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The use of antidepressants has been steadily increasing. Even though the amount of evidence on the usefulness of personalized drug dosing in depression treatment is growing, there is still resistance and skepticism among physicians and regulators regarding the implementation of CYP450 genotyping and therapeutic drug monitoring in psychiatric clinical practice. The aim of this study was to quantify the opinions of psychiatrists and patients from three large psychiatric clinics in Belgrade, Serbia, and to examine what requirements need to be met to make changes in clinical guidelines or recommendations. All participants completed an anonymous questionnaire that was developed at the Faculty of Pharmacy, University of Belgrade. Fourteen practicing psychiatrists and 30 patients currently treated for depression completed the questionnaire. Distributions of opinion scores were compared between the psychiatrists and patients upon the visual inspection of the violin plots. Our results show that psychiatrists predominantly have a positive opinion on personalized dosing in psychiatry and that patients are most likely to comply with new approaches in depression pharmacotherapy. However, due to the long time needed for regulatory change, it is very unlikely that personalized dosing would be rapidly implemented in clinical practice, even if adequate evidence was to emerge. Upotreba antidepresiva je u stalnom porastu. Iako raste količina dokaza o korisnosti personalizovanog doziranja lekova u lečenju depresije, još uvek postoji veliki otpor i skepticizam među lekarima i regulatorima u pogledu primene CYP450 genotipizacije i terapijskog praćenja lekova u psihijatrijskoj kliničkoj praksi. Cilj ove studije je bio da se kvantifikuju mišljenja psihijatara i pacijenata sa tri velike psihijatrijske klinike u Beogradu, u Srbiji, i da se ispita koji zahtevi treba da budu ispunjeni da bi se izvršile promene u kliničkim smernicama ili preporukama za doziranje antidepresiva. Svi učesnici su popunili anonimni upitnik koji je izrađen na Farmaceutskom fakultetu Univerziteta u Beogradu. Upitnik je popunilo 44 učesnika, od kojih 14 psihijatara i 30 pacijenata koji se trenutno leče od depresije. Dodatno je kontaktiran i jedan stručnjak za farmakologiju. Distribucija ocena mišljenja je poređena između psihijatara i pacijenata nakon vizuelnog pregleda violina dijagrama. Naši rezultati pokazuju da psihijatri uglavnom imaju pozitivno mišljenje o personalizovanom doziranju u psihijatriji i da bi se pacijenti većinski pridržavali novih pristupa u farmakoterapiji depresije. Međutim, malo je verovatno da bi regulatorna tela u Srbiji brzo ažurirala svoje smernice, čak i ako bi se pojavili adekvatni dokazi.

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.Statini i nesteroidni protuupalni lijekovi (NSAID) učestalo se propisuju, pa i kao konkomitantna terapija. Postoji značajna interindividualna razlika u osjetljivosti na njihove najčešće nuspojave. Rizični čimbenici za razvoj nuspojava tih lijekova mogu biti povezani s lijekom i pacijentom ili s vanjskim čimbenicima. Polifarmacija je česta u kroničnih bolesnika i povećava rizik od razvoja interakcija lijekova. Istodobna primjena lijekovima koji inhibiraju CYP, UGT, ABC i / ili SLC prijenosnike lijekova (ABCB1, ABCG2 i OATP1B1) povezana je s produljenjem bioraspoloživosti lijekova, što rezultira povećanim rizikom od razvoja nuspojava. S tim u vezi, predstavljamo slučaj 46-godišnje žene koja je tijekom dvije godine doživjela akutno oštećenje bubrega i jetre, kao i mialgiju, dok je uzimala diklofenak, atorvastatin, fiksnu kombinaciju simvastatina / fenofibrata istovremeno s nekoliko drugih lijekova, uključujući pantoprazol i furosemid. Analiza dobivenih farmakogenetičkih rezultata te pregled dosadašnjeg znanja u tom području upućuju na zaključke da interakcije lijek-lijekgen mogu produljiti bioraspoloživost primijenjenih lijekova. Mehanizam se argumentirano temelji na sporijoj sposobnosti detoksikacije i smanjenoj eliminaciji putem jetre i bubrega, što rezultira toksičnošću za više organa. Jednako tako, prikazuje se važnost polimorfizama CYP u biotransformaciji endogenih supstrata poput arahidonske kiseline i u njihovoj modulacijskoj ulozi u patofiziološkim procesima. Danas postoje prilično značajni znanstveni dokazi o određenim farmakogenetičkim spoznajama koji rezultiraju povećanim rizikom od razvoja nuspojava za spomenute lijekove, no unatoč tomu, farmakogenetička analiza prije uvođenja lijekova u terapiju još nije uvedena u redovitu kliničku praksu.

Background The most common psychiatric complications due to dopaminergic treatment in Parkinson’s disease are visual hallucinations and impulse control disorders. Their development depends on clinical and genetic factors. Methods We evaluated the simultaneous effect of 16 clinical and 34 genetic variables on the occurrence of visual hallucinations and impulse control disorders. Altogether, 214 Parkinson’s disease patients were enrolled. Their demographic, clinical, and genotype data were obtained. Clinical and clinical-pharmacogenetic models were built by The Least Absolute Shrinkage and Selection Operator penalized logistic regression. The predictive capacity was evaluated with the cross-validated area under the receiver operating characteristic curve (AUC). Results The clinical-pharmacogenetic index for prediction of visual hallucinations encompassed age at diagnosis (OR = 0.99), rapid eye movement (REM) sleep behavior disorder (OR = 2.27), depression (OR = 1.0002), IL6 rs1800795 (OR = 0.99), GPX1 s1050450 (OR = 1.07), COMT rs165815 (OR = 0.69), MAOB rs1799836 (OR = 0.97), DRD3 rs6280 (OR = 1.32), and BIRC5 rs8073069 (OR = 0.94). The clinical-pharmacogenetic index for prediction of impulse control disorders encompassed age at diagnosis (OR = 0.95), depression (OR = 1.75), beta-blockers (OR = 0.99), coffee consumption (OR = 0.97), NOS1 rs2682826 (OR = 1.15), SLC6A3 rs393795 (OR = 1.27), SLC22A1 rs628031 (OR = 1.19), DRD2 rs1799732 (OR = 0.88), DRD3 rs6280 (OR = 0.88), and NRG1 rs3924999 (OR = 0.96). The cross-validated AUCs of clinical and clinical-pharmacogenetic models for visual hallucinations were 0.60 and 0.59, respectively. The AUCs of clinical and clinical-pharmacogenetic models for impulse control disorders were 0.72 and 0.71, respectively. The AUCs show that the addition of selected genetic variables to the analysis does not contribute to better prediction of visual hallucinations and impulse control disorders. Conclusions Models could be improved by a larger cohort and by addition of other types of Parkinson’s disease biomarkers to the analysis.

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants – 16.2 and 20.4 %, respectively – nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.

Individual variation in response to drugs is an important clinical problem, which ranges from failure to respond to the drug, over adverse reactions to drugs, to interactions among drugs being administered concurrently. Numerous findings indicate that the differences in the patients response on the same drug are caused by genetic variations. This is the subject of pharmacogenetics. Although pharmacogenetics generally equated with the concept of pharmacogenomics, pharmacogenetics is primarily related to variations in a single gene that influence the on drug response, while pharmacogenomics is a broader term, which studies how all of the genes (the genome) can influence responses to drugs. In focus of this paper will be individual variation in response to drugs arising from single nucleotide polymorphisms in genes encoding the drug target proteins, enzymes that metabolize drugs, drug transporters, and polymorphisms of genes responsible for toxicity and hypersensitivity to drugs. Determination of pharmacogenetic profile of patients could point out patients who are at increased risk of adverse drug effects (for which drug should be applied at lower doses or other drugs can be used) and those in which are likely to achieve the desired therapeutic effect, and so to enable individualization of therapy. Individualne varijacije u odgovoru na lekove važan su klinički problem i mogu dovesti do potpunog odsustva reakcije na lek i pojave neželjenih reakcija na lekove. Brojni nalazi ukazuju da su razlike u odgovoru bolesnika na isti lek uslovljene genetskim varijacijama, i predmet su istraživanja farmakogenetike. Iako se farmakogenetika uglavnom izjednačuje sa pojmom farmakogenomika, farmakogenetika se uglavnom odnosi na varijacije u jednom genu koje utiču na odgovor na lek, dok je farmakogenomika šira oblast, koja ispituje kako svi geni u genomu povezani sa metabolizmom određenog leka mogu uticati na odgovor na dati lek. U ovom radu prevashodno će biti opisane individualne varijacije u odgovoru na lekove koje nastaju usled jednonukletidnih polimorfizama u genima koji kodiraju ciljne proteine lekova, enzime koji metabolišu lekove, transportere lekova, kao i polimorfizmi gena koji su odgovorni za toksičnost i preosetljivost na lekove. Određivanje farmakogenetskog profila bolesnika moglo bi da ukaže na bolesnike koji su u povećanom riziku od pojave neželjenih efekata lekova (kod kojih bi trebalo da se primene niže doze ili drugi lekovi) i na one kod kojih će se najverovatnije postići željeni terapijski efekat, odnosno da omogući individualizaciju terapije.

Farmakoģenētika pēta indivīdu ģenētisko īpatnību ietekmi uz zāļu vielas atbildes reakciju. Mutācijas gēnos var ietekmēt zāļu vielu metabolisma ātrumu – palēninot to vai pretēji – paātrinot metabolisma procesus, kā rezultātā terapija var būt neefektīva. Darba “Eksoma dati farmakoģenētikas pielietojumā / aspektā /gaismā” mērķis bija analizēt eksoma datus, noskaidrot un pierādīt piecu pacientu mutācijas, kuras saistītas ar medikamentu metabolismu. Tika veikta eksoma datu analīze, PCR sekvenēšanas reakcijas, sekvenēšanas rezultātu analīze, aprakstīto mutāciju apkopošana. Darbā tika izmantoti 5 paraugu eksoma dati. Tika analizētas CYP2C19, CYP2D6, CYP4F2, CYP2C9 un CYP2B6 gēnu sekvenču variācijas. 4 paraugiem tika pierādītas mutācijas rs3758581, rs16947, rs1065852, 2108622, rs1057910 un rs3745274., Pharmacogenetics investigates the impact of individual genetic features on the drug substance response. Gene mutations can affect drug substances rate of metabolism by slowing it or vice versa - by speeding up the metabolic processes, which can lead to inefficiency of the treatment. The purpose of the paper "Exome sequencing use in pharmacogenetics" was to analyze exome data to clarify and demonstrate the mutations associated with drug metabolism of five patients. Exome data analysis, reactions of PCR sequencing and analysis of results sequencing was performed; the described mutation were collected. The study used a sample of 5 exome data. CYP2C19, CYP2D6, CYP4F2, CYP2C9, CYP2B6 gene sequence variations were analyzed. Mutations rs3758581, rs16947, rs1065852, 2108622, rs1057910 and rs37452744 were found in 4 samples.

Darba aktualitāte: Otrā tipa cukura diabēta (2TCD) prevalence pieaug gan Latvijas, gan pasaules mērogā. Pacientiem ir nepieciešama personalizēta pieeja, kas labāk ļautu sasniegt terapijas mērķi un izvairīties no komplikācijām. Sulfonilurea (SU) preparāti ir viena no visbiežāk izmantotajām perorālo antidiabētisko preparātu klasēm, tāpēc ir būtiski apzināt šo preparātu individuālos efektus. Pētījuma mērķis: Noskaidrot, vai SU preparātu farmakoģenētika ietekmē 2TCD pacientu ārstēšanas rezultātu. Metodes un materiāli: Longitudinālā prospektīvā pētījumā tika iesaistīti 315 2TCD pacienti, retrospektīvi tika iesaistīti 162, no kuriem kopumā sulfonilurea preparātus bija lietojuši 162, atlases kritērijiem atbilda 51 pacients, kas tika iekļauts statistiskajā analīzē. Tika noteikta gēnu polimorfismu efektivitāte terapijā ar SU preparātiem iepriekš ziņotiem polimorfismiem, kā arī izvērtēta 2TCD riska gēnu un to polimorfismu ietekme uz terapijas mērķi. Rezultāti un secinājumi: Jau zināmajiem polimorfismiem, kam ir ietekme uz SU efektivitāti (rs12255372 (TCF7L2), rs7903146 (TCF7L2), rs5210 (KCNJ11), rs10494366 (NOS1AP), rs7754840 (CDKAL1), rs757110 (ABCC8)), mūsu izlasē netika atrasta statistiski nozīmīga saistība. Pārbaudot 2TCD riska gēnu polimorfismus, tika atrasta statistiski nozīmīga saistība polimorfismam rs2237895 (KCNQ1) ar SU efektivitāti, palielināts C alēļu skaits saistījās ar labāku Δ HbA1c neatkarīgi no SU lietošanas ilguma vai devas. Būtu nepieciešama tālāka izpēte polimorfisma rs2237895 (KCNQ1) ietekmei uz terapijas efektivitāti pacientiem, kas lietojuši SU preparātus, plašākos pētījumos., Background: The prevalence of type 2 diabetes is increasing all around the world. Understanding an individual`s genetic background is believed to be key to realizing personalized medicine that aims to maximize drug efficacy and minimize complications. Sulphonylureas are widely used class of oral antidiabetic medications, it is essential to explore individual effects of these medications. Aims: To find out if pharmacogenetics of sulphonylureas afftects treatment outcome of type 2 diabetes. Methods: Overall 477 type 2 diabetes patients were recruited: 315 in prospective follow – up study, 162 – retrospectively. 162 of them had been taking sulphonylureas, selection criteria met 51 patient who were included in statistical analysis. We determined if there are associations between previously reported polymorphisms and efficacy of sulphonylureas. We also investigated if there is impact of risk genes of type 2 diabetes on efficacy of sulphonylureas. Results and conclusions: We did not found statistically significant association between previously reported polymorphisms (rs12255372 (TCF7L2), rs7903146 (TCF7L2), rs5210 (KCNJ11), rs10494366 (NOS1AP), rs7754840 (CDKAL1), rs757110 (ABCC8)) which affect treatment efficacy of sulphonylureas and outcome of treatment. We found new association between type 2 diabetes risk gene polymorphism rs2237895 (KCNQ1) and efficacy of sulphonylureas. Carriers with greater number of C alleles had better Δ HbA1c after treatment with sulphonylureas. Further pharmacogenetic studies are necessary to confirm our findings and reveal underlying mechanisms in larger populations.

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV–1–infected patients dramatically since it was launched in 1996, but there are still many challenges in the provision of HAART, especially to children in resource limited countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI) forms part of the recommended national first line antiretroviral treatment regimen for children older than 3 years and weighing more than 10 kg in South Africa. Limited pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1– infected children is available. EFV is primarily metabolised by hepatic CYP2B6 isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual variability in hepatic expression and activity. The single nucleotide change, 516G>T, on the CYP2B6 gene has consistently been associated with elevated EFV plasma levels in different ethnic populations and these are more frequently observed in populations of African descent. The recommended therapeutic range of EFV plasma levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml. In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders, with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy (ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic, Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics approval was obtained to conduct this study. The objectives of this investigation were to: develop and validate a suitable LCMS/ MS method to accurately determine plasma EFV levels from this study population, determine the prevalence and effect of CYP2B6 516G>T polymorphism on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F) value of EFV, identify covariates that influence the clearance of EFV in HIV–1– infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24 months post–HAART initiation. The main findings of the measured mid–dose EFV plasma concentrations showed that sub–therapeutic concentrations (4 ug/ml) represented 29.5% (192/649). A significant number of the samples (47.5%) were outside the accepted therapeutic range during this 24 month follow–up period. Possible reasons contributing to this include genetic variation in drug metabolism and non–adherence. Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42% 516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant frequency was relatively high at 41%. This also supports and explains why such a large number (29.5%) of the mid–dose interval plasma samples were above (>4 ug/ml) the accepted therapeutic range. Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T genotypes were consistently predictive of the log EFV concentrations at all times (P = 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P4 ug/ml) and most side effects subsided spontaneously. 89% of the participants were virally suppressed at 24 months post–HAART. The efficacy of this EFV–based treatment did not affect the three genotype groups differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post– HAART initiation. We found no association of the CYP2B6 516G>T polymorphism and side effects reported after 1 month of treatment within this study population. The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were, 2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion variability (IOV) in a PK model for a longitudinal study was again highlighted by this investigation. To our knowledge, this is the first study in black South African HIV–1–infected children with measured sequential EFV plasma concentrations which also investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma concentrations and the population clearance (CL/F) value of EFV in a longitudinal study over a period of 24 months post–HAART initiation. Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.