CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6

The Quantum Hall Effect with Wilczek's charged magnetic flux tubes instead of electrons

Composites formed from charged particles and magnetic flux tubes, proposed by Wilczek, are one model for anyons - particles obeying fractional statistics. Here we propose a scheme for realizing charged flux tubes, in which a charged object with an intrinsic magnetic dipole moment is placed between two semi-infinite blocks of a high permeability ($\mu_r$) material, and the images of the magnetic moment create an effective flux tube. We show that the scheme can lead to a realization of Wilczek's anyons, when a two-dimensional electron system, which exhibits the integer quantum Hall effect (IQHE), is sandwiched between two blocks of the high-$\mu_r$ material with a temporally fast response (in the cyclotron and Larmor frequency range). The signature of Wilczek's anyons is a slight shift of the resistivity at the plateau of the IQHE. Thus, the quest for high-$\mu_r$ materials at high frequencies, which is underway in the field of metamaterials, and the quest for anyons, are here found to be on the same avenue.Comment: are welcom

Design of a Steel Manufacturing Hall : Undergraduate Thesis

Na temelju zadanih podataka čelične hale potrebno je dimenzionirati glavnu nosivu konstrukciju, sekundarne nosače te spregove konstrukcije. Objekt se nalazi na području Splita. Proračun se provodi na temelju krajnjeg graničnog stanja (KGS) i graničnog stanja uporabljivosti (GSU). Opterećenja koja se javljaju na konstrukciji su stalno: vlastita težina i promjenjivo: snijeg i vjetar. Rezultati unutarnjih sila dobiveni su u računalnom programu „Scia Engineer 2016“Based on the information about a steel manufacturing hall, our assignment is to design this structure: it is main supporting structure, secondary structure and bracings. Object is located in Split. Estimate is based on ultimate limit state (ULS) and serviceability limit states (SLS). Loads are permanent: self weight and variable: snow and wind. Results are from „Scia Engineer 2016

Unapređenje personalizacije doziranja psihijatrijskih lekova uz pomoć molekularne dijagnostike

Determining the correct dose, with the aim to achieve optimal exposure, is very important in psychiatric clinical practice, since underexposed patients are less likely to respond to treatment and since adverse drug reactions likelihood and severity is increased in overexposed patients. CYP2C19 and CYP2D6 enzymes metabolize majority of psychiatric drugs and their genetic polymorphism determines patient’s metabolic capacity. The aim was to evaluate the clinical utility of therapeutic drug concentration monitoring and preemptive CYP genotyping. Several retrospective and prospective cohorts of patients, with known CYP genotype and drug levels, were analyzed with the aim to evaluate the association between CYP2C19 and CYP2D6 metabolizer categories on drug exposure, efficacy, and tolerability. Based on 4,700 patients, currently available CYP2D6 metabolizer categorization is not correct and it needs revisions (1). Based on data from 8,379 patients, clinically relevant changes in escitalopram and sertraline exposure are detected in CYP2C19 slow metabolizers, while clinically relevant changes in aripiprazole and risperidone exposure are detected in CYP2D6 slow metabolizers (2). Under standard dosing, almost a half of patients treated with these four drugs are not exposed to optimal drug levels. Since such a substantial amount of patients is wrongly dosed for these four drugs, therapeutic drug monitoring of blood concentration, appropriate metabolizer categorization, and pre-emptive CYP genotyping can improve treatment outcomes for these drugs.Utvrđivanje tačne doze leka, sa ciljem da se postigne optimalna izloženost leku, je veoma važna u psihijatrijskoj kliničkoj praksi, zato što subdozirani pacijenti lošije odgovaraju na lek, a predozirani pacijenti bivaju izloženi neželjenim efektima češće i neželjeni efekti su intenzivniji. CYP2C19 i CYP2D6 enzimi metabolišu većinu psihijatrijskih lekova i genetski polimorfizam na odgovarajućim genima određuje metabolički kapacitet pacijenta. Cilj je bio da se oceni klinička korisnost terapeutskog praćenja koncentracije leka i genotipizacije CYP gena. Nekoliko retrospektivnih i prospektivnih kohorti pacijenata, sa poznatim vrednostima koncentracije leka i CYP genotipom su analizirani sa ciljem evaluacije i kvantifikacije uticaja CYP2C19 i CYP2D6 metaboličkih kategorija na izloženost psihijatrijskim lekovima, kao i na efikasnost i sigurnost terapije ovim lekovima. Na osnovu podataka dobijenih na 4.700 pacijenata, trenutno važeća klasifikacija CYP2D6 metaboličkih kategorija nije tačna i potrebno ju je izmeniti (1). Na osnovu podataka dobijenih na 8.379 pacijenata, klinički značajne promene izloženosti escitalopramu i sertralinu su primećene kod CYP2C19 sporih metabolizera, dok su klinički značajne promene izloženosti aripiprazolu i risperidonu primećene kod CYP2D6 sporih metabolizera (2). Pod standardnim doznim režimom, gotovo polovina pacijenata nije izložena optimalnoj koncentraciji ova četiri leka. Budući da je značajan broj pacijenata pod terapijom pogrešnom dozom ova četiri leka, terapeutsko praćenje nivoa leka u krvi, adekvatna kategorizacija metabolizera i CYP genotipizacija pre početka terapije mogu da poboljšaju ishod terapije ovim lekovima.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Main Design of the Residential-Business Building in Mejaši Street in Split : Master's Thesis

U radu je prikazan glavni projekt stambeno-poslovne zgrade koja se nalazi u Ulici Mejaši u Splitu. Građevina se sastoji od dva dijela (zgrade), ukupne katnosti nad zemljom: 10 i 5 katova te ukopanom garažom koja ih povezuje, ukupne katnosti 2 kata. Građevina je izvedena u armiranom betonu, sve monolitne izvedbe s armirano-betonskim zidovima, stupovima i armirano-betonskim pločama kao međukatnom konstrukcijom. Projekt sadrži: tehnički opis konstrukcije, opće i posebne tehničke uvjete, plan kontrole i osiguranja kvalitete, proračun nosivih konstrukcijskih elemenata i karakteristične građevinske nacrte i armaturne planove.Main design of the residential-business building, which is positioned in Mejaši Street in Split, is presented in this work. The building is consist of two separate parts (two buildings), with total number of uperground stories: 10 and 5, and underground garage with two stories, which connect this two parts. Building is made of reinforced concrete elements: walls, columns and ceiling slabs, all casting in site. The work include technical description of the structure, general and particular conditions of civil engineering works, control plan and quality assurance plan, calculation of the main structural elements as well as characteristic structural plans and reinforcement plans

Main Design of the Residential-Business Building in Mejaši Street in Split : Master's Thesis

U radu je prikazan glavni projekt stambeno-poslovne zgrade koja se nalazi u Ulici Mejaši u Splitu. Građevina se sastoji od dva dijela (zgrade), ukupne katnosti nad zemljom: 10 i 5 katova te ukopanom garažom koja ih povezuje, ukupne katnosti 2 kata. Građevina je izvedena u armiranom betonu, sve monolitne izvedbe s armirano-betonskim zidovima, stupovima i armirano-betonskim pločama kao međukatnom konstrukcijom. Projekt sadrži: tehnički opis konstrukcije, opće i posebne tehničke uvjete, plan kontrole i osiguranja kvalitete, proračun nosivih konstrukcijskih elemenata i karakteristične građevinske nacrte i armaturne planove.Main design of the residential-business building, which is positioned in Mejaši Street in Split, is presented in this work. The building is consist of two separate parts (two buildings), with total number of uperground stories: 10 and 5, and underground garage with two stories, which connect this two parts. Building is made of reinforced concrete elements: walls, columns and ceiling slabs, all casting in site. The work include technical description of the structure, general and particular conditions of civil engineering works, control plan and quality assurance plan, calculation of the main structural elements as well as characteristic structural plans and reinforcement plans

The Harper-Hofstadter Hamiltonian and conical diffraction in photonic lattices with grating assisted tunneling

We introduce a grating assisted tunneling scheme for tunable synthetic magnetic fields in photonic lattices, which can be implemented at optical frequencies in optically induced one- and two-dimensional dielectric photonic lattices. We demonstrate a conical diffraction pattern in particular realization of these lattices which possess Dirac points in $k$-space, as a signature of the synthetic magnetic fields. The two-dimensional photonic lattice with grating assisted tunneling constitutes the realization of the Harper-Hofstadter Hamiltonian.Comment: are welcome; figures 2c,d obtained with somewhat better parameter value

Design of a Steel Manufacturing Hall : Undergraduate Thesis

Na temelju zadanih podataka čelične hale potrebno je dimenzionirati glavnu nosivu konstrukciju, sekundarne nosače te spregove konstrukcije. Objekt se nalazi na području Splita. Proračun se provodi na temelju krajnjeg graničnog stanja (KGS) i graničnog stanja uporabljivosti (GSU). Opterećenja koja se javljaju na konstrukciji su stalno: vlastita težina i promjenjivo: snijeg i vjetar. Rezultati unutarnjih sila dobiveni su u računalnom programu „Scia Engineer 2016“Based on the information about a steel manufacturing hall, our assignment is to design this structure: it is main supporting structure, secondary structure and bracings. Object is located in Split. Estimate is based on ultimate limit state (ULS) and serviceability limit states (SLS). Loads are permanent: self weight and variable: snow and wind. Results are from „Scia Engineer 2016

Stav pacijenata i psihijatara o trenutnom stanju farmakoterapije depresije u Srbiji i mogućnosti uvođenja personalizovane farmakoterapije i njenim potencijalnim efektima

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

Da li su adultna neurogeneza i glukokortikoidna signalizacija spona između stresa i depresije?

Depression contributes substantially to disease burden worldwide; however despite of this, the progress in understanding its pathophysiology has been extremely slow and the discovery of new therapeutic mechanisms is at a near standstill. The molecular targets of current major classes of antidepressants were all reverse engineered from drugs previously discovered by serendipitous clinical observations. Since the existence of adult-born neurons was unequivocally documented, adult neurogenesis became a very promising, but also very hyped target for antidepressant drugs. Introduction of corticotrophin releasing hormone inhibitors aimed to exploit a prospective reduction of glucocorticoid-mediated inhibition of adult neurogenesis with the aim to produce antidepressant effect. Although these drugs failed to demonstrate efficiency in phase three clinical trials, they provided the following valuable lesions for the future: (1) Inter-species differences between animals and humans should be considered very carefully, (2) Animal model phenotypes mimicking depression should be more robust, preferably shown by multiple behavioral paradigms, and (3) variability between different subgroups of depression should be taken into consideration because of the pronounced heterogeneity of the disease.Iako depresija značajno doprinosi morbiditetu na globalnom nivou, napredak u razumevanju patofiziologije ove bolesti je izuzetno spor, pa su posledično, otkrića novih terapeutskih mehanizama praktično u zastoju. Ciljni molekuli preko kojih deluju antidepresivi koji su danas u upotrebi identifikovani su reverznim inženjeringom lekova otkrivenih empirijski, kliničkim zapažanjima. Otkad je jasno pokazano postojanje novonastalih neurona, adultna neurogeneza je postala izuzetno atraktivna potencijalna meta delovanja kandidata za antidepresivne lekove. Uvođenje inhibitora kortikotropin-oslobađajućeg hormona imalo je za cilj da se iskoristi činjenica da glukokortikoidni hormoni inhibiraju adultnu neurogenezu i time doprinose antisdepresivnom efektu. Iako su se ovi lekovi pokazali kao neefikasni u trećoj fazi kliničkih studija, naučene su sledeće važne lekcije za budućnost: (1) razlike u funkcionisanju mozga ljudi i životinja moraju biti pažljivo razmotrene, (2) da bi se zaključilo da animalni model ima depresivni fenotip, isti je potrebno ubedljivo demonstrirati, po mogućstvu korišćenjem većeg broja bihejvioralnih testova i (3) varijacije u simptomima između različitih podklasa depresije treba uzeti u obzir imajući u vidu heterogenost oboljenja