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  - Stojanović, Ivan
AU  - Kaitović, Marko
AU  - Novaković, Aleksandra
AU  - Vuković, Petar
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3273
AB  - Introduction. Mitral valve calcifications are frequent finding in Barlow disease. This is making mitral repair surgery even more demanding in already complex valve pathology. Case report. A fifty-five-year-old Barlow disease patient underwent a mitral repair surgery due to posterior leaflet prolapse at P2 level and extensive posterior leaflet and annular calcifications as well. The prolapsed scallop was resected, while P1 and P3 scallops were detached from the annulus. After complete posterior annulus decalcification, so formed the large atrio-ventricular defect was reconstructed with the autologous pericardial patch and double suture line technique. The P1 and P3 segments were reattached there by the sliding technique and sutured with no strain. Annuloplasty was performed with a saddle rigid ring No 36. The patient was discharged nine days after the surgery with just a trace of mitral regurgitation. Conclusion. Annular decalcification and reconstruction in the patients with calcified Barlow mitral disease is necessary for safe and durable mitral valve surgical repair.
AB  - Uvod. Kalcifikacije mitralne valvule su čest nalaz kod bolesnika sa Barlovljevom bolesti što čini rekonstruktivnu hirurgiju zalistka kod ovih bolesnika znatno složenijom. Prikaz bolesnika. Bolesniku starom 55 godina je urađena rekonstrukcija mitralnog zalistka zbog prolapsa posteriornog listića i značajnih kalcifikacija na P2 segmentu i posteriornom anulusu. Nakon resekcije P2 segmenta i odvajanja P1 i P3 segmenta od anulusa, urađena je kompletna resekcija velikog kalcifikata sa skoro polovine obima posteriornog anulusa. Nastali atrioventrikularnog defekt rekonstruisan je autolognim perikardom elipsoidnog oblika sašivenim u dva sloja. P1 i P3 segment su potom reinplantirani na rekonstruisani anulus i međusobno spojeni. Rekonstruktivna procedura je kompletirana anuloplastikom pomoću sedlastog rigidnog prstena veličine 36. Bolesnik je otpušten devetog postoperativnog dana sa neznatnom mitralnom regurgitacijom. Zaključak. Dekalcifikacija posteriornog anulusa uz preciznu rekonstrukciju nastalog atrioventikularnog defekta je neophodna procedura za bezbednu i funkcionalno trajnu rekonstrukciju mitralnog zalistka.
PB  - Vojnomedicinska akademija - Institut za naučne informacije, Beograd
T2  - Vojnosanitetski pregled
T1  - Reconstructive surgery of an extremely calcified mitral valve in a Barlow disease patient: A case report
T1  - Rekonstruktivna hirurgija ekstremno kalcifikovane mitralne valvule kod bolesnika sa Barlovljevom bolesti
VL  - 76
IS  - 5
SP  - 552
EP  - 554
DO  - 10.2298/VSP170312117S
ER  - 

@article{
author = "Stojanović, Ivan and Kaitović, Marko and Novaković, Aleksandra and Vuković, Petar",
year = "2019",
abstract = "Introduction. Mitral valve calcifications are frequent finding in Barlow disease. This is making mitral repair surgery even more demanding in already complex valve pathology. Case report. A fifty-five-year-old Barlow disease patient underwent a mitral repair surgery due to posterior leaflet prolapse at P2 level and extensive posterior leaflet and annular calcifications as well. The prolapsed scallop was resected, while P1 and P3 scallops were detached from the annulus. After complete posterior annulus decalcification, so formed the large atrio-ventricular defect was reconstructed with the autologous pericardial patch and double suture line technique. The P1 and P3 segments were reattached there by the sliding technique and sutured with no strain. Annuloplasty was performed with a saddle rigid ring No 36. The patient was discharged nine days after the surgery with just a trace of mitral regurgitation. Conclusion. Annular decalcification and reconstruction in the patients with calcified Barlow mitral disease is necessary for safe and durable mitral valve surgical repair., Uvod. Kalcifikacije mitralne valvule su čest nalaz kod bolesnika sa Barlovljevom bolesti što čini rekonstruktivnu hirurgiju zalistka kod ovih bolesnika znatno složenijom. Prikaz bolesnika. Bolesniku starom 55 godina je urađena rekonstrukcija mitralnog zalistka zbog prolapsa posteriornog listića i značajnih kalcifikacija na P2 segmentu i posteriornom anulusu. Nakon resekcije P2 segmenta i odvajanja P1 i P3 segmenta od anulusa, urađena je kompletna resekcija velikog kalcifikata sa skoro polovine obima posteriornog anulusa. Nastali atrioventrikularnog defekt rekonstruisan je autolognim perikardom elipsoidnog oblika sašivenim u dva sloja. P1 i P3 segment su potom reinplantirani na rekonstruisani anulus i međusobno spojeni. Rekonstruktivna procedura je kompletirana anuloplastikom pomoću sedlastog rigidnog prstena veličine 36. Bolesnik je otpušten devetog postoperativnog dana sa neznatnom mitralnom regurgitacijom. Zaključak. Dekalcifikacija posteriornog anulusa uz preciznu rekonstrukciju nastalog atrioventikularnog defekta je neophodna procedura za bezbednu i funkcionalno trajnu rekonstrukciju mitralnog zalistka.",
publisher = "Vojnomedicinska akademija - Institut za naučne informacije, Beograd",
journal = "Vojnosanitetski pregled",
title = "Reconstructive surgery of an extremely calcified mitral valve in a Barlow disease patient: A case report, Rekonstruktivna hirurgija ekstremno kalcifikovane mitralne valvule kod bolesnika sa Barlovljevom bolesti",
volume = "76",
number = "5",
pages = "552-554",
doi = "10.2298/VSP170312117S"
}

Stojanović, I., Kaitović, M., Novaković, A.,& Vuković, P.. (2019). Reconstructive surgery of an extremely calcified mitral valve in a Barlow disease patient: A case report. in Vojnosanitetski pregled
Vojnomedicinska akademija - Institut za naučne informacije, Beograd., 76(5), 552-554.
https://doi.org/10.2298/VSP170312117S

Stojanović I, Kaitović M, Novaković A, Vuković P. Reconstructive surgery of an extremely calcified mitral valve in a Barlow disease patient: A case report. in Vojnosanitetski pregled. 2019;76(5):552-554.
doi:10.2298/VSP170312117S .

Stojanović, Ivan, Kaitović, Marko, Novaković, Aleksandra, Vuković, Petar, "Reconstructive surgery of an extremely calcified mitral valve in a Barlow disease patient: A case report" in Vojnosanitetski pregled, 76, no. 5 (2019):552-554,
https://doi.org/10.2298/VSP170312117S . .