TY  - JOUR
AU  - Milosavljević, Filip
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5593
AB  - The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.
PB  - Elsevier B.V.
T2  - European Neuropsychopharmacology
T1  - Current level of evidence for improvement of antidepressant efficacy and
tolerability by pharmacogenomic-guided treatment: A Systematic review
and meta-analysis of randomized controlled clinical trials
VL  - 81
SP  - 43
EP  - 52
DO  - 10.1016/j.euroneuro.2024.01.005
ER  - 

@article{
author = "Milosavljević, Filip and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2024",
abstract = "The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.",
publisher = "Elsevier B.V.",
journal = "European Neuropsychopharmacology",
title = "Current level of evidence for improvement of antidepressant efficacy and
tolerability by pharmacogenomic-guided treatment: A Systematic review
and meta-analysis of randomized controlled clinical trials",
volume = "81",
pages = "43-52",
doi = "10.1016/j.euroneuro.2024.01.005"
}

Milosavljević, F., Molden, E., Ingelman-Sundberg, M.,& Jukić, M.. (2024). Current level of evidence for improvement of antidepressant efficacy and
tolerability by pharmacogenomic-guided treatment: A Systematic review
and meta-analysis of randomized controlled clinical trials. in European Neuropsychopharmacology
Elsevier B.V.., 81, 43-52.
https://doi.org/10.1016/j.euroneuro.2024.01.005

Milosavljević F, Molden E, Ingelman-Sundberg M, Jukić M. Current level of evidence for improvement of antidepressant efficacy and
tolerability by pharmacogenomic-guided treatment: A Systematic review
and meta-analysis of randomized controlled clinical trials. in European Neuropsychopharmacology. 2024;81:43-52.
doi:10.1016/j.euroneuro.2024.01.005 .

Milosavljević, Filip, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "Current level of evidence for improvement of antidepressant efficacy and
tolerability by pharmacogenomic-guided treatment: A Systematic review
and meta-analysis of randomized controlled clinical trials" in European Neuropsychopharmacology, 81 (2024):43-52,
https://doi.org/10.1016/j.euroneuro.2024.01.005 . .

TY  - JOUR
AU  - Milosavljević, Filip
AU  - Brusini, Irene
AU  - Atanasov, Andrea
AU  - Manojlović, Marina
AU  - Vučić, Marija
AU  - Oreščanin-Dušić, Zorana
AU  - Brkljačić, Jelena
AU  - Miljević, Čedo
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Wang, Chunliang
AU  - Damberg, Peter
AU  - Pešić, Vesna
AU  - Tyndale, Rachel F.
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4516
AB  - Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
PB  - John Wiley and Sons Inc
T2  - Neuropathology and Applied Neurobiology
T1  - The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
VL  - 49
IS  - 1
DO  - 10.1111/nan.12867
ER  - 

@article{
author = "Milosavljević, Filip and Brusini, Irene and Atanasov, Andrea and Manojlović, Marina and Vučić, Marija and Oreščanin-Dušić, Zorana and Brkljačić, Jelena and Miljević, Čedo and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Wang, Chunliang and Damberg, Peter and Pešić, Vesna and Tyndale, Rachel F. and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2023",
abstract = "Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.",
publisher = "John Wiley and Sons Inc",
journal = "Neuropathology and Applied Neurobiology",
title = "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia",
volume = "49",
number = "1",
doi = "10.1111/nan.12867"
}

Milosavljević, F., Brusini, I., Atanasov, A., Manojlović, M., Vučić, M., Oreščanin-Dušić, Z., Brkljačić, J., Miljević, Č., Nikolić-Kokić, A., Blagojević, D., Wang, C., Damberg, P., Pešić, V., Tyndale, R. F., Ingelman-Sundberg, M.,& Jukić, M.. (2023). The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology
John Wiley and Sons Inc., 49(1).
https://doi.org/10.1111/nan.12867

Milosavljević F, Brusini I, Atanasov A, Manojlović M, Vučić M, Oreščanin-Dušić Z, Brkljačić J, Miljević Č, Nikolić-Kokić A, Blagojević D, Wang C, Damberg P, Pešić V, Tyndale RF, Ingelman-Sundberg M, Jukić M. The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology. 2023;49(1).
doi:10.1111/nan.12867 .

Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin-Dušić, Zorana, Brkljačić, Jelena, Miljević, Čedo, Nikolić-Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel F., Ingelman-Sundberg, Magnus, Jukić, Marin, "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia" in Neuropathology and Applied Neurobiology, 49, no. 1 (2023),
https://doi.org/10.1111/nan.12867 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Milosavljević, Filip
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4307
AB  - Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.
PB  - Elsevier Ltd
T2  - Trends in Pharmacological Sciences
T1  - Pharmacogenomics in treatment of depression and psychosis: an update
VL  - 43
IS  - 12
SP  - 1055
EP  - 1069
DO  - 10.1016/j.tips.2022.09.011
ER  - 

@article{
author = "Jukić, Marin and Milosavljević, Filip and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.",
publisher = "Elsevier Ltd",
journal = "Trends in Pharmacological Sciences",
title = "Pharmacogenomics in treatment of depression and psychosis: an update",
volume = "43",
number = "12",
pages = "1055-1069",
doi = "10.1016/j.tips.2022.09.011"
}

Jukić, M., Milosavljević, F., Molden, E.,& Ingelman-Sundberg, M.. (2022). Pharmacogenomics in treatment of depression and psychosis: an update. in Trends in Pharmacological Sciences
Elsevier Ltd., 43(12), 1055-1069.
https://doi.org/10.1016/j.tips.2022.09.011

Jukić M, Milosavljević F, Molden E, Ingelman-Sundberg M. Pharmacogenomics in treatment of depression and psychosis: an update. in Trends in Pharmacological Sciences. 2022;43(12):1055-1069.
doi:10.1016/j.tips.2022.09.011 .

Jukić, Marin, Milosavljević, Filip, Molden, Espen, Ingelman-Sundberg, Magnus, "Pharmacogenomics in treatment of depression and psychosis: an update" in Trends in Pharmacological Sciences, 43, no. 12 (2022):1055-1069,
https://doi.org/10.1016/j.tips.2022.09.011 . .

TY  - JOUR
AU  - Pridgeon, Chris
AU  - Bolhuis, Dian
AU  - Milosavljević, Filip
AU  - Manojlović, Marina
AU  - Végvári, Ákos
AU  - Gaetani, Massimiliano
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4111
AB  - The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.
PB  - MDPI
T2  - Cells
T1  - Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids
VL  - 11
IS  - 10
DO  - 10.3390/cells11101597
ER  - 

@article{
author = "Pridgeon, Chris and Bolhuis, Dian and Milosavljević, Filip and Manojlović, Marina and Végvári, Ákos and Gaetani, Massimiliano and Jukić, Marin and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.",
publisher = "MDPI",
journal = "Cells",
title = "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids",
volume = "11",
number = "10",
doi = "10.3390/cells11101597"
}

Pridgeon, C., Bolhuis, D., Milosavljević, F., Manojlović, M., Végvári, Á., Gaetani, M., Jukić, M.,& Ingelman-Sundberg, M.. (2022). Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells
MDPI., 11(10).
https://doi.org/10.3390/cells11101597

Pridgeon C, Bolhuis D, Milosavljević F, Manojlović M, Végvári Á, Gaetani M, Jukić M, Ingelman-Sundberg M. Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells. 2022;11(10).
doi:10.3390/cells11101597 .

Pridgeon, Chris, Bolhuis, Dian, Milosavljević, Filip, Manojlović, Marina, Végvári, Ákos, Gaetani, Massimiliano, Jukić, Marin, Ingelman-Sundberg, Magnus, "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids" in Cells, 11, no. 10 (2022),
https://doi.org/10.3390/cells11101597 . .

TY  - JOUR
AU  - Joković, Danilo
AU  - Milosavljević, Filip
AU  - Stojanović, Zvezdana
AU  - Šupić, Gordana
AU  - Vojvodić, Danilo
AU  - Uzelac, Bojana
AU  - Jukić, Marin
AU  - Petković Ćurčin, Aleksandra
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4080
AB  - The inter-individual variability in CYP2C19-mediated metabolism may affect the antidepressant treatment. The aim of this study is to evaluate differences in antidepressant efficacy and tolerability between different CYP2C19 metabolizer categories in inpatients suffering from major depressive disorder. The cohort was divided into experimental groups based on CYP2C19 genotype and it contained 24 slow (SMs), 41 normal (NMs), and 37 fast metabolizers (FMs). Efficacy and tolerability were assessed at baseline, and after two and four weeks as a follow- up. The primary efficacy measurement was the change from baseline in Hamilton’s Depression Rating Scale (HAMD), while the primary tolerability measurement was the Toronto Side-Effects Scale (TSES) intensity scores at the last visit. The reduction in HAMD score was 36% less pronounced and response rate was exceedingly less prevalent (75% lower) in SMs, compared with NMs. The TSES intensity score was increased in SMs, compared with NMs, by 43% for central nervous system and by 22% for gastrointestinal adverse drug reactions. No sig- nificant differences in measured parameters were observed between NMs and FMs. Compared with NM and RM, lower antidepressant efficacy and tolerability was observed in SMs; this association is likely connected with the lower SM capacity to metabolize antidepressant drugs.
PB  - Elsevier Ireland Ltd
T2  - Psychiatry Research
T1  - CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability
VL  - 312
DO  - 10.1016/j.psychres.2022.114535
ER  - 

@article{
author = "Joković, Danilo and Milosavljević, Filip and Stojanović, Zvezdana and Šupić, Gordana and Vojvodić, Danilo and Uzelac, Bojana and Jukić, Marin and Petković Ćurčin, Aleksandra",
year = "2022",
abstract = "The inter-individual variability in CYP2C19-mediated metabolism may affect the antidepressant treatment. The aim of this study is to evaluate differences in antidepressant efficacy and tolerability between different CYP2C19 metabolizer categories in inpatients suffering from major depressive disorder. The cohort was divided into experimental groups based on CYP2C19 genotype and it contained 24 slow (SMs), 41 normal (NMs), and 37 fast metabolizers (FMs). Efficacy and tolerability were assessed at baseline, and after two and four weeks as a follow- up. The primary efficacy measurement was the change from baseline in Hamilton’s Depression Rating Scale (HAMD), while the primary tolerability measurement was the Toronto Side-Effects Scale (TSES) intensity scores at the last visit. The reduction in HAMD score was 36% less pronounced and response rate was exceedingly less prevalent (75% lower) in SMs, compared with NMs. The TSES intensity score was increased in SMs, compared with NMs, by 43% for central nervous system and by 22% for gastrointestinal adverse drug reactions. No sig- nificant differences in measured parameters were observed between NMs and FMs. Compared with NM and RM, lower antidepressant efficacy and tolerability was observed in SMs; this association is likely connected with the lower SM capacity to metabolize antidepressant drugs.",
publisher = "Elsevier Ireland Ltd",
journal = "Psychiatry Research",
title = "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability",
volume = "312",
doi = "10.1016/j.psychres.2022.114535"
}

Joković, D., Milosavljević, F., Stojanović, Z., Šupić, G., Vojvodić, D., Uzelac, B., Jukić, M.,& Petković Ćurčin, A.. (2022). CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability. in Psychiatry Research
Elsevier Ireland Ltd., 312.
https://doi.org/10.1016/j.psychres.2022.114535

Joković D, Milosavljević F, Stojanović Z, Šupić G, Vojvodić D, Uzelac B, Jukić M, Petković Ćurčin A. CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability. in Psychiatry Research. 2022;312.
doi:10.1016/j.psychres.2022.114535 .

Joković, Danilo, Milosavljević, Filip, Stojanović, Zvezdana, Šupić, Gordana, Vojvodić, Danilo, Uzelac, Bojana, Jukić, Marin, Petković Ćurčin, Aleksandra, "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability" in Psychiatry Research, 312 (2022),
https://doi.org/10.1016/j.psychres.2022.114535 . .

TY  - THES
AU  - Milosavljević, Filip
PY  - 2022
UR  - https://eteze.bg.ac.rs/application/showtheses?thesesId=9082
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:29312/bdef:Content/download
UR  - https://plus.cobiss.net/cobiss/sr/sr/bib/80769289
UR  - https://nardus.mpn.gov.rs/handle/123456789/21427
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4969
AB  - Postoji mogućnost da genetski predodređene razlike između osoba u kapacitetu CYP450enzima mogu uticati na farmakoterapiju u psihijatriji. Cilj ovog istraživanja bio je preciznakvantifikacije uticaja CYP2C19/CYP2D6 fenotipa na izloženost antidepresivima iantipsihoticima metodom meta-analize odnosa srednjih vrednosti. Drugi cilj bio jeispitivanje uticaja CYP2C19 fenotipa na efikasnost i podnošljivost antidepresiva pomoćukliničke studije u kojoj su hospitalizovani pacijenti praćeni četiri nedelje.Serija meta-analiza podataka iz 94 jedinstvene studije na ukupno 8379 precizno jekvantifikovala povećanu izloženost escitalopramu (+163%; 95%CI: +140%, 189%;n=1262, p<0,0001) i sertralinu (+38%; 95%CI: +27%, +51%; n=917, p<0,0001) kod osobasa genetski predviđenim smanjenim kapacitetom CYP2C19 enzima, kao i povećanuizloženost risperidonu (+36%; 95%CI: +28%, +44%; n=1492, p<0,0001), aripiprazolu(+48%; 95%CI: +41%, +57%; n=1038, p<0,0001) i haloperidolu (+68%; CI95%: 40%,102%; n=423, p<0.0001) kod osoba sa genetski predviđenim smanjenim kapacitetomCYP2D6 enzima. Klinička studija demonstrirala je da su, u toku četiri nedelje, osobe sasporijim CYP2C19 metabolizmom imale 36% (95%CI: 20-52%, p<0,0001) manje izraženopoboljšanje simptoma depresije (praćeno Hamilton skalom za depresiju) i značajno većiintenzitet neželjenih efekata vezanih za gastrointestinalni (q=0,002) i centralni nervnisistem (q=0,045) što je mereno Toronto skalom, u odnosu na kontrolne osobe.Zbog visoke preciznosti kvantifikacije, rezultati meta-analiza mogu poslužiti kao osnova zakliničke smernice za precizno doziranje ispitivanih lekova na osnovu CYP2C19/CYP2D6genotipa. Takođe, rezultati kliničke studije naglašavaju da CYP2C19 genotip može bitiklinički važna informacija u psihijatrijskoj praksi.
AB  - Genetically predicted interindividual differences in activites of CYP450 enzymes maysignificantly influence pharmacotherapy in psychiatry. The aim of this research was toprecisely quantify the influence of CYP2C19/CYP2D6 phenotype on the exposure toantidepressants and antipsychotics with ratio-of-means meta-analysis. Other aim was todetermine the influence of CYP2C19 phenotype on the efficacy and tolerability ofantidepressants in the clinical study of inpatients that were monitored for four weeks.Meta-analyses of the data from 94 unique studies and 8379 participants preciselyquantified the increased exposure to escitalopram (+163%; 95%CI: +140%, 189%;n=1262, p<0.0001) and sertraline (+38%; 95%CI: +27%, +51%; n=917, p<0.0001) inparticipants with genetically predicted decreased CYP2C19 capacity; and increasedexposure to risperidon (+36%; 95%CI: +28%, +44%; n=1492, p<0.0001), aripiprazole(+48%; 95%CI: +41%, +57%; n=1038, p<0.0001) and haloperidol (+68%; CI95%: 40%,102%; n=423, p<0.0001) in participants with genetically predicted decreased CYP2D6enzyme capacity. Clinical study revealed that, during 4 weeks, patients with decreasedCYP2C19 activity had 36% (95%CI: 20-52%, p<0.0001) less pronounced depressionsymptom improvement (monitored with Hamilton depression rating scale), and significantlyhigher intensity of central nervous system (q=0.002) and gastrointestinal (q=0.042)adverse reactions (monitored with Toronto adverse reaction scale), compared to controls.Due to high quantification precision, results of the meta-analyses may serve as a basis forprecise dosing guidelines, for examined drugs, that are based on CYP2C19/CYP2D6genotype. Also, clinical study results suggest that CYP2C19 genotype may be usefulclinical information in psychiatric practice.
PB  - Универзитет у Београду, Фармацеутски факултет
T2  - Универзитет у Београду
T1  - Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera
UR  - https://hdl.handle.net/21.15107/rcub_nardus_21427
ER  - 

@phdthesis{
author = "Milosavljević, Filip",
year = "2022",
abstract = "Postoji mogućnost da genetski predodređene razlike između osoba u kapacitetu CYP450enzima mogu uticati na farmakoterapiju u psihijatriji. Cilj ovog istraživanja bio je preciznakvantifikacije uticaja CYP2C19/CYP2D6 fenotipa na izloženost antidepresivima iantipsihoticima metodom meta-analize odnosa srednjih vrednosti. Drugi cilj bio jeispitivanje uticaja CYP2C19 fenotipa na efikasnost i podnošljivost antidepresiva pomoćukliničke studije u kojoj su hospitalizovani pacijenti praćeni četiri nedelje.Serija meta-analiza podataka iz 94 jedinstvene studije na ukupno 8379 precizno jekvantifikovala povećanu izloženost escitalopramu (+163%; 95%CI: +140%, 189%;n=1262, p<0,0001) i sertralinu (+38%; 95%CI: +27%, +51%; n=917, p<0,0001) kod osobasa genetski predviđenim smanjenim kapacitetom CYP2C19 enzima, kao i povećanuizloženost risperidonu (+36%; 95%CI: +28%, +44%; n=1492, p<0,0001), aripiprazolu(+48%; 95%CI: +41%, +57%; n=1038, p<0,0001) i haloperidolu (+68%; CI95%: 40%,102%; n=423, p<0.0001) kod osoba sa genetski predviđenim smanjenim kapacitetomCYP2D6 enzima. Klinička studija demonstrirala je da su, u toku četiri nedelje, osobe sasporijim CYP2C19 metabolizmom imale 36% (95%CI: 20-52%, p<0,0001) manje izraženopoboljšanje simptoma depresije (praćeno Hamilton skalom za depresiju) i značajno većiintenzitet neželjenih efekata vezanih za gastrointestinalni (q=0,002) i centralni nervnisistem (q=0,045) što je mereno Toronto skalom, u odnosu na kontrolne osobe.Zbog visoke preciznosti kvantifikacije, rezultati meta-analiza mogu poslužiti kao osnova zakliničke smernice za precizno doziranje ispitivanih lekova na osnovu CYP2C19/CYP2D6genotipa. Takođe, rezultati kliničke studije naglašavaju da CYP2C19 genotip može bitiklinički važna informacija u psihijatrijskoj praksi., Genetically predicted interindividual differences in activites of CYP450 enzymes maysignificantly influence pharmacotherapy in psychiatry. The aim of this research was toprecisely quantify the influence of CYP2C19/CYP2D6 phenotype on the exposure toantidepressants and antipsychotics with ratio-of-means meta-analysis. Other aim was todetermine the influence of CYP2C19 phenotype on the efficacy and tolerability ofantidepressants in the clinical study of inpatients that were monitored for four weeks.Meta-analyses of the data from 94 unique studies and 8379 participants preciselyquantified the increased exposure to escitalopram (+163%; 95%CI: +140%, 189%;n=1262, p<0.0001) and sertraline (+38%; 95%CI: +27%, +51%; n=917, p<0.0001) inparticipants with genetically predicted decreased CYP2C19 capacity; and increasedexposure to risperidon (+36%; 95%CI: +28%, +44%; n=1492, p<0.0001), aripiprazole(+48%; 95%CI: +41%, +57%; n=1038, p<0.0001) and haloperidol (+68%; CI95%: 40%,102%; n=423, p<0.0001) in participants with genetically predicted decreased CYP2D6enzyme capacity. Clinical study revealed that, during 4 weeks, patients with decreasedCYP2C19 activity had 36% (95%CI: 20-52%, p<0.0001) less pronounced depressionsymptom improvement (monitored with Hamilton depression rating scale), and significantlyhigher intensity of central nervous system (q=0.002) and gastrointestinal (q=0.042)adverse reactions (monitored with Toronto adverse reaction scale), compared to controls.Due to high quantification precision, results of the meta-analyses may serve as a basis forprecise dosing guidelines, for examined drugs, that are based on CYP2C19/CYP2D6genotype. Also, clinical study results suggest that CYP2C19 genotype may be usefulclinical information in psychiatric practice.",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera",
url = "https://hdl.handle.net/21.15107/rcub_nardus_21427"
}

Milosavljević, F.. (2022). Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera. in Универзитет у Београду
Универзитет у Београду, Фармацеутски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_21427

Milosavljević F. Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera. in Универзитет у Београду. 2022;.
https://hdl.handle.net/21.15107/rcub_nardus_21427 .

Milosavljević, Filip, "Meta-analiza podataka o razlikama u izloženosti psihijatrijskim lekovima između sporih i normalnih CYP2C19/CYP2D6 metabolizera" in Универзитет у Београду (2022),
https://hdl.handle.net/21.15107/rcub_nardus_21427 .

TY  - JOUR
AU  - Jeremić, Aleksandra
AU  - Milosavljević, Filip
AU  - Opanković, Ana
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4305
AB  - 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.
AB  - 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.
PB  - Pharmaceutical Association of Serbia
T2  - Arhiv za farmaciju
T1  - Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects
T1  - Stav pacijenata i psihijatara o trenutnom stanju farmakoterapije depresije u Srbiji i mogućnosti uvođenja personalizovane farmakoterapije i njenim potencijalnim efektima
VL  - 72
IS  - 4
SP  - 381
EP  - 391
DO  - 10.5937/arhfarm72-37613
ER  - 

@article{
author = "Jeremić, Aleksandra and Milosavljević, Filip and Opanković, Ana and Jukić, Marin",
year = "2022",
abstract = "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.",
publisher = "Pharmaceutical Association of Serbia",
journal = "Arhiv za farmaciju",
title = "Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects, Stav pacijenata i psihijatara o trenutnom stanju farmakoterapije depresije u Srbiji i mogućnosti uvođenja personalizovane farmakoterapije i njenim potencijalnim efektima",
volume = "72",
number = "4",
pages = "381-391",
doi = "10.5937/arhfarm72-37613"
}

Jeremić, A., Milosavljević, F., Opanković, A.,& Jukić, M.. (2022). Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects. in Arhiv za farmaciju
Pharmaceutical Association of Serbia., 72(4), 381-391.
https://doi.org/10.5937/arhfarm72-37613

Jeremić A, Milosavljević F, Opanković A, Jukić M. Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects. in Arhiv za farmaciju. 2022;72(4):381-391.
doi:10.5937/arhfarm72-37613 .

Jeremić, Aleksandra, Milosavljević, Filip, Opanković, Ana, Jukić, Marin, "Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects" in Arhiv za farmaciju, 72, no. 4 (2022):381-391,
https://doi.org/10.5937/arhfarm72-37613 . .

TY  - CONF
AU  - Manojlović, Marina
AU  - Milosavljević, Filip
AU  - Atanasov, Andrea
AU  - Batinić, Bojan
AU  - Sitarica, Pavle
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4728
AB  - Background: Due to the COVID-19 pandemic, the prevalence of anxiety and
depression disorders increased by approximately 25-30% [1]. Reasons behind
this are likely associated with the increased average daily level of stress, especially during social isolation. Since one of the main adolescence hallmarks is
formation of meaningful social and love relationships, it represents a particularly
vulnerable period for social stress [2]. The aim of this study was to evaluate
whether isolation stress during the adolescence causes general and social anxiety
in rats.
Methods: Sprague-Dawley rats of both sexes were used for the adolescence social
isolation experiment. From the fourth postnatal week, 24 rats were single caged
and therefore subjected to the social isolation stress, while 24 non-stressed
control rats remained in groups of four per cage and were handled three times a
week. All rats were handled daily for one week and weighted before behavioural
tests. From eleventh week, rats were subjected to the open field, elevated plus
maze, and three-chamber sociability tests, with two-day gap between different
tests. In open field test, time spent in the centre was measured, while in the
elevated plus maze test, the time spent in open arms, normalized to time spent in
all arms was measured; reduction in values of these parameters was interpreted
as general anxiety. In the social preference test, social preference ratio was
calculated for each animal, according to the previously published protocol [3],
and reduction in this ratio was interpreted as social anxiety. 2-way ANOVA, with
sex and isolation stress as factors, was used for parametric data analysis, and
Fischer’s post hoc test was used to detect statistically significant between group
differences. Kruskal-Wallis test was used for non-parametric data analysis, and
Mann-Whitney post hoc test with multiple comparison correction was used to
detect statistically significant between group differences.
Results: Compared to control rats, time spent in the centre of open field (-44%
[95%CI: -76%, -12%] p¼0,008) and total distance travelled (-17% [95%CI:
-32%, -2%], p¼0.028) were decreased in isolated males, but not in females
(p>0.1). In elevated plus maze test, time spent in the open arms was significantly
decreased in male isolated rats (isolated: [median: 0.76, IQR: 0.00 – 2.06] vs
control: [median: 4.96, IQR: 2.04 – 17.75], p¼0.034); however, this change did
not remain significant after multiple comparisons corrections. In sociability tests,
both male and female isolated rats exhibited increase in social preference ratio
(+32% [95%CI: 12%, 51%], p¼0.002) and preference for novel animal over
familiar one (+48% [95%CI: 10%, 86%], p¼0.015), compared to control rats.
Body weight, measured after six weeks of social isolation at week ten, was
increased in isolated male compared to control rats (+19% [95%CI: 14%, 24%],
p<0.001), while there was no such difference observed in female rats.
Conclusion: Social isolation caused increase in general anxiety in male, but not
female rats. In addition, both male and female rats exhibited robust increase in
preference for social interaction and novel social stimulus, which is the result
opposite from the expected social anxiety as initially hypothesized.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats
VL  - 1
IS  - Supplement 2
SP  - 19
EP  - 19
DO  - 10.1016/j.nsa.2022.100149
ER  - 

@conference{
author = "Manojlović, Marina and Milosavljević, Filip and Atanasov, Andrea and Batinić, Bojan and Sitarica, Pavle and Jukić, Marin",
year = "2022",
abstract = "Background: Due to the COVID-19 pandemic, the prevalence of anxiety and
depression disorders increased by approximately 25-30% [1]. Reasons behind
this are likely associated with the increased average daily level of stress, especially during social isolation. Since one of the main adolescence hallmarks is
formation of meaningful social and love relationships, it represents a particularly
vulnerable period for social stress [2]. The aim of this study was to evaluate
whether isolation stress during the adolescence causes general and social anxiety
in rats.
Methods: Sprague-Dawley rats of both sexes were used for the adolescence social
isolation experiment. From the fourth postnatal week, 24 rats were single caged
and therefore subjected to the social isolation stress, while 24 non-stressed
control rats remained in groups of four per cage and were handled three times a
week. All rats were handled daily for one week and weighted before behavioural
tests. From eleventh week, rats were subjected to the open field, elevated plus
maze, and three-chamber sociability tests, with two-day gap between different
tests. In open field test, time spent in the centre was measured, while in the
elevated plus maze test, the time spent in open arms, normalized to time spent in
all arms was measured; reduction in values of these parameters was interpreted
as general anxiety. In the social preference test, social preference ratio was
calculated for each animal, according to the previously published protocol [3],
and reduction in this ratio was interpreted as social anxiety. 2-way ANOVA, with
sex and isolation stress as factors, was used for parametric data analysis, and
Fischer’s post hoc test was used to detect statistically significant between group
differences. Kruskal-Wallis test was used for non-parametric data analysis, and
Mann-Whitney post hoc test with multiple comparison correction was used to
detect statistically significant between group differences.
Results: Compared to control rats, time spent in the centre of open field (-44%
[95%CI: -76%, -12%] p¼0,008) and total distance travelled (-17% [95%CI:
-32%, -2%], p¼0.028) were decreased in isolated males, but not in females
(p>0.1). In elevated plus maze test, time spent in the open arms was significantly
decreased in male isolated rats (isolated: [median: 0.76, IQR: 0.00 – 2.06] vs
control: [median: 4.96, IQR: 2.04 – 17.75], p¼0.034); however, this change did
not remain significant after multiple comparisons corrections. In sociability tests,
both male and female isolated rats exhibited increase in social preference ratio
(+32% [95%CI: 12%, 51%], p¼0.002) and preference for novel animal over
familiar one (+48% [95%CI: 10%, 86%], p¼0.015), compared to control rats.
Body weight, measured after six weeks of social isolation at week ten, was
increased in isolated male compared to control rats (+19% [95%CI: 14%, 24%],
p<0.001), while there was no such difference observed in female rats.
Conclusion: Social isolation caused increase in general anxiety in male, but not
female rats. In addition, both male and female rats exhibited robust increase in
preference for social interaction and novel social stimulus, which is the result
opposite from the expected social anxiety as initially hypothesized.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats",
volume = "1",
number = "Supplement 2",
pages = "19-19",
doi = "10.1016/j.nsa.2022.100149"
}

Manojlović, M., Milosavljević, F., Atanasov, A., Batinić, B., Sitarica, P.,& Jukić, M.. (2022). Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats. in Neuroscience Applied
Elsevier., 1(Supplement 2), 19-19.
https://doi.org/10.1016/j.nsa.2022.100149

Manojlović M, Milosavljević F, Atanasov A, Batinić B, Sitarica P, Jukić M. Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats. in Neuroscience Applied. 2022;1(Supplement 2):19-19.
doi:10.1016/j.nsa.2022.100149 .

Manojlović, Marina, Milosavljević, Filip, Atanasov, Andrea, Batinić, Bojan, Sitarica, Pavle, Jukić, Marin, "Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats" in Neuroscience Applied, 1, no. Supplement 2 (2022):19-19,
https://doi.org/10.1016/j.nsa.2022.100149 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Brusini, Irene
AU  - Atanasov, Andrea
AU  - Manojlović, Marina
AU  - Vučić, Marija
AU  - Oreščanin-Dušić, Zorana
AU  - Brkljačić, Jelena
AU  - Sitarica, Pavle
AU  - Miljević, Čedo
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Wang, Chunliang
AU  - Damberg, Peter
AU  - Pešić, Vesna
AU  - Tyndale, Rachel
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4729
AB  - Background: Animal models are essential for understanding aetiology and pathophysiology of movement disorders. Previously, it had been found that mice transgenic for the human CYP2C19 gene, which is expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality [1, 2]. The aim of this study was to characterize motoric phenotype of the CYP2C19 transgenic mouse and validate its potential usefulness as an animal model for ataxia.

Methods: Experiments were performed on CYP2C19 transgenic mice and control wild-type littermate mice. Body weight of mice was measured between the 21st and 42nd postnatal day. Mouse gait was analysed with footprint test [3] in young animals at four time points and once in adult mice. The maximal height of hindpaw elevation while walking was measured offline from the video footage of the footprint test. Motoric function was quantified by the rotarod and beam-walking tests. Structural differences in 20 brain regions of wild-type and transgenic mice were investigated with 9.4T gadolinium-enhanced postmortem neuroimaging. Antioxidative enzyme status was determined in the brain tissue in order to assess potential differences in the brain oxidative-antioxidative balance between wild-type and transgenic mice. When multiple brain regions or multiple antioxidant enzyme activities were analysed, p-values were FDR corrected for multiple comparisons.

Results: CYP2C19 transgenic (TG) animals exhibited approximately 5-10% reduced body weight (p=0.015) during 3rd and 4th postnatal week, while after postnatal day 31, the differences in the body weight were no longer statistically significant. The TG animals exhibited approximately two fold higher maximal hindpaw elevation in young (2.1-fold [CI95%: 2.0, 2.2], p<0.0001) and adult mice (1.9-fold [CI95%: 1.8, 2.1], p<0.0001), compared to wild-types. In the 5th postnatal week, all transgenic mice exhibited increase in elevation of both hindpaws, while after this point they gradually started exhibiting unilateral phenotype until almost all (49 of 51) animals became unilaterally affected in the adulthood. Footprint analysis and rotarod test did not detect significant differences (p>0.1) between TG and control mice in any of the analysed parameters, accounting for all examined time points. CYP2C19 transgenic mice exhibited 14% increase in beam crossing time (14%, [95%CI: 6.4, 22], p=0.0014) and 5.6-fold more paw-slips (p<0.0001, n=89) in the beam-walking test. CYP2C19 transgenic mice exhibited profound reduction in cerebellar volume (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59) and moderate reduction in hippocampal volume (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59); compared to the corresponding volumes measured in WT mice. Superoxide dismutase activity was slightly increased (1.14-fold [CI95%: 1.06, 1.23], p=0.0010, q=0.023) in the cerebelli and moderately increased (1.3-fold, [CI95%: 1.18, 1.47], p<0.0001, q=0.0013) in the hippocampi of transgenic mice compared to wild-types, while glutathione reductase activity was significantly increased (1.2-fold [CI95%: 1.13, 1.35], p<0.0001, q=0.0021) in the hippocampi of TG mice.

Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function, functional motoric impairments and reduced cerebellar volume. CYP2C19 transgenic mice can be a useful tool for the studies focused on understanding the physiology of cerebellar development, as well as aetiology and pathophysiology of cerebellum-related disorders.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia
VL  - 1
IS  - Supplement 2
SP  - 64
EP  - 64
DO  - 10.1016/j.nsa.2022.100236
ER  - 

@conference{
author = "Milosavljević, Filip and Brusini, Irene and Atanasov, Andrea and Manojlović, Marina and Vučić, Marija and Oreščanin-Dušić, Zorana and Brkljačić, Jelena and Sitarica, Pavle and Miljević, Čedo and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Wang, Chunliang and Damberg, Peter and Pešić, Vesna and Tyndale, Rachel and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2022",
abstract = "Background: Animal models are essential for understanding aetiology and pathophysiology of movement disorders. Previously, it had been found that mice transgenic for the human CYP2C19 gene, which is expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality [1, 2]. The aim of this study was to characterize motoric phenotype of the CYP2C19 transgenic mouse and validate its potential usefulness as an animal model for ataxia.

Methods: Experiments were performed on CYP2C19 transgenic mice and control wild-type littermate mice. Body weight of mice was measured between the 21st and 42nd postnatal day. Mouse gait was analysed with footprint test [3] in young animals at four time points and once in adult mice. The maximal height of hindpaw elevation while walking was measured offline from the video footage of the footprint test. Motoric function was quantified by the rotarod and beam-walking tests. Structural differences in 20 brain regions of wild-type and transgenic mice were investigated with 9.4T gadolinium-enhanced postmortem neuroimaging. Antioxidative enzyme status was determined in the brain tissue in order to assess potential differences in the brain oxidative-antioxidative balance between wild-type and transgenic mice. When multiple brain regions or multiple antioxidant enzyme activities were analysed, p-values were FDR corrected for multiple comparisons.

Results: CYP2C19 transgenic (TG) animals exhibited approximately 5-10% reduced body weight (p=0.015) during 3rd and 4th postnatal week, while after postnatal day 31, the differences in the body weight were no longer statistically significant. The TG animals exhibited approximately two fold higher maximal hindpaw elevation in young (2.1-fold [CI95%: 2.0, 2.2], p<0.0001) and adult mice (1.9-fold [CI95%: 1.8, 2.1], p<0.0001), compared to wild-types. In the 5th postnatal week, all transgenic mice exhibited increase in elevation of both hindpaws, while after this point they gradually started exhibiting unilateral phenotype until almost all (49 of 51) animals became unilaterally affected in the adulthood. Footprint analysis and rotarod test did not detect significant differences (p>0.1) between TG and control mice in any of the analysed parameters, accounting for all examined time points. CYP2C19 transgenic mice exhibited 14% increase in beam crossing time (14%, [95%CI: 6.4, 22], p=0.0014) and 5.6-fold more paw-slips (p<0.0001, n=89) in the beam-walking test. CYP2C19 transgenic mice exhibited profound reduction in cerebellar volume (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59) and moderate reduction in hippocampal volume (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59); compared to the corresponding volumes measured in WT mice. Superoxide dismutase activity was slightly increased (1.14-fold [CI95%: 1.06, 1.23], p=0.0010, q=0.023) in the cerebelli and moderately increased (1.3-fold, [CI95%: 1.18, 1.47], p<0.0001, q=0.0013) in the hippocampi of transgenic mice compared to wild-types, while glutathione reductase activity was significantly increased (1.2-fold [CI95%: 1.13, 1.35], p<0.0001, q=0.0021) in the hippocampi of TG mice.

Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function, functional motoric impairments and reduced cerebellar volume. CYP2C19 transgenic mice can be a useful tool for the studies focused on understanding the physiology of cerebellar development, as well as aetiology and pathophysiology of cerebellum-related disorders.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia",
volume = "1",
number = "Supplement 2",
pages = "64-64",
doi = "10.1016/j.nsa.2022.100236"
}

Milosavljević, F., Brusini, I., Atanasov, A., Manojlović, M., Vučić, M., Oreščanin-Dušić, Z., Brkljačić, J., Sitarica, P., Miljević, Č., Nikolić-Kokić, A., Blagojević, D., Wang, C., Damberg, P., Pešić, V., Tyndale, R., Ingelman-Sundberg, M.,& Jukić, M.. (2022). Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia. in Neuroscience Applied
Elsevier., 1(Supplement 2), 64-64.
https://doi.org/10.1016/j.nsa.2022.100236

Milosavljević F, Brusini I, Atanasov A, Manojlović M, Vučić M, Oreščanin-Dušić Z, Brkljačić J, Sitarica P, Miljević Č, Nikolić-Kokić A, Blagojević D, Wang C, Damberg P, Pešić V, Tyndale R, Ingelman-Sundberg M, Jukić M. Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia. in Neuroscience Applied. 2022;1(Supplement 2):64-64.
doi:10.1016/j.nsa.2022.100236 .

Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin-Dušić, Zorana, Brkljačić, Jelena, Sitarica, Pavle, Miljević, Čedo, Nikolić-Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel, Ingelman-Sundberg, Magnus, Jukić, Marin, "Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia" in Neuroscience Applied, 1, no. Supplement 2 (2022):64-64,
https://doi.org/10.1016/j.nsa.2022.100236 . .

TY  - CONF
AU  - Joković, Danilo
AU  - Milosavljević, Filip
AU  - Stojanović, Zvezdana
AU  - Šupić, Gordana
AU  - Vojvodić, Danilo
AU  - Jukić, Marin
AU  - Uzelac, Bojana
AU  - Petković-Ćurčić, Aleksandra
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4730
AB  - Introduction: Available antidepressants are not always effective and the discovery of new antidepressants is slow. Since most antidepressants are metabolized by polymorphic CYP450 liver enzymes, it has been hypothesized that personalized dosing that takes into the account genotype-predicted CYP450 enzyme capacity may improve their effectiveness [1]. Even though it is well known that CYP450 polymorphism impacts plasma levels of many antidepressants [2,3], available evidence on the impact of CYP450 polymorphism on antidepressant efficacy and tolerability is insufficiently strong and often conflicting.

Aim: The aim of this study was to test if CYP2C19 genotype influences efficacy and tolerability of antidepressant therapy in the cohort of 102 inpatients.

Methods: The study was performed at the Military Medical Academy in Belgrade, Serbia. Patients hospitalized for depression and treated with at least one antidepressant were included if they signed the informed consent form. Patients were monitored at the hospital admission and after two and four weeks of follow-up. The drug efficacy was measured with HAM-D (Hamilton depression rating) scale, while tolerability was monitored by TSES (Toronto Side-effects scale) [4]. Patients were retrospectively genotyped for CYP2C19 after the study completion and subsequently categorized as Slow (SM), Normal (NM), or Fast metabolizers (FM). Differences between CYP2C19 metabolizer groups at week four were compared with ANCOVA for HAM-D score, Kruskal-Wallis test for TSES and binary-logistic regression for response rate. Individual adverse reactions were analysed with post-hoc Man-Whitney test.

Results: In total, 102 patients were included; 41 were NM controls, 24 were SM and 37 were RM. Most commonly prescribed primary antidepressants were escitalopram (n=20), trazodone (n=14), mirtazapine (n=12), sertraline (n=12) and venlafaxine (n=10). The fluoxetine-equivalent doses were the not different across groups (p>0.1). While all categories experienced significant reduction in HAMD score during 4 weeks, compared with NMs, the reduction was 36% ([CI95%: 20% - 52%], p<0.0001) less pronounced among SMs. Similarly, response rate was 75% lower in SMs compared with NMs (NM: 34/41 vs SM: 5/24, p<0.0001); response was defined as ≥50% reduction in HAMD score [5]. Finally, SM patients had higher median intensity scores than NMs at week 4 (NM median: 2.5 [IQR: 2.0 - 3.2] vs SM median: 3.2 [IQR: 2.8 - 3.7]; p=0.021, q=0.042). Post hoc analysis revealed that increased burden of nervousness, agitation, and dyspepsia contributed the most to the worse tolerability in SMs. There were no significant differences between FM and NM patients in any of the measured outcomes.

Conclusions: This study revealed that, in the cohort of inpatients treated with heterogeneous antidepressants, the reduced CYP2C19 metabolic capacity is associated with worse therapy efficacy and tolerability, whereas the increased CYP2C19 metabolic capacity is not. Therefore, it is likely that SM group does not receive the appropriate treatment under standard psychiatric practice, which is in most cases unaware of the patients’ CYP2C19 genotype. Even though this study does not have sufficient power for an unequivocal conclusion related to the need of pre-emptive CYP2C19 genotyping of antidepressant treated patients, it contributes to the body of already existing evidence on the clinical usefulness of CYP2C19 genotyping in psychiatry.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients
VL  - 1
IS  - Supplement 2
SP  - 54
EP  - 55
DO  - 10.1016/j.nsa.2022.100217
ER  - 

@conference{
author = "Joković, Danilo and Milosavljević, Filip and Stojanović, Zvezdana and Šupić, Gordana and Vojvodić, Danilo and Jukić, Marin and Uzelac, Bojana and Petković-Ćurčić, Aleksandra",
year = "2022",
abstract = "Introduction: Available antidepressants are not always effective and the discovery of new antidepressants is slow. Since most antidepressants are metabolized by polymorphic CYP450 liver enzymes, it has been hypothesized that personalized dosing that takes into the account genotype-predicted CYP450 enzyme capacity may improve their effectiveness [1]. Even though it is well known that CYP450 polymorphism impacts plasma levels of many antidepressants [2,3], available evidence on the impact of CYP450 polymorphism on antidepressant efficacy and tolerability is insufficiently strong and often conflicting.

Aim: The aim of this study was to test if CYP2C19 genotype influences efficacy and tolerability of antidepressant therapy in the cohort of 102 inpatients.

Methods: The study was performed at the Military Medical Academy in Belgrade, Serbia. Patients hospitalized for depression and treated with at least one antidepressant were included if they signed the informed consent form. Patients were monitored at the hospital admission and after two and four weeks of follow-up. The drug efficacy was measured with HAM-D (Hamilton depression rating) scale, while tolerability was monitored by TSES (Toronto Side-effects scale) [4]. Patients were retrospectively genotyped for CYP2C19 after the study completion and subsequently categorized as Slow (SM), Normal (NM), or Fast metabolizers (FM). Differences between CYP2C19 metabolizer groups at week four were compared with ANCOVA for HAM-D score, Kruskal-Wallis test for TSES and binary-logistic regression for response rate. Individual adverse reactions were analysed with post-hoc Man-Whitney test.

Results: In total, 102 patients were included; 41 were NM controls, 24 were SM and 37 were RM. Most commonly prescribed primary antidepressants were escitalopram (n=20), trazodone (n=14), mirtazapine (n=12), sertraline (n=12) and venlafaxine (n=10). The fluoxetine-equivalent doses were the not different across groups (p>0.1). While all categories experienced significant reduction in HAMD score during 4 weeks, compared with NMs, the reduction was 36% ([CI95%: 20% - 52%], p<0.0001) less pronounced among SMs. Similarly, response rate was 75% lower in SMs compared with NMs (NM: 34/41 vs SM: 5/24, p<0.0001); response was defined as ≥50% reduction in HAMD score [5]. Finally, SM patients had higher median intensity scores than NMs at week 4 (NM median: 2.5 [IQR: 2.0 - 3.2] vs SM median: 3.2 [IQR: 2.8 - 3.7]; p=0.021, q=0.042). Post hoc analysis revealed that increased burden of nervousness, agitation, and dyspepsia contributed the most to the worse tolerability in SMs. There were no significant differences between FM and NM patients in any of the measured outcomes.

Conclusions: This study revealed that, in the cohort of inpatients treated with heterogeneous antidepressants, the reduced CYP2C19 metabolic capacity is associated with worse therapy efficacy and tolerability, whereas the increased CYP2C19 metabolic capacity is not. Therefore, it is likely that SM group does not receive the appropriate treatment under standard psychiatric practice, which is in most cases unaware of the patients’ CYP2C19 genotype. Even though this study does not have sufficient power for an unequivocal conclusion related to the need of pre-emptive CYP2C19 genotyping of antidepressant treated patients, it contributes to the body of already existing evidence on the clinical usefulness of CYP2C19 genotyping in psychiatry.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients",
volume = "1",
number = "Supplement 2",
pages = "54-55",
doi = "10.1016/j.nsa.2022.100217"
}

Joković, D., Milosavljević, F., Stojanović, Z., Šupić, G., Vojvodić, D., Jukić, M., Uzelac, B.,& Petković-Ćurčić, A.. (2022). CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients. in Neuroscience Applied
Elsevier., 1(Supplement 2), 54-55.
https://doi.org/10.1016/j.nsa.2022.100217

Joković D, Milosavljević F, Stojanović Z, Šupić G, Vojvodić D, Jukić M, Uzelac B, Petković-Ćurčić A. CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients. in Neuroscience Applied. 2022;1(Supplement 2):54-55.
doi:10.1016/j.nsa.2022.100217 .

Joković, Danilo, Milosavljević, Filip, Stojanović, Zvezdana, Šupić, Gordana, Vojvodić, Danilo, Jukić, Marin, Uzelac, Bojana, Petković-Ćurčić, Aleksandra, "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients" in Neuroscience Applied, 1, no. Supplement 2 (2022):54-55,
https://doi.org/10.1016/j.nsa.2022.100217 . .

TY  - CONF
AU  - Vuković, Petar
AU  - Jeremić, Aleksandra
AU  - Vezmar, Milica
AU  - Pešić, Danilo
AU  - Drakulić, Jelena
AU  - Milosavljević, Filip
AU  - Miljević, Čedo
AU  - Marić-Bojović, Nađa
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4732
AB  - Background: Considering the negative impact of anxiety and depression on society and lack of emergence of new antidepressants, it is of paramount importance to utilize the available treatment options in the best manner possible. Escitalopram is a commonly prescribed antidepressant that is predominantly metabolized by the polymorphic CYP2C19 liver enzyme and consequently, CYP2C19 genotype affects escitalopram metabolism. Previous report showed a strong association between CYP2C19 genotype and escitalopram exposure [1]; therefore, CYP2C19 genotype is a potentially clinically relevant feature in escitalopram treatment, since underdosed patients exhibit lower escitalopram treatment effectiveness [2] and since escitalopram adverse drug reactions (ADR) are dose dependent [3]. Objective of this prospective cohort clinical trial is to evaluate the impact of escitalopram dose adjustment based on escitalopram exposure on treatment efficacy and safety.

Methods: In this prospective cohort study patients suffering from depression were assessed for potential clinical benefits of a personalized dosing regimen for escitalopram, which is based on therapeutic drug monitoring of escitalopram plasma level. Treatment effectiveness was evaluated based on Hamilton depression rating scale (HAM-D), which was performed one day prior to escitalopram treatment initiation (Baseline, Visit 0), as well as after four (Visit 1) and eight (Visit 2) weeks of follow-up. Side effect assessment was based on Scandinavian UKU Side effects rating scale, which was performed at V1 and V2. In case of need, dose adjustment was performed at V1 and was guided by the measured steady state drug plasma level using HPLC two weeks after treatment initiation, with the aim to achieve the optimal exposure to escitalopram in every patient at V2. Relative change in HAM-D and UKU scale readouts from V1 to V2, were compared between comparator (dose was adjusted) and control (dose was not adjusted) groups by independent samples t-test and Chi-square test, respectively. The study protocol in full detail is available on clincaltrials.gov [4]

Results: To this day, 25 participants completed the study, and out of these, 19 participants required dose adjustment between visits. There were no statistically significant differences in the change in HAM-D scores from V1 to V2 between groups (p>0.1). In the comparator group, 11/19 patients reported ADRs, compared to 2/6 patients in control group. Appearance of new, or worsening of the existing ADRs between V1 and V2 was reported in 6/19 patients in the comparator group and in 1/6 patients in the control group. There was no statistically significant difference between groups in ADR emergence or worsening (p>0.1)

Conclusion: The dose of escitalopram in 19 participants was augmented, but did not show statistically significant improvement in treatment effectiveness when compared to control group. There was no statistically significant increase in ADR frequencies in the dose augmentation group either, which is in concordance with the hypothesis that dose increase in underdosed patients does not lead to the increase of ADR frequency and severity. Noteworthy, since this report represents interim analysis on a sample which is approximately one fourth of the planned cohort, the conclusions are not yet unequivocal.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment
VL  - 1
IS  - Supplement 2
SP  - 331
EP  - 332
DO  - 10.1016/j.nsa.2022.100765
ER  - 

@conference{
author = "Vuković, Petar and Jeremić, Aleksandra and Vezmar, Milica and Pešić, Danilo and Drakulić, Jelena and Milosavljević, Filip and Miljević, Čedo and Marić-Bojović, Nađa and Jukić, Marin",
year = "2022",
abstract = "Background: Considering the negative impact of anxiety and depression on society and lack of emergence of new antidepressants, it is of paramount importance to utilize the available treatment options in the best manner possible. Escitalopram is a commonly prescribed antidepressant that is predominantly metabolized by the polymorphic CYP2C19 liver enzyme and consequently, CYP2C19 genotype affects escitalopram metabolism. Previous report showed a strong association between CYP2C19 genotype and escitalopram exposure [1]; therefore, CYP2C19 genotype is a potentially clinically relevant feature in escitalopram treatment, since underdosed patients exhibit lower escitalopram treatment effectiveness [2] and since escitalopram adverse drug reactions (ADR) are dose dependent [3]. Objective of this prospective cohort clinical trial is to evaluate the impact of escitalopram dose adjustment based on escitalopram exposure on treatment efficacy and safety.

Methods: In this prospective cohort study patients suffering from depression were assessed for potential clinical benefits of a personalized dosing regimen for escitalopram, which is based on therapeutic drug monitoring of escitalopram plasma level. Treatment effectiveness was evaluated based on Hamilton depression rating scale (HAM-D), which was performed one day prior to escitalopram treatment initiation (Baseline, Visit 0), as well as after four (Visit 1) and eight (Visit 2) weeks of follow-up. Side effect assessment was based on Scandinavian UKU Side effects rating scale, which was performed at V1 and V2. In case of need, dose adjustment was performed at V1 and was guided by the measured steady state drug plasma level using HPLC two weeks after treatment initiation, with the aim to achieve the optimal exposure to escitalopram in every patient at V2. Relative change in HAM-D and UKU scale readouts from V1 to V2, were compared between comparator (dose was adjusted) and control (dose was not adjusted) groups by independent samples t-test and Chi-square test, respectively. The study protocol in full detail is available on clincaltrials.gov [4]

Results: To this day, 25 participants completed the study, and out of these, 19 participants required dose adjustment between visits. There were no statistically significant differences in the change in HAM-D scores from V1 to V2 between groups (p>0.1). In the comparator group, 11/19 patients reported ADRs, compared to 2/6 patients in control group. Appearance of new, or worsening of the existing ADRs between V1 and V2 was reported in 6/19 patients in the comparator group and in 1/6 patients in the control group. There was no statistically significant difference between groups in ADR emergence or worsening (p>0.1)

Conclusion: The dose of escitalopram in 19 participants was augmented, but did not show statistically significant improvement in treatment effectiveness when compared to control group. There was no statistically significant increase in ADR frequencies in the dose augmentation group either, which is in concordance with the hypothesis that dose increase in underdosed patients does not lead to the increase of ADR frequency and severity. Noteworthy, since this report represents interim analysis on a sample which is approximately one fourth of the planned cohort, the conclusions are not yet unequivocal.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment",
volume = "1",
number = "Supplement 2",
pages = "331-332",
doi = "10.1016/j.nsa.2022.100765"
}

Vuković, P., Jeremić, A., Vezmar, M., Pešić, D., Drakulić, J., Milosavljević, F., Miljević, Č., Marić-Bojović, N.,& Jukić, M.. (2022). Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment. in Neuroscience Applied
Elsevier., 1(Supplement 2), 331-332.
https://doi.org/10.1016/j.nsa.2022.100765

Vuković P, Jeremić A, Vezmar M, Pešić D, Drakulić J, Milosavljević F, Miljević Č, Marić-Bojović N, Jukić M. Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment. in Neuroscience Applied. 2022;1(Supplement 2):331-332.
doi:10.1016/j.nsa.2022.100765 .

Vuković, Petar, Jeremić, Aleksandra, Vezmar, Milica, Pešić, Danilo, Drakulić, Jelena, Milosavljević, Filip, Miljević, Čedo, Marić-Bojović, Nađa, Jukić, Marin, "Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment" in Neuroscience Applied, 1, no. Supplement 2 (2022):331-332,
https://doi.org/10.1016/j.nsa.2022.100765 . .

TY  - CONF
AU  - Jeremić, Aleksandra
AU  - Vuković, Petar
AU  - Vezmar, Milica
AU  - Pešić, Danilo
AU  - Drakulić, Jelena
AU  - Milosavljević, Filip
AU  - Miljević, Čedo
AU  - Marković, Bojan
AU  - Marić-Bojović, Nađa
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4731
AB  - Background: Depression causes significant burden to the society world-wide. Escitalopram is a commonly prescribed antidepressant, predominantly metabolized by the polymorphic CYP2C19 enzyme; however, this drug isn’t always effective [1]. The CYP2C19 genotype determines the CYP2C19 enzymatic capacity and CYP2C19*2 is the main loss-of-function (Null) allele [2]. In the most psychiatric clinics worldwide, escitalopram therapy usually starts with the standard recommended dose of 10 mg/day, regardless of CYP2C19 genotype [3]. The objective of this study was the quantification of difference in the escitalopram exposure among patients between genetically associated CYP2C19 slow and normal metabolizers, considering also the body weight [4].

Methods: In this ongoing prospective cross sectional study, the drug concentration was measured in 53 outpatients treated with 10 mg of escitalopram, 2 weeks after treatment initiation, 24 hours after the last dose. Measured plasma concentration was 25-50 ng/ml was considered the ideal drug exposure. [5] If the drug concentration was 5-25 ng/ml, patients were classified as underdosed/underexposed, while patients with drug concentration <5ng/ml were classified as non-compliers and excluded from the further analysis. Patients were genotyped by polymerase chain reaction–based assay for the CYP2C19*2 allele. All participants were included from the Institute for Mental Health in Belgrade outpatient clinic and daily hospital. The patients were classified based on their CYP2C19 genotype; those carrying CYP2C19*2 variant alleles were categorized into slow metabolizer group, while non-carriers were categorized into normal metabolizer group. Difference in body weight and age between slow and metabolizer groups was analysed by the Mann-Whitney’s test. The effects of CYP2C19 metabolizer category (normal vs. slow metabolizer) and body weight on escitalopram plasma level were evaluated by the linear regression model.

Results: Out of 53 outpatients, who completed the study to date, 24 participants were slow metabolizers and 29 participants were normal metabolizers. After two weeks of treatment with 10mg of escitalopram, only 13 patients (24%) were within the therapeutic range (25-50ng/ml), no patient was underexposed, while the remaining 40 patients were underexposed. Median age body weight in the slow metabolizers group were 41 years [IQR: 27-47] and 77kg [IQR: 65-88,5], while in normal metabolizers group age and body weight were 35 years [IQR: 22-49] and 66kg [IQR: 59-88]. The drug level increase due to lower body weight and due to occurrence of CYP2C19*2 allele observed in the regression equation did not reach statistical significance.

Conclusion: While the result directionality was in accordance with the previously published studies, the effects of body weight and CYP2C19*2 allele occurrence were not significant in the analysed cohort. The absence of significant effects was likely due to still limited power of the study. Since this interim analysis includes only approximately one third of patients compared with what had been originally planned, it is expected that firmer conclusions related to the combined effect of CYP2C19 genotype and body weight on escitalopram exposure will emerge after all planned patients are included.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study
VL  - 1
IS  - Supplement 2
SP  - 330
EP  - 331
DO  - 10.1016/j.nsa.2022.100763
ER  - 

@conference{
author = "Jeremić, Aleksandra and Vuković, Petar and Vezmar, Milica and Pešić, Danilo and Drakulić, Jelena and Milosavljević, Filip and Miljević, Čedo and Marković, Bojan and Marić-Bojović, Nađa and Jukić, Marin",
year = "2022",
abstract = "Background: Depression causes significant burden to the society world-wide. Escitalopram is a commonly prescribed antidepressant, predominantly metabolized by the polymorphic CYP2C19 enzyme; however, this drug isn’t always effective [1]. The CYP2C19 genotype determines the CYP2C19 enzymatic capacity and CYP2C19*2 is the main loss-of-function (Null) allele [2]. In the most psychiatric clinics worldwide, escitalopram therapy usually starts with the standard recommended dose of 10 mg/day, regardless of CYP2C19 genotype [3]. The objective of this study was the quantification of difference in the escitalopram exposure among patients between genetically associated CYP2C19 slow and normal metabolizers, considering also the body weight [4].

Methods: In this ongoing prospective cross sectional study, the drug concentration was measured in 53 outpatients treated with 10 mg of escitalopram, 2 weeks after treatment initiation, 24 hours after the last dose. Measured plasma concentration was 25-50 ng/ml was considered the ideal drug exposure. [5] If the drug concentration was 5-25 ng/ml, patients were classified as underdosed/underexposed, while patients with drug concentration <5ng/ml were classified as non-compliers and excluded from the further analysis. Patients were genotyped by polymerase chain reaction–based assay for the CYP2C19*2 allele. All participants were included from the Institute for Mental Health in Belgrade outpatient clinic and daily hospital. The patients were classified based on their CYP2C19 genotype; those carrying CYP2C19*2 variant alleles were categorized into slow metabolizer group, while non-carriers were categorized into normal metabolizer group. Difference in body weight and age between slow and metabolizer groups was analysed by the Mann-Whitney’s test. The effects of CYP2C19 metabolizer category (normal vs. slow metabolizer) and body weight on escitalopram plasma level were evaluated by the linear regression model.

Results: Out of 53 outpatients, who completed the study to date, 24 participants were slow metabolizers and 29 participants were normal metabolizers. After two weeks of treatment with 10mg of escitalopram, only 13 patients (24%) were within the therapeutic range (25-50ng/ml), no patient was underexposed, while the remaining 40 patients were underexposed. Median age body weight in the slow metabolizers group were 41 years [IQR: 27-47] and 77kg [IQR: 65-88,5], while in normal metabolizers group age and body weight were 35 years [IQR: 22-49] and 66kg [IQR: 59-88]. The drug level increase due to lower body weight and due to occurrence of CYP2C19*2 allele observed in the regression equation did not reach statistical significance.

Conclusion: While the result directionality was in accordance with the previously published studies, the effects of body weight and CYP2C19*2 allele occurrence were not significant in the analysed cohort. The absence of significant effects was likely due to still limited power of the study. Since this interim analysis includes only approximately one third of patients compared with what had been originally planned, it is expected that firmer conclusions related to the combined effect of CYP2C19 genotype and body weight on escitalopram exposure will emerge after all planned patients are included.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study",
volume = "1",
number = "Supplement 2",
pages = "330-331",
doi = "10.1016/j.nsa.2022.100763"
}

Jeremić, A., Vuković, P., Vezmar, M., Pešić, D., Drakulić, J., Milosavljević, F., Miljević, Č., Marković, B., Marić-Bojović, N.,& Jukić, M.. (2022). Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study. in Neuroscience Applied
Elsevier., 1(Supplement 2), 330-331.
https://doi.org/10.1016/j.nsa.2022.100763

Jeremić A, Vuković P, Vezmar M, Pešić D, Drakulić J, Milosavljević F, Miljević Č, Marković B, Marić-Bojović N, Jukić M. Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study. in Neuroscience Applied. 2022;1(Supplement 2):330-331.
doi:10.1016/j.nsa.2022.100763 .

Jeremić, Aleksandra, Vuković, Petar, Vezmar, Milica, Pešić, Danilo, Drakulić, Jelena, Milosavljević, Filip, Miljević, Čedo, Marković, Bojan, Marić-Bojović, Nađa, Jukić, Marin, "Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study" in Neuroscience Applied, 1, no. Supplement 2 (2022):330-331,
https://doi.org/10.1016/j.nsa.2022.100763 . .

TY  - JOUR
AU  - Jeremić, Aleksandra
AU  - Milosavljević, Filip
AU  - Vladimirov, Sandra
AU  - Batinić, Bojan
AU  - Marković, Bojan
AU  - Jukić, Marin
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4733
AB  - Simultaneous quantification of multiple psychiatric drugs is important for the therapeutic
drug monitoring of psychiatric patients. In addition, it would be highly advantageous if the
method could be simple, straightforward, and not time-consuming. A 200 µl plasma sample was
deproteinized, drugs were separated by a ZORBAX Eclipse XDB-Phenyl column with the
mobile phase composed of acetonitrile and 0.1 % formic acid in water (60:40, v/v), and recorded
in the MRM mode by using a positive electrospray source with tandem mass spectrometry
detection. The dynamic range was 2–256 ng/ml for all the analyzed drugs, except escitalopram
(8-256 ng/ml). Quality control samples were prepared in quintuplicates in three relevant
concentrations for each drug. Coefficients of determination (R2
) were higher than 0.99, while the
relative difference between nominal and measured concentrations (RE) and CV were lower than
15% for all targets. High performance liquid chromatography coupled with the mass detector
(HPLC-MS/MS) method for simultaneous determination of sertraline, escitalopram, risperidone
366
and paliperidone in human plasma was validated with respect to selectivity, linearity, accuracy,
precision, matrix effect and stability. This method has significant advantages in terms of low
sample volume (200 µl), short preparation time (3 hours) and short runtime per sample (4
minutes).
AB  - Simultana kvantifikacija većeg broja psihijatrijskih lekova je 
važna za terapijsko praćenje 
psihijatrijskih  pacijenata.  Takođe
,  od  značaja  iz  praktičnih  ra
zloga  bi  bilo  da  metoda  bude 
jednostavna,  laka  za  izvođenje  i 
da  ne  zahteva  puno  vremena.  Uz
orak  plazme  (200  μl)  je 
deproteinizovan i izvršeno je h
romatografsko razdvajanje lekova
 na 
ZORBAX Eclipse XDB-
Phenyl  koloni  sa  mobilnom  fazom  sačinjenom  od  acetonitrila  i  vo
denog  rastvora 
0,1% 
mravlje kiseline
 (
60:40, v/v). Maseni spektri snimani su u MRM modu korišćenjem i
zvora sa 
elektrosprej pozitivnom jonizacijom i tandemske masene detekcij
e. Ispitivani opseg koncentracija 
bio je 2–256 ng/ml za sve analizirane lekove, osim za escitalop
ram, gde je bio 8-256 ng/ml. 
Kontrolni  uzorci  su  pripremani  u
  kvintuplikatu  u  tri  relevantne
  koncentracije  za  svaki  lek. 
Determinacioni koeficijenti (R
2
) bili su veći od 0,99, dok su relativna razlika između nominal
nih 
i merenih koncentracija (RV) i koeficijent varijacije (CV) bili
 manji od 15% za sve analite. 
Metoda  tečne  hromatografije  visoki
h  performansi  uparena  sa  tand
em  masenim  detektorom 
(HPLC-MS/MS) je validirana u pogledu selektivnosti, linearnosti
, tačnosti, preciznosti, efekata 
matriksa  i  stabilnosti  za  simultano  određivanje 
sertralina,  escitaloprama,  risperidona  i 
paliperidona u humanoj plazmi. Metoda zahteva malu zapreminu uz
orka (200 μl), kratke pripreme 
uzorka (3 sata) i kratko vreme tr
ajanja pojedinačnog merenja (4
 minuta).
T2  - Arhiv za farmaciju
T1  - Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma
T1  - Validacija brze i jednostavne hromatografske 
metode za simultanu kvantifikaciju nivoa 
sertralina, escitaloprama, risperidona i 
paliperidona u humanoj plazmi
VL  - 71
IS  - 5
SP  - 365
EP  - 377
DO  - 10.5937/arhfarm71-31163
ER  - 

@article{
author = "Jeremić, Aleksandra and Milosavljević, Filip and Vladimirov, Sandra and Batinić, Bojan and Marković, Bojan and Jukić, Marin",
year = "2021",
abstract = "Simultaneous quantification of multiple psychiatric drugs is important for the therapeutic
drug monitoring of psychiatric patients. In addition, it would be highly advantageous if the
method could be simple, straightforward, and not time-consuming. A 200 µl plasma sample was
deproteinized, drugs were separated by a ZORBAX Eclipse XDB-Phenyl column with the
mobile phase composed of acetonitrile and 0.1 % formic acid in water (60:40, v/v), and recorded
in the MRM mode by using a positive electrospray source with tandem mass spectrometry
detection. The dynamic range was 2–256 ng/ml for all the analyzed drugs, except escitalopram
(8-256 ng/ml). Quality control samples were prepared in quintuplicates in three relevant
concentrations for each drug. Coefficients of determination (R2
) were higher than 0.99, while the
relative difference between nominal and measured concentrations (RE) and CV were lower than
15% for all targets. High performance liquid chromatography coupled with the mass detector
(HPLC-MS/MS) method for simultaneous determination of sertraline, escitalopram, risperidone
366
and paliperidone in human plasma was validated with respect to selectivity, linearity, accuracy,
precision, matrix effect and stability. This method has significant advantages in terms of low
sample volume (200 µl), short preparation time (3 hours) and short runtime per sample (4
minutes)., Simultana kvantifikacija većeg broja psihijatrijskih lekova je 
važna za terapijsko praćenje 
psihijatrijskih  pacijenata.  Takođe
,  od  značaja  iz  praktičnih  ra
zloga  bi  bilo  da  metoda  bude 
jednostavna,  laka  za  izvođenje  i 
da  ne  zahteva  puno  vremena.  Uz
orak  plazme  (200  μl)  je 
deproteinizovan i izvršeno je h
romatografsko razdvajanje lekova
 na 
ZORBAX Eclipse XDB-
Phenyl  koloni  sa  mobilnom  fazom  sačinjenom  od  acetonitrila  i  vo
denog  rastvora 
0,1% 
mravlje kiseline
 (
60:40, v/v). Maseni spektri snimani su u MRM modu korišćenjem i
zvora sa 
elektrosprej pozitivnom jonizacijom i tandemske masene detekcij
e. Ispitivani opseg koncentracija 
bio je 2–256 ng/ml za sve analizirane lekove, osim za escitalop
ram, gde je bio 8-256 ng/ml. 
Kontrolni  uzorci  su  pripremani  u
  kvintuplikatu  u  tri  relevantne
  koncentracije  za  svaki  lek. 
Determinacioni koeficijenti (R
2
) bili su veći od 0,99, dok su relativna razlika između nominal
nih 
i merenih koncentracija (RV) i koeficijent varijacije (CV) bili
 manji od 15% za sve analite. 
Metoda  tečne  hromatografije  visoki
h  performansi  uparena  sa  tand
em  masenim  detektorom 
(HPLC-MS/MS) je validirana u pogledu selektivnosti, linearnosti
, tačnosti, preciznosti, efekata 
matriksa  i  stabilnosti  za  simultano  određivanje 
sertralina,  escitaloprama,  risperidona  i 
paliperidona u humanoj plazmi. Metoda zahteva malu zapreminu uz
orka (200 μl), kratke pripreme 
uzorka (3 sata) i kratko vreme tr
ajanja pojedinačnog merenja (4
 minuta).",
journal = "Arhiv za farmaciju",
title = "Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma, Validacija brze i jednostavne hromatografske 
metode za simultanu kvantifikaciju nivoa 
sertralina, escitaloprama, risperidona i 
paliperidona u humanoj plazmi",
volume = "71",
number = "5",
pages = "365-377",
doi = "10.5937/arhfarm71-31163"
}

Jeremić, A., Milosavljević, F., Vladimirov, S., Batinić, B., Marković, B.,& Jukić, M.. (2021). Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma. in Arhiv za farmaciju, 71(5), 365-377.
https://doi.org/10.5937/arhfarm71-31163

Jeremić A, Milosavljević F, Vladimirov S, Batinić B, Marković B, Jukić M. Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma. in Arhiv za farmaciju. 2021;71(5):365-377.
doi:10.5937/arhfarm71-31163 .

Jeremić, Aleksandra, Milosavljević, Filip, Vladimirov, Sandra, Batinić, Bojan, Marković, Bojan, Jukić, Marin, "Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma" in Arhiv za farmaciju, 71, no. 5 (2021):365-377,
https://doi.org/10.5937/arhfarm71-31163 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pavlović, Zorana
AU  - Miljević, Čedo
AU  - Pešić, Vesna
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Leucht, Stefan
AU  - Jukić, Marin
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4761
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis
VL  - 40
IS  - Supplement 1
SP  - S250
EP  - S251
DO  - 10.1016/j.euroneuro.2020.09.325
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pavlović, Zorana and Miljević, Čedo and Pešić, Vesna and Molden, Espen and Ingelman-Sundberg, Magnus and Leucht, Stefan and Jukić, Marin",
year = "2020",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis",
volume = "40",
number = "Supplement 1",
pages = "S250-S251",
doi = "10.1016/j.euroneuro.2020.09.325"
}

Milosavljević, F., Bukvić, N., Pavlović, Z., Miljević, Č., Pešić, V., Molden, E., Ingelman-Sundberg, M., Leucht, S.,& Jukić, M.. (2020). Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis. in European Neuropsychopharmacology
Elsevier., 40(Supplement 1), S250-S251.
https://doi.org/10.1016/j.euroneuro.2020.09.325

Milosavljević F, Bukvić N, Pavlović Z, Miljević Č, Pešić V, Molden E, Ingelman-Sundberg M, Leucht S, Jukić M. Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis. in European Neuropsychopharmacology. 2020;40(Supplement 1):S250-S251.
doi:10.1016/j.euroneuro.2020.09.325 .

Milosavljević, Filip, Bukvić, Nikola, Pavlović, Zorana, Miljević, Čedo, Pešić, Vesna, Molden, Espen, Ingelman-Sundberg, Magnus, Leucht, Stefan, Jukić, Marin, "Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis" in European Neuropsychopharmacology, 40, no. Supplement 1 (2020):S250-S251,
https://doi.org/10.1016/j.euroneuro.2020.09.325 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Vučić, Marija
AU  - Manojlović, Marina
AU  - Miloševski, Teodora
AU  - Batinić, Bojan
AU  - Novalen, Maria
AU  - Miksys, Sharon
AU  - Tyndale, Rachel
AU  - Ingelman-Sundberg, Magnus
AU  - Pešić, Vesna
AU  - Jukić, Marin
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4753
AB  - Introduction: CYP2C19 transgenic mouse (2C19TG) is generated by the insertion of 12 copies of the human CYP2C19 gene into mouse genome. This animal model is a tool to study the neurodevelopmental role of CYP2C19 in vivo, since this enzyme is expressed in the foetal brains of 2C19TG mice and humans. Previous studies [1,2] showed anxiety and depression-like behaviour in these mice, while the aim of this study was to characterize the motoric function of the 2C19TG mouse.
Methods: Whole brain dopamine concentration was measured in the brain homogenate of 23 adult mice by the HPLC-MS method. Motoric function in 50 mutant and 43 control mice of both genders was tested by the rotarod and beam walking tests. Beam walking test was repeated after treatment with dopaminergic receptor antagonists, Ecopipam (0.1 mg/kg) and Raclopride (0.25 mg/kg) as a follow-up. The sections of 10 6-month old and 8 15-months old mice were stained with anti-tyrosine hydroxylase antibody and the number of dopaminergic neurons was counted on histological slides under microscope. Next, after transcardial perfusion of 30 2C19TG and 30 control mice of both genders with contrast agent (4% Paraformaldehyde, 0.05M Gadoteridole, 0.01M Phosphate buffered saline, pH=7.4), cranium containing the whole brain was scanned overnight by the 9.4T MRI scanner. The volumes of 39 brain regions were quantified according to the mouse brain atlas [3]. Student's t-test and two-way ANOVA were used to evaluate statistical significance of between-group differences.
Results: Adult 2C19TG mice are hyperdopaminergic, as they exhibit 15% increased dopamine concentration (p<0.001). They also show hyperkinetic motoric phenotype with the ataxia-like walking pattern and pathological clasping reflex. In the beam walking test 2C19TG mice had 20% longer beam crossing time (p=0.007) and 60% more paw slips (p<0.001) then the controls, and this motoric impairment could not be improved with antidopaminergic drugs. Both younger and older 2C19TG mice exhibited only a marginal reduction in the number of dopaminergic neurons of both substantia nigra and ventral tegmental area in a subset of coronal sections. This was confirmed by the gadolinium-enhanced neuroimaging that showed no change in substantia nigra volume in 2C19TG mice. On the other hand, significant differences in volume were identified in 11 regions, including cerebellum (-8.3% p<0.001) and striatum (+3.0%, p<0.001), which are the regions connected with the motoric function. The volumetric changes were detected in the hippocampus (-1.3%, p=0.027), amygdala (+2.8%, p<0.001), septum (+3.3%, p=0.014) and nucleus accumbens (+3.5, p=0.004) of 2C19TG mice. These brain regions are involved in emotional and motivational functions.
Conclusion: Ataxia-like motoric phenotype in 2C19TG transgenic mice is probably caused by changes in cerebellum, while hyperdopaminergism is most likely the compensatory adaptation, whereas the changes in the hippocampus, amygdala, septum, and nucleus accumbens may be connected with the mutants’ depression-like phenotype and susceptibility to stress. Therefore, CYP2C19 transgenic mouse in potentially useful model of hyperkinetic disorders, and our findings hint at the possible impact of CYP2C19 enzyme on the development of the several brain regions involved in motor and emotional functioning.
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene
VL  - 40
IS  - 1
SP  - S207
EP  - S208
DO  - 10.1016/j.euroneuro.2020.09.271
ER  - 

@conference{
author = "Milosavljević, Filip and Vučić, Marija and Manojlović, Marina and Miloševski, Teodora and Batinić, Bojan and Novalen, Maria and Miksys, Sharon and Tyndale, Rachel and Ingelman-Sundberg, Magnus and Pešić, Vesna and Jukić, Marin",
year = "2020",
abstract = "Introduction: CYP2C19 transgenic mouse (2C19TG) is generated by the insertion of 12 copies of the human CYP2C19 gene into mouse genome. This animal model is a tool to study the neurodevelopmental role of CYP2C19 in vivo, since this enzyme is expressed in the foetal brains of 2C19TG mice and humans. Previous studies [1,2] showed anxiety and depression-like behaviour in these mice, while the aim of this study was to characterize the motoric function of the 2C19TG mouse.
Methods: Whole brain dopamine concentration was measured in the brain homogenate of 23 adult mice by the HPLC-MS method. Motoric function in 50 mutant and 43 control mice of both genders was tested by the rotarod and beam walking tests. Beam walking test was repeated after treatment with dopaminergic receptor antagonists, Ecopipam (0.1 mg/kg) and Raclopride (0.25 mg/kg) as a follow-up. The sections of 10 6-month old and 8 15-months old mice were stained with anti-tyrosine hydroxylase antibody and the number of dopaminergic neurons was counted on histological slides under microscope. Next, after transcardial perfusion of 30 2C19TG and 30 control mice of both genders with contrast agent (4% Paraformaldehyde, 0.05M Gadoteridole, 0.01M Phosphate buffered saline, pH=7.4), cranium containing the whole brain was scanned overnight by the 9.4T MRI scanner. The volumes of 39 brain regions were quantified according to the mouse brain atlas [3]. Student's t-test and two-way ANOVA were used to evaluate statistical significance of between-group differences.
Results: Adult 2C19TG mice are hyperdopaminergic, as they exhibit 15% increased dopamine concentration (p<0.001). They also show hyperkinetic motoric phenotype with the ataxia-like walking pattern and pathological clasping reflex. In the beam walking test 2C19TG mice had 20% longer beam crossing time (p=0.007) and 60% more paw slips (p<0.001) then the controls, and this motoric impairment could not be improved with antidopaminergic drugs. Both younger and older 2C19TG mice exhibited only a marginal reduction in the number of dopaminergic neurons of both substantia nigra and ventral tegmental area in a subset of coronal sections. This was confirmed by the gadolinium-enhanced neuroimaging that showed no change in substantia nigra volume in 2C19TG mice. On the other hand, significant differences in volume were identified in 11 regions, including cerebellum (-8.3% p<0.001) and striatum (+3.0%, p<0.001), which are the regions connected with the motoric function. The volumetric changes were detected in the hippocampus (-1.3%, p=0.027), amygdala (+2.8%, p<0.001), septum (+3.3%, p=0.014) and nucleus accumbens (+3.5, p=0.004) of 2C19TG mice. These brain regions are involved in emotional and motivational functions.
Conclusion: Ataxia-like motoric phenotype in 2C19TG transgenic mice is probably caused by changes in cerebellum, while hyperdopaminergism is most likely the compensatory adaptation, whereas the changes in the hippocampus, amygdala, septum, and nucleus accumbens may be connected with the mutants’ depression-like phenotype and susceptibility to stress. Therefore, CYP2C19 transgenic mouse in potentially useful model of hyperkinetic disorders, and our findings hint at the possible impact of CYP2C19 enzyme on the development of the several brain regions involved in motor and emotional functioning.",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene",
volume = "40",
number = "1",
pages = "S207-S208",
doi = "10.1016/j.euroneuro.2020.09.271"
}

Milosavljević, F., Vučić, M., Manojlović, M., Miloševski, T., Batinić, B., Novalen, M., Miksys, S., Tyndale, R., Ingelman-Sundberg, M., Pešić, V.,& Jukić, M.. (2020). Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene. in European Neuropsychopharmacology
Elsevier., 40(1), S207-S208.
https://doi.org/10.1016/j.euroneuro.2020.09.271

Milosavljević F, Vučić M, Manojlović M, Miloševski T, Batinić B, Novalen M, Miksys S, Tyndale R, Ingelman-Sundberg M, Pešić V, Jukić M. Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene. in European Neuropsychopharmacology. 2020;40(1):S207-S208.
doi:10.1016/j.euroneuro.2020.09.271 .

Milosavljević, Filip, Vučić, Marija, Manojlović, Marina, Miloševski, Teodora, Batinić, Bojan, Novalen, Maria, Miksys, Sharon, Tyndale, Rachel, Ingelman-Sundberg, Magnus, Pešić, Vesna, Jukić, Marin, "Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene" in European Neuropsychopharmacology, 40, no. 1 (2020):S207-S208,
https://doi.org/10.1016/j.euroneuro.2020.09.271 . .

TY  - JOUR
AU  - Kapor, Slobodan
AU  - Aksić, Milan
AU  - Puškaš, Laslo
AU  - Jukić, Marin
AU  - Poleksić, Joko
AU  - Milosavljević, Filip
AU  - Bjelica, Suncica
AU  - Filipović, Branislav
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3735
AB  - Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.
PB  - Frontiers Media S.A.
T2  - Frontiers in Neuroanatomy
T1  - Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats
VL  - 14
DO  - 10.3389/fnana.2020.578900
ER  - 

@article{
author = "Kapor, Slobodan and Aksić, Milan and Puškaš, Laslo and Jukić, Marin and Poleksić, Joko and Milosavljević, Filip and Bjelica, Suncica and Filipović, Branislav",
year = "2020",
abstract = "Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Neuroanatomy",
title = "Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats",
volume = "14",
doi = "10.3389/fnana.2020.578900"
}

Kapor, S., Aksić, M., Puškaš, L., Jukić, M., Poleksić, J., Milosavljević, F., Bjelica, S.,& Filipović, B.. (2020). Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats. in Frontiers in Neuroanatomy
Frontiers Media S.A.., 14.
https://doi.org/10.3389/fnana.2020.578900

Kapor S, Aksić M, Puškaš L, Jukić M, Poleksić J, Milosavljević F, Bjelica S, Filipović B. Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats. in Frontiers in Neuroanatomy. 2020;14.
doi:10.3389/fnana.2020.578900 .

Kapor, Slobodan, Aksić, Milan, Puškaš, Laslo, Jukić, Marin, Poleksić, Joko, Milosavljević, Filip, Bjelica, Suncica, Filipović, Branislav, "Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats" in Frontiers in Neuroanatomy, 14 (2020),
https://doi.org/10.3389/fnana.2020.578900 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pešić, Vesna
AU  - Pavlović, Zorana
AU  - Miljević, Čedo
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4752
PB  - Springer Nature
C3  - Neuropsychopharmacology
T1  - Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status
IS  - 44
SP  - 139
DO  - 10.1038/s41386-019-0545-y
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pešić, Vesna and Pavlović, Zorana and Miljević, Čedo and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2019",
publisher = "Springer Nature",
journal = "Neuropsychopharmacology",
title = "Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status",
number = "44",
pages = "139",
doi = "10.1038/s41386-019-0545-y"
}

Milosavljević, F., Bukvić, N., Pešić, V., Pavlović, Z., Miljević, Č., Molden, E., Ingelman-Sundberg, M.,& Jukić, M.. (2019). Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status. in Neuropsychopharmacology
Springer Nature.(44), 139.
https://doi.org/10.1038/s41386-019-0545-y

Milosavljević F, Bukvić N, Pešić V, Pavlović Z, Miljević Č, Molden E, Ingelman-Sundberg M, Jukić M. Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status. in Neuropsychopharmacology. 2019;(44):139.
doi:10.1038/s41386-019-0545-y .

Milosavljević, Filip, Bukvić, Nikola, Pešić, Vesna, Pavlović, Zorana, Miljević, Čedo, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status" in Neuropsychopharmacology, no. 44 (2019):139,
https://doi.org/10.1038/s41386-019-0545-y . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pešić, Vesna
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4754
AB  - Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree.
Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval)
Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed.
Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis
VL  - 29
IS  - 6
SP  - S533
EP  - S534
DO  - 10.1016/j.euroneuro.2019.09.824
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pešić, Vesna and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2019",
abstract = "Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree.
Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval)
Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed.
Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis",
volume = "29",
number = "6",
pages = "S533-S534",
doi = "10.1016/j.euroneuro.2019.09.824"
}

Milosavljević, F., Bukvić, N., Pešić, V., Molden, E., Ingelman-Sundberg, M.,& Jukić, M.. (2019). Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis. in European Neuropsychopharmacology
Elsevier., 29(6), S533-S534.
https://doi.org/10.1016/j.euroneuro.2019.09.824

Milosavljević F, Bukvić N, Pešić V, Molden E, Ingelman-Sundberg M, Jukić M. Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis. in European Neuropsychopharmacology. 2019;29(6):S533-S534.
doi:10.1016/j.euroneuro.2019.09.824 .

Milosavljević, Filip, Bukvić, Nikola, Pešić, Vesna, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis" in European Neuropsychopharmacology, 29, no. 6 (2019):S533-S534,
https://doi.org/10.1016/j.euroneuro.2019.09.824 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Vučić, M.
AU  - Manojlović, Marina
AU  - Ašujić, N.
AU  - Batinić, Bojan
AU  - Novalen, M.
AU  - Miksys, S.
AU  - Tyndale, R.F.
AU  - Ingelman-Sundberg, Magnus
AU  - Pešić, Vesna
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3297
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia
VL  - 29
IS  - Supplement 2
SP  - S672
EP  - S673
DO  - 10.1016/j.euroneuro.2019.01.056
ER  - 

@conference{
author = "Milosavljević, Filip and Vučić, M. and Manojlović, Marina and Ašujić, N. and Batinić, Bojan and Novalen, M. and Miksys, S. and Tyndale, R.F. and Ingelman-Sundberg, Magnus and Pešić, Vesna and Jukić, Marin",
year = "2019",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia",
volume = "29",
number = "Supplement 2",
pages = "S672-S673",
doi = "10.1016/j.euroneuro.2019.01.056"
}

Milosavljević, F., Vučić, M., Manojlović, M., Ašujić, N., Batinić, B., Novalen, M., Miksys, S., Tyndale, R.F., Ingelman-Sundberg, M., Pešić, V.,& Jukić, M.. (2019). Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 29(Supplement 2), S672-S673.
https://doi.org/10.1016/j.euroneuro.2019.01.056

Milosavljević F, Vučić M, Manojlović M, Ašujić N, Batinić B, Novalen M, Miksys S, Tyndale R, Ingelman-Sundberg M, Pešić V, Jukić M. Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia. in European Neuropsychopharmacology. 2019;29(Supplement 2):S672-S673.
doi:10.1016/j.euroneuro.2019.01.056 .

Milosavljević, Filip, Vučić, M., Manojlović, Marina, Ašujić, N., Batinić, Bojan, Novalen, M., Miksys, S., Tyndale, R.F., Ingelman-Sundberg, Magnus, Pešić, Vesna, Jukić, Marin, "Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia" in European Neuropsychopharmacology, 29, no. Supplement 2 (2019):S672-S673,
https://doi.org/10.1016/j.euroneuro.2019.01.056 . .

TY  - CONF
AU  - Baralić, Katarina
AU  - Ćurčić, Marijana
AU  - Antonijević, Evica
AU  - Bulat, Zorica
AU  - Janković, Saša
AU  - Todorović, Milica
AU  - Milosavljević, Filip
AU  - Kotur-Stevuljević, Jelena
AU  - Kalimanovska, Vesna
AU  - Matović, Vesna
AU  - Antonijević, Biljana
AU  - Đukić-Ćosić, Danijela
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2889
PB  - Elsevier Ireland Ltd, Clare
C3  - Toxicology Letters
T1  - Obesity in relation with erythrocyte lead level in people exposed to environmental lead in Belgrade, Serbia
VL  - 280
IS  - Supplement 1
SP  - S179
EP  - S179
DO  - 10.1016/j.toxlet.2017.07.501
ER  - 

@conference{
author = "Baralić, Katarina and Ćurčić, Marijana and Antonijević, Evica and Bulat, Zorica and Janković, Saša and Todorović, Milica and Milosavljević, Filip and Kotur-Stevuljević, Jelena and Kalimanovska, Vesna and Matović, Vesna and Antonijević, Biljana and Đukić-Ćosić, Danijela",
year = "2017",
publisher = "Elsevier Ireland Ltd, Clare",
journal = "Toxicology Letters",
title = "Obesity in relation with erythrocyte lead level in people exposed to environmental lead in Belgrade, Serbia",
volume = "280",
number = "Supplement 1",
pages = "S179-S179",
doi = "10.1016/j.toxlet.2017.07.501"
}

Baralić, K., Ćurčić, M., Antonijević, E., Bulat, Z., Janković, S., Todorović, M., Milosavljević, F., Kotur-Stevuljević, J., Kalimanovska, V., Matović, V., Antonijević, B.,& Đukić-Ćosić, D.. (2017). Obesity in relation with erythrocyte lead level in people exposed to environmental lead in Belgrade, Serbia. in Toxicology Letters
Elsevier Ireland Ltd, Clare., 280(Supplement 1), S179-S179.
https://doi.org/10.1016/j.toxlet.2017.07.501

Baralić K, Ćurčić M, Antonijević E, Bulat Z, Janković S, Todorović M, Milosavljević F, Kotur-Stevuljević J, Kalimanovska V, Matović V, Antonijević B, Đukić-Ćosić D. Obesity in relation with erythrocyte lead level in people exposed to environmental lead in Belgrade, Serbia. in Toxicology Letters. 2017;280(Supplement 1):S179-S179.
doi:10.1016/j.toxlet.2017.07.501 .

Baralić, Katarina, Ćurčić, Marijana, Antonijević, Evica, Bulat, Zorica, Janković, Saša, Todorović, Milica, Milosavljević, Filip, Kotur-Stevuljević, Jelena, Kalimanovska, Vesna, Matović, Vesna, Antonijević, Biljana, Đukić-Ćosić, Danijela, "Obesity in relation with erythrocyte lead level in people exposed to environmental lead in Belgrade, Serbia" in Toxicology Letters, 280, no. Supplement 1 (2017):S179-S179,
https://doi.org/10.1016/j.toxlet.2017.07.501 . .