina u istodobnoj terapiji što može biti klinički značajno.
Mycophenolic acid (MPA) displays variable pharmacokinetics (PK). It is metabolized by UGTs to MPA-glucuronide which is subject to enterohepatic recirculation. Biliary and kidney excretion involves multidrug resistant protein 2 (MRP2) coded by ABCC2. We assessed steady-state PK of MPA in renal allograft recipients in respect to donor and recipient ABCC2 genotypes, along with other clinical covariates including commedication with cyclosporine or tacrolimus. Patients (n=68, men=53%, age 15-72 years) were treated with mycophenolate sodium (EC-MPS) (n= 45, 2x720 mg/day) or mycophenolate mofetil (MMF) (n=23, 2x500 to 2x1000 mg/day), and all received cyclosporine (n=43) or tacrolimus (n= 25) and corticosteroids. Blood samples were taken during one dosing-interval (12 hrs) at 0, 0.5, 1, 2, 3, 8, and 12 h after the morning dose. MPA was analysed by HPLC method. Genotyping of -24C>T and 1249G>A was performed by Real-time PCR method. PK parameters (ln-transformed) were analysed by fitting generalized linear models with independents: age, sex, body mass index, treatment (EC-MPS or MMF), calcineurin inhibitor type, donor and recipient genotypes (-24C>T and 1249G>A). Regarding the donor ABCC2 genotypes: -24T allele was independently associated with lower Cmin (geometric mean ratio, GMR=0.61, 90% CI 0.40-0.92), lower trough Co (GMR=0.54, 0.35-0.83), lower trough C12 (GMR 0.61, 0.37-0.99) and greater MPA concentration oscillations (GMR=1.88, 1.09-3.23). Regarding the recipient genotypes: 1249A allele was independently associated with lower Cmin (GMR=0.55, 0.36-0.66), lower trough C12 (GMR=0.54, 0.32-0.90) and greater % swing (GMR=1.85, 1.05-3.28). Patients treated with cyclosporine and who were carriers of ABCC2 1249A (low activity) , had a 30% lower AUC MPA compared to the patients treated with tacrolimus and who had the high activity genotype, 1249GG. The combination of cyclosporine and variant alleles ABCC2 (-24T, 1249A) was associated with a Cmax / AUC, increased by 60 % and 52 %. In conclusion, the pharmacokinetics of MPA is significantly affected by the donor and recipient ABCC2 polymorphisms and cyclosporine in concomitant therapy, which could be clinically relevant.
The thesis is
Pojem „personalizovaná medicína“ sa v posledných rokoch spomína čoraz častejšie v súvislosti so snahami čo najlepšie prispôsobiť medikamentóznu, ale aj režimovú liečbu potrebám a požiadavkám ...jednotlivých pacientov. Personalizácia antidiabetickej liečby prekonala svoj vývoj v kontexte nárastu poznatkov týkajúcich sa cukrovky. Od úrovne empirickej sa posunula na úroveň fenotypickú, ktorá umožnila rozlišovanie medzi jednotlivými typmi diabetu. V rámci diabetu 2. typu sa od 60. rokov minulého storočia aplikovala patogenetická personalizácia, ktorá vychádzala z predpokladov, že u niektorých pacientov prevažuje inzulínová rezistencia a u iných deficit sekrécie inzulínu. Bioštatistická personalizácia (medicína dôkazov) viedla k dôkazom, na základe ktorých bol metformín zaradený do odporúčaní pre liečbu diabetu 2. typu ako liek prvej voľby. Randomizované štúdie v prvom desaťročí 21. storočia síce nedokázali superioritu žiadnej z iných liečebných modalít ako prídavnej liečby k metformínu, ale viedli k individualizácii cieľov glykemickej kompenzácie. V súčasnej dobe sa personalizácia posúva na úroveň farmakogenetickú, od ktorej môžeme v najbližších rokoch očakávať individualizáciu liečby v zmysle výberu liekov prvej, druhej a tretej voľby v závislosti od panelu kľúčových génových polymorfizmov charakterizujúcich citlivosť jedinca na konkrétne antidiabetiká. V konečnom dôsledku by mala byť „liečba ušitá na mieru“ vybratá na podklade syntézy patogenetických, bioštatistických a farmakogenetických poznatkov, čo bude reflektovať transláciu výsledkov základného biomedicinískeho výskumu do klinickej praxe. Kľúčové slová: diabetes 2. typu – farmakogenetika – medicína dôkazov – patogenéza – personalizovaná liečba
In recent years, the term “personalized medicine“ has been increasingly mentioned in relation to the endeavours to tailor the pharmaceutical as well as regimen therapy to the needs and requirements of individual patients. The personalization of antidiabetic treatment has undergone a dramatic advancement in relation to the expansion of knowledge about diabetes. From the empirical it moved forward to the phenotypic level which made it possible to differentiate between individual types of diabetes. The pathogenetic personalization which began to be used within Type 2 diabetes in the 1960s, was based on the assumption that while insulin resistance predominates in some patients, others are mainly affected by insulin secretion deficit. Biostatistics-personalized medicine (evidence based medicine) gathered evidence based on which metformin was included in recommendations on the therapy for Type 2 diabetes as a first-line drug. Although randomized studies during the first decade of the 21st century did not prove superiority of any other treatment modality as an adjunctive therapy used with metformin, they brought with them individualization of the goals of glycemic control. At present, personalization is heading towards the pharmacogenetic level that will enable in the near future individualized therapy in terms of choice of first-, second- and third-line drugs depending on the panel of key gene polymorphisms which characterize sensitivity of an individual to specific antidiabetics. Finally, the “tailor-maded therapy“ should be chosen based on a synthesis of pathogenetic, biostatistic and pharmacogenetic knowledge that will reflect the translation of results of the basic biomedical research into the clinical practice. Key words: evidence based medicine – pathogenesis – personalized therapy – pharmacogenetics – type 2 diabetes
Ivan Tkáč
The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. ...Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.
A. Paulík, J. Grim, S. Filip
Perorální antikoagulační léčba antagonisty K vitaminu (warfarin, acenokumarol a fenprokumon v Evropě, warfarin v USA, Kanadě, Asii a Africe) je široce rozšířená léčba v prevenci a léčbě žilního ...tromboembolismu, zvláště u nemocných s žilní trombózou a nemocných s fi brilací síní. Je všeobecně známo, že existuje značná interindividuální variabilita, vyžadující u řady nemocných časté laboratorní sledování a úpravu dávek. Účinnost léčby je sledována pomocí normalizovaného tromboplastinového času INR (International Normalized Ratio). Léčebné dávky jsou upravovány tak, aby bylo dosaženo doporučených hodnot INR. Cílem léčby je dosažení optimálního stavu, při němž se zabrání vzniku trombózy a nedojde ke krvácivým komplikacím. Farmakogenetické výzkumy posledního desetiletí prokázaly, že biotransformaci warfarinu ovlivňuje cytochrom P450. Cílovým enzymem warfarinu je však vitamin K-epoxid reduktáza s podjednotkou 1 (VKORC1), která je warfarinem ireverzibilně blokována. I když se na trhu v posledních letech objevují nová antitrombotika s přímým působením na klíčové koagulační faktory, je i nadále místo kumarinových antikoagulancií nezastupitelné. Klíčová slova: warfarin, kumarinová antikoagulancia, cytochrom P450, izoformy cytochromu P450 CyP2C9*2,*3, vitamin K-epoxid reduktáza (VKORC1).
Oral anticoagulation by vitamin K antagonists is widely used (warfarin, acenocoumarol and phenprocoumon in Europe and warfarin in the USA, Canada, Asia and Africa) to prevent or treat thrombosis, particularly in patients with venous thrombosis or atrial fi brillation. It is well known that great inter-individual variation of dose-response exists and requires frequent laboratory monitoring and dose modifi cation. Treatment effi cacy is evaluated by the International Normalized Ratio (INR). Doses of warfarin are adjusted to reach the optimal INR value. The aim is the optimal state – neither thrombosis nor bleeding complications. The pharmacogenetic research in last ten years showed that warfarin biotransformation is infl uenced by cytochrome P450. The main enzyme – vitamin K-epoxide reductase complex subunit 1 (VKORC1) is irreversibly blocked by warfarin treatment. Even if new antithrombotic drugs with direct target on key coagulation factors are known and available, the position of coumarin anticoagulants will be still important and irreplaceable. Key words: warfarin, coumarin anticoagulants, cytochrome P450, isoforms of cytochrome P450 CyP2C9 *2,*3, vitamin K-epoxide reductase subunit 1 (VKORC1).
Šlechtová J., Hajšmanová Z.
Lit.: 21
PDF