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  - 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  - 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  - 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  - 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  - JOUR
AU  - Miljević, Čedo D.
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Milovanović, Maja
AU  - Munjiza, Ana
AU  - Jukić, Marin
AU  - Pešić, Vesna
AU  - Lecić-Tosevski, Dušica
AU  - Spasić, Mihajlo B.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3058
AB  - To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (S-FE, n = 19), patients in relapse (S-R, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between S-FE, S-R and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in S-FE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the S-FE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.
PB  - Elsevier Ireland Ltd, Clare
T2  - Psychoneuroendocrinology
T1  - Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients
VL  - 269
SP  - 746
EP  - 752
DO  - 10.1016/j.psychres.2018.09.009
ER  - 

@article{
author = "Miljević, Čedo D. and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Milovanović, Maja and Munjiza, Ana and Jukić, Marin and Pešić, Vesna and Lecić-Tosevski, Dušica and Spasić, Mihajlo B.",
year = "2018",
abstract = "To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (S-FE, n = 19), patients in relapse (S-R, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between S-FE, S-R and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in S-FE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the S-FE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.",
publisher = "Elsevier Ireland Ltd, Clare",
journal = "Psychoneuroendocrinology",
title = "Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients",
volume = "269",
pages = "746-752",
doi = "10.1016/j.psychres.2018.09.009"
}

Miljević, Č. D., Nikolić-Kokić, A., Blagojević, D., Milovanović, M., Munjiza, A., Jukić, M., Pešić, V., Lecić-Tosevski, D.,& Spasić, M. B.. (2018). Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients. in Psychoneuroendocrinology
Elsevier Ireland Ltd, Clare., 269, 746-752.
https://doi.org/10.1016/j.psychres.2018.09.009

Miljević ČD, Nikolić-Kokić A, Blagojević D, Milovanović M, Munjiza A, Jukić M, Pešić V, Lecić-Tosevski D, Spasić MB. Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients. in Psychoneuroendocrinology. 2018;269:746-752.
doi:10.1016/j.psychres.2018.09.009 .

Miljević, Čedo D., Nikolić-Kokić, Aleksandra, Blagojević, Duško, Milovanović, Maja, Munjiza, Ana, Jukić, Marin, Pešić, Vesna, Lecić-Tosevski, Dušica, Spasić, Mihajlo B., "Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients" in Psychoneuroendocrinology, 269 (2018):746-752,
https://doi.org/10.1016/j.psychres.2018.09.009 . .

TY  - CONF
AU  - Miljević, Čedo D.
AU  - Crnobarić, C.
AU  - Vidović, Bojana
AU  - Đorđević, Brižita
AU  - Lecić-Tosevski, Dušica
PY  - 2011
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1502
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Parameters of oxidative stress and antioxidative protection in patients with schizophrenia
VL  - 21
IS  - Supplement 3
SP  - S467
EP  - S467
DO  - 10.1016/S0924-977X(11)70757-X
ER  - 

@conference{
author = "Miljević, Čedo D. and Crnobarić, C. and Vidović, Bojana and Đorđević, Brižita and Lecić-Tosevski, Dušica",
year = "2011",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Parameters of oxidative stress and antioxidative protection in patients with schizophrenia",
volume = "21",
number = "Supplement 3",
pages = "S467-S467",
doi = "10.1016/S0924-977X(11)70757-X"
}

Miljević, Č. D., Crnobarić, C., Vidović, B., Đorđević, B.,& Lecić-Tosevski, D.. (2011). Parameters of oxidative stress and antioxidative protection in patients with schizophrenia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 21(Supplement 3), S467-S467.
https://doi.org/10.1016/S0924-977X(11)70757-X

Miljević ČD, Crnobarić C, Vidović B, Đorđević B, Lecić-Tosevski D. Parameters of oxidative stress and antioxidative protection in patients with schizophrenia. in European Neuropsychopharmacology. 2011;21(Supplement 3):S467-S467.
doi:10.1016/S0924-977X(11)70757-X .

Miljević, Čedo D., Crnobarić, C., Vidović, Bojana, Đorđević, Brižita, Lecić-Tosevski, Dušica, "Parameters of oxidative stress and antioxidative protection in patients with schizophrenia" in European Neuropsychopharmacology, 21, no. Supplement 3 (2011):S467-S467,
https://doi.org/10.1016/S0924-977X(11)70757-X . .