TY  - JOUR
AU  - Platanić Arizanović, Lena
AU  - Gligorijević, Nikola
AU  - Cvijetić, Ilija
AU  - Mijatović, Aleksandar
AU  - Krstić Ristivojević, Maja
AU  - Minić, Simeon
AU  - Nikolić Kokić, Aleksandra
AU  - Miljević, Čedo
AU  - Nikolić, Milan
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/6482
AB  - Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes
are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van’t Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ  interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~10^4 M^-1), the highest observed for clozapine (2.2 x 10^4 M^-1 at 25 °C). The clozapine binding showed “friendly” effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible “foe”. Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.
PB  - Multidisciplinary Digital Publishing Institute (MDPI)
T2  - International Journal of Molecular Sciences
T1  - Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?
VL  - 24
IS  - 10
SP  - 8921
DO  - 10.3390/ijms24108921
ER  - 

@article{
author = "Platanić Arizanović, Lena and Gligorijević, Nikola and Cvijetić, Ilija and Mijatović, Aleksandar and Krstić Ristivojević, Maja and Minić, Simeon and Nikolić Kokić, Aleksandra and Miljević, Čedo and Nikolić, Milan",
year = "2023",
abstract = "Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes
are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van’t Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ  interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~10^4 M^-1), the highest observed for clozapine (2.2 x 10^4 M^-1 at 25 °C). The clozapine binding showed “friendly” effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible “foe”. Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
journal = "International Journal of Molecular Sciences",
title = "Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?",
volume = "24",
number = "10",
pages = "8921",
doi = "10.3390/ijms24108921"
}

Platanić Arizanović, L., Gligorijević, N., Cvijetić, I., Mijatović, A., Krstić Ristivojević, M., Minić, S., Nikolić Kokić, A., Miljević, Č.,& Nikolić, M.. (2023). Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?. in International Journal of Molecular Sciences
Multidisciplinary Digital Publishing Institute (MDPI)., 24(10), 8921.
https://doi.org/10.3390/ijms24108921

Platanić Arizanović L, Gligorijević N, Cvijetić I, Mijatović A, Krstić Ristivojević M, Minić S, Nikolić Kokić A, Miljević Č, Nikolić M. Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?. in International Journal of Molecular Sciences. 2023;24(10):8921.
doi:10.3390/ijms24108921 .

Platanić Arizanović, Lena, Gligorijević, Nikola, Cvijetić, Ilija, Mijatović, Aleksandar, Krstić Ristivojević, Maja, Minić, Simeon, Nikolić Kokić, Aleksandra, Miljević, Čedo, Nikolić, Milan, "Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?" in International Journal of Molecular Sciences, 24, no. 10 (2023):8921,
https://doi.org/10.3390/ijms24108921 . .

TY  - JOUR
AU  - Nikolić Kokić, Aleksandra
AU  - Tatalović, Nikola
AU  - Brkljačić, Jelena
AU  - Mijović, Milica
AU  - Nestorović, Vojkan
AU  - Mijušković, Ana
AU  - Oreščanin-Dušić, Zorana
AU  - Vidonja Uzelac, Teodora
AU  - Nikolić, Milan
AU  - Spasić, Snežana
AU  - Blagojević, Duško
AU  - Miljević, Čedo
PY  - 2022
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/5557
AB  - Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs)
for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken
to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a
recommended daily dose for atypical antipsychotic therapy), induced histopathological changes
both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis
VL  - 23
IS  - 22
SP  - 13698
DO  - 10.3390/ijms232213698
ER  - 

@article{
author = "Nikolić Kokić, Aleksandra and Tatalović, Nikola and Brkljačić, Jelena and Mijović, Milica and Nestorović, Vojkan and Mijušković, Ana and Oreščanin-Dušić, Zorana and Vidonja Uzelac, Teodora and Nikolić, Milan and Spasić, Snežana and Blagojević, Duško and Miljević, Čedo",
year = "2022",
abstract = "Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs)
for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken
to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a
recommended daily dose for atypical antipsychotic therapy), induced histopathological changes
both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis",
volume = "23",
number = "22",
pages = "13698",
doi = "10.3390/ijms232213698"
}

Nikolić Kokić, A., Tatalović, N., Brkljačić, J., Mijović, M., Nestorović, V., Mijušković, A., Oreščanin-Dušić, Z., Vidonja Uzelac, T., Nikolić, M., Spasić, S., Blagojević, D.,& Miljević, Č.. (2022). Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis. in International Journal of Molecular Sciences
MDPI., 23(22), 13698.
https://doi.org/10.3390/ijms232213698

Nikolić Kokić A, Tatalović N, Brkljačić J, Mijović M, Nestorović V, Mijušković A, Oreščanin-Dušić Z, Vidonja Uzelac T, Nikolić M, Spasić S, Blagojević D, Miljević Č. Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis. in International Journal of Molecular Sciences. 2022;23(22):13698.
doi:10.3390/ijms232213698 .

Nikolić Kokić, Aleksandra, Tatalović, Nikola, Brkljačić, Jelena, Mijović, Milica, Nestorović, Vojkan, Mijušković, Ana, Oreščanin-Dušić, Zorana, Vidonja Uzelac, Teodora, Nikolić, Milan, Spasić, Snežana, Blagojević, Duško, Miljević, Čedo, "Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis" in International Journal of Molecular Sciences, 23, no. 22 (2022):13698,
https://doi.org/10.3390/ijms232213698 . .

TY  - JOUR
AU  - Platanović Arizanović, Lena
AU  - Nikolić-Kokić, Aleksandra
AU  - Brkljačić, Jelena
AU  - Tatalović, Nikola
AU  - Miler, Marko
AU  - Oreščanin-Dušić, Zorana
AU  - Vidonja Uzelac, Teodora
AU  - Nikolić, Milan
AU  - Milošević, Verica
AU  - Blagojević, Duško
AU  - Spasić, Snežana
AU  - Miljević, Čedo
PY  - 2021
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3967
AB  - Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.
PB  - Taylor & Francis
T2  - Journal of Toxicology and Environmental Health, Part A
T1  - Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction
VL  - 84
IS  - 4
SP  - 173
EP  - 182
DO  - 10.1080/15287394.2020.1844827
ER  - 

@article{
author = "Platanović Arizanović, Lena and Nikolić-Kokić, Aleksandra and Brkljačić, Jelena and Tatalović, Nikola and Miler, Marko and Oreščanin-Dušić, Zorana and Vidonja Uzelac, Teodora and Nikolić, Milan and Milošević, Verica and Blagojević, Duško and Spasić, Snežana and Miljević, Čedo",
year = "2021",
abstract = "Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.",
publisher = "Taylor & Francis",
journal = "Journal of Toxicology and Environmental Health, Part A",
title = "Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction",
volume = "84",
number = "4",
pages = "173-182",
doi = "10.1080/15287394.2020.1844827"
}

Platanović Arizanović, L., Nikolić-Kokić, A., Brkljačić, J., Tatalović, N., Miler, M., Oreščanin-Dušić, Z., Vidonja Uzelac, T., Nikolić, M., Milošević, V., Blagojević, D., Spasić, S.,& Miljević, Č.. (2021). Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction. in Journal of Toxicology and Environmental Health, Part A
Taylor & Francis., 84(4), 173-182.
https://doi.org/10.1080/15287394.2020.1844827

Platanović Arizanović L, Nikolić-Kokić A, Brkljačić J, Tatalović N, Miler M, Oreščanin-Dušić Z, Vidonja Uzelac T, Nikolić M, Milošević V, Blagojević D, Spasić S, Miljević Č. Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction. in Journal of Toxicology and Environmental Health, Part A. 2021;84(4):173-182.
doi:10.1080/15287394.2020.1844827 .

Platanović Arizanović, Lena, Nikolić-Kokić, Aleksandra, Brkljačić, Jelena, Tatalović, Nikola, Miler, Marko, Oreščanin-Dušić, Zorana, Vidonja Uzelac, Teodora, Nikolić, Milan, Milošević, Verica, Blagojević, Duško, Spasić, Snežana, Miljević, Čedo, "Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction" in Journal of Toxicology and Environmental Health, Part A, 84, no. 4 (2021):173-182,
https://doi.org/10.1080/15287394.2020.1844827 . .