TY  - JOUR
AU  - Uzelac, Tamara N.
AU  - Nikolić-Kokić, Aleksandra
AU  - Spasić, Snežana D.
AU  - Mačvanin, Mirjana T.
AU  - Nikolić, Milan R.
AU  - Mandić, Ljuba M.
AU  - Jovanović, Vesna B.
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0009279719310257?via%3Dihub
UR  - http://www.ncbi.nlm.nih.gov/pubmed/31400341
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3454
AB  - Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia.
T2  - Chemico-Biological Interactions
T1  - Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content.
VL  - 311
DO  - 10.1016/j.cbi.2019.108787
SP  - 108787
ER  - 

@article{
author = "Uzelac, Tamara N. and Nikolić-Kokić, Aleksandra and Spasić, Snežana D. and Mačvanin, Mirjana T. and Nikolić, Milan R. and Mandić, Ljuba M. and Jovanović, Vesna B.",
year = "2019",
abstract = "Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia.",
journal = "Chemico-Biological Interactions",
title = "Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content.",
volume = "311",
doi = "10.1016/j.cbi.2019.108787",
pages = "108787"
}

Uzelac, T. N., Nikolić-Kokić, A., Spasić, S. D., Mačvanin, M. T., Nikolić, M. R., Mandić, L. M.,& Jovanović, V. B.. (2019). Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content.. in Chemico-Biological Interactions, 311, 108787.
https://doi.org/10.1016/j.cbi.2019.108787

Uzelac TN, Nikolić-Kokić A, Spasić SD, Mačvanin MT, Nikolić MR, Mandić LM, Jovanović VB. Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content.. in Chemico-Biological Interactions. 2019;311:108787.
doi:10.1016/j.cbi.2019.108787 .

Uzelac, Tamara N., Nikolić-Kokić, Aleksandra, Spasić, Snežana D., Mačvanin, Mirjana T., Nikolić, Milan R., Mandić, Ljuba M., Jovanović, Vesna B., "Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content." in Chemico-Biological Interactions, 311 (2019):108787,
https://doi.org/10.1016/j.cbi.2019.108787 . .

TY  - JOUR
AU  - Nikolić-Kokić, Aleksandra
AU  - Tatalović, Nikola
AU  - Brkljačić, Jelena
AU  - Mijović, Milica
AU  - Mijušković, Ana
AU  - Miler, Marko
AU  - Oreščanin Dušić, Zorana
AU  - Nikolić, Milan
AU  - Milošević, Verica
AU  - Blagojević, Duško
AU  - Spasić, Mihajlo
AU  - Miljević, Čedo
PY  - 2018
UR  - https://www.tandfonline.com/doi/full/10.1080/15287394.2018.1495587
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3121
AB  - Atypical antipsychotics produce severe side effects including myocarditis that may be attributed to oxidative stress. The aim of this study was to investigate the influence of clozapine, ziprasidone, and sertindole on rat heart morphology and determine whether redox imbalane plays a role in development of histopathological changes. Adult 3-month-old male Wistar rats were treated with recommended daily dose for selected drugs. After 4 week treatment histopathological analysis of the heart was performed and expression and activity of antioxidant enzymes determined. All examined drugs induced histopathological changes that were characterized as toxic myocarditis. Degenerative changes in cardiomyocytes were accompanied by lymphocytic infiltration as well as pericardial histopathological alterations in all treated groups. The least prominent changes were observed in sertindole-treated animals, and most severe with clozapine. Clozapine increased superoxide dismutase 1 (SOD1) activity while ziprasidone reduced glutathione reductase (GR) activity. Sertindole exerted no marked effect on antioxidant enzyme function in the heart even though myocardial degeneration was noted. In conclusion, treatment with clozapine or ziprasidone induced pathophysiological alterations in rat heart, which appeared to be associated disturbances in antioxidant capacity. Abbreviation: AAP, Atypical antipsychotics; ROS, reactive oxygen species; SOD1, Copper-zinc superoxide dismutase; SOD2, Manganese superoxide dismutase; CAT, Catalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; H&E, hematoxylin and eosin stain; TNF- α, tumor necrosis factor alpha.
T2  - Journal of Toxicology and Environmental Health, Part A
T1  - Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function
IS  - 17
VL  - 81
DO  - 10.1080/15287394.2018.1495587
SP  - 844
EP  - 853
ER  - 

@article{
author = "Nikolić-Kokić, Aleksandra and Tatalović, Nikola and Brkljačić, Jelena and Mijović, Milica and Mijušković, Ana and Miler, Marko and Oreščanin Dušić, Zorana and Nikolić, Milan and Milošević, Verica and Blagojević, Duško and Spasić, Mihajlo and Miljević, Čedo",
year = "2018",
abstract = "Atypical antipsychotics produce severe side effects including myocarditis that may be attributed to oxidative stress. The aim of this study was to investigate the influence of clozapine, ziprasidone, and sertindole on rat heart morphology and determine whether redox imbalane plays a role in development of histopathological changes. Adult 3-month-old male Wistar rats were treated with recommended daily dose for selected drugs. After 4 week treatment histopathological analysis of the heart was performed and expression and activity of antioxidant enzymes determined. All examined drugs induced histopathological changes that were characterized as toxic myocarditis. Degenerative changes in cardiomyocytes were accompanied by lymphocytic infiltration as well as pericardial histopathological alterations in all treated groups. The least prominent changes were observed in sertindole-treated animals, and most severe with clozapine. Clozapine increased superoxide dismutase 1 (SOD1) activity while ziprasidone reduced glutathione reductase (GR) activity. Sertindole exerted no marked effect on antioxidant enzyme function in the heart even though myocardial degeneration was noted. In conclusion, treatment with clozapine or ziprasidone induced pathophysiological alterations in rat heart, which appeared to be associated disturbances in antioxidant capacity. Abbreviation: AAP, Atypical antipsychotics; ROS, reactive oxygen species; SOD1, Copper-zinc superoxide dismutase; SOD2, Manganese superoxide dismutase; CAT, Catalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; H&E, hematoxylin and eosin stain; TNF- α, tumor necrosis factor alpha.",
journal = "Journal of Toxicology and Environmental Health, Part A",
title = "Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function",
number = "17",
volume = "81",
doi = "10.1080/15287394.2018.1495587",
pages = "844-853"
}

Nikolić-Kokić, A., Tatalović, N., Brkljačić, J., Mijović, M., Mijušković, A., Miler, M., Oreščanin Dušić, Z., Nikolić, M., Milošević, V., Blagojević, D., Spasić, M.,& Miljević, Č.. (2018). Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function. in Journal of Toxicology and Environmental Health, Part A, 81(17), 844-853.
https://doi.org/10.1080/15287394.2018.1495587

Nikolić-Kokić A, Tatalović N, Brkljačić J, Mijović M, Mijušković A, Miler M, Oreščanin Dušić Z, Nikolić M, Milošević V, Blagojević D, Spasić M, Miljević Č. Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function. in Journal of Toxicology and Environmental Health, Part A. 2018;81(17):844-853.
doi:10.1080/15287394.2018.1495587 .

Nikolić-Kokić, Aleksandra, Tatalović, Nikola, Brkljačić, Jelena, Mijović, Milica, Mijušković, Ana, Miler, Marko, Oreščanin Dušić, Zorana, Nikolić, Milan, Milošević, Verica, Blagojević, Duško, Spasić, Mihajlo, Miljević, Čedo, "Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function" in Journal of Toxicology and Environmental Health, Part A, 81, no. 17 (2018):844-853,
https://doi.org/10.1080/15287394.2018.1495587 . .

TY  - JOUR
AU  - Miljević, Cedo D
AU  - Nikolić, Milan R
AU  - Nikolić-Kokić, Aleksandra
AU  - Jones, David R
AU  - Niketić, Vesna P
AU  - Lecić-Tosevski, Dusica M
AU  - Spasić, Mihajlo
PY  - 2010
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1395
AB  - Objective: Despite clozapine's unique effectiveness in patients with schizophrenia, a number of adverse effects have been recognised including abnormalities in lipid and glucose metabolisms. A high clozapine level in red blood cells (RBCs) and disturbed anti-oxidant enzyme activities in blood from schizophrenic patients prompted us to investigate lipid status and anti-oxidant enzyme defence in the blood of chronic schizophrenic patients on long-term clozapine therapy. Methods: Plasma lipids, RBC anti-oxidant enzyme activities and haemoglobin (Hb) content were measured using established procedures in a group of eighteen chronically-medicated (average 630 days of therapy) schizophrenic patients receiving clozapine (average dose of 295 mg/day) and data were compared with those from a group of eighteen well-matched normal controls. Results: Significantly higher levels of plasma triglycerides (by 47%, p<0.01) and total cholesterol and phospholipids (by 8% and 11%, respectively p<0.05) in patients were found. CuZn-superoxide dismutase (SOD1) activity was markedly higher (by 35%, p<0.001) while selenium-dependent glutathione peroxidase (GSH-Px1) activity was markedly lower (by 41%, p<0.001) in patients. In addition, metHb and HbA1c levels in patients were significantly higher (by 58% and 25%. respectively p<0.001). SOD1 activity was negatively correlated (p<0.001) to GSH-Px1 activity in patients. Conclusions:The findings support the view that ongoing oxidative stress may be a mechanism by which clozapine induces some adverse effects that increase the risk of diabetes and metabolic syndrome. If valid, this would indicate that in parallel with long-term clozapine treatment, schizophrenic patients could be encouraged to make some lifestyle changes to limit the detrimental effects of the medication. (C) 2009 Elsevier Inc. All rights reserved.
T2  - Progress in Neuro-Psychopharmacology & Biological Psychiatry
T1  - Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients
IS  - 2
VL  - 34
EP  - 307
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1395
ER  - 

@article{
author = "Miljević, Cedo D and Nikolić, Milan R and Nikolić-Kokić, Aleksandra and Jones, David R and Niketić, Vesna P and Lecić-Tosevski, Dusica M and Spasić, Mihajlo",
year = "2010",
abstract = "Objective: Despite clozapine's unique effectiveness in patients with schizophrenia, a number of adverse effects have been recognised including abnormalities in lipid and glucose metabolisms. A high clozapine level in red blood cells (RBCs) and disturbed anti-oxidant enzyme activities in blood from schizophrenic patients prompted us to investigate lipid status and anti-oxidant enzyme defence in the blood of chronic schizophrenic patients on long-term clozapine therapy. Methods: Plasma lipids, RBC anti-oxidant enzyme activities and haemoglobin (Hb) content were measured using established procedures in a group of eighteen chronically-medicated (average 630 days of therapy) schizophrenic patients receiving clozapine (average dose of 295 mg/day) and data were compared with those from a group of eighteen well-matched normal controls. Results: Significantly higher levels of plasma triglycerides (by 47%, p<0.01) and total cholesterol and phospholipids (by 8% and 11%, respectively p<0.05) in patients were found. CuZn-superoxide dismutase (SOD1) activity was markedly higher (by 35%, p<0.001) while selenium-dependent glutathione peroxidase (GSH-Px1) activity was markedly lower (by 41%, p<0.001) in patients. In addition, metHb and HbA1c levels in patients were significantly higher (by 58% and 25%. respectively p<0.001). SOD1 activity was negatively correlated (p<0.001) to GSH-Px1 activity in patients. Conclusions:The findings support the view that ongoing oxidative stress may be a mechanism by which clozapine induces some adverse effects that increase the risk of diabetes and metabolic syndrome. If valid, this would indicate that in parallel with long-term clozapine treatment, schizophrenic patients could be encouraged to make some lifestyle changes to limit the detrimental effects of the medication. (C) 2009 Elsevier Inc. All rights reserved.",
journal = "Progress in Neuro-Psychopharmacology & Biological Psychiatry",
title = "Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients",
number = "2",
volume = "34",
pages = "307",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1395"
}

Miljević, C. D., Nikolić, M. R., Nikolić-Kokić, A., Jones, D. R., Niketić, V. P., Lecić-Tosevski, D. M.,& Spasić, M.. (2010). Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients. in Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34(2).
https://hdl.handle.net/21.15107/rcub_ibiss_1395

Miljević CD, Nikolić MR, Nikolić-Kokić A, Jones DR, Niketić VP, Lecić-Tosevski DM, Spasić M. Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients. in Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2010;34(2):null-307.
https://hdl.handle.net/21.15107/rcub_ibiss_1395 .

Miljević, Cedo D, Nikolić, Milan R, Nikolić-Kokić, Aleksandra, Jones, David R, Niketić, Vesna P, Lecić-Tosevski, Dusica M, Spasić, Mihajlo, "Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients" in Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34, no. 2 (2010),
https://hdl.handle.net/21.15107/rcub_ibiss_1395 .