TY  - JOUR
AU  - Ilić, Tanja
AU  - Đoković, Jelena
AU  - Nikolić, Ines
AU  - Mitrović, Jelena
AU  - Pantelić, Ivana
AU  - Savić, Snežana
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4515
AB  - Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood–brain barrier (BBB). The growing availability of innovative excipients/ligands allowing improved brain targeting and controlled drug release makes the lipid nanocarriers a reasonable choice to overcome the factors impeding drug delivery through the BBB. However, a wide variety of methods, study designs and experimental conditions utilized in the literature hinder their systematic comparison, and thus slows the advances in brain-targeting by lipid-based nanoparticles. This review provides an overview of the methods most commonly utilized during the preclinical testing of liposomes, nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers intended for the treatment of various CNS disorders via the parenteral route. In order to fully elucidate the structure, stability, safety profiles, biodistribution, metabolism, pharmacokinetics and immunological effects of such lipid-based nanoparticles, a transdisciplinary approach to preclinical characterization is mandatory, covering a comprehensive set of physical, chemical, in vitro and in vivo biological testing.
PB  - MDPI
T2  - Pharmaceutics
T1  - Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation
VL  - 15
IS  - 2
DO  - 10.3390/pharmaceutics15020443
ER  - 

@article{
author = "Ilić, Tanja and Đoković, Jelena and Nikolić, Ines and Mitrović, Jelena and Pantelić, Ivana and Savić, Snežana and Savić, Miroslav",
year = "2023",
abstract = "Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood–brain barrier (BBB). The growing availability of innovative excipients/ligands allowing improved brain targeting and controlled drug release makes the lipid nanocarriers a reasonable choice to overcome the factors impeding drug delivery through the BBB. However, a wide variety of methods, study designs and experimental conditions utilized in the literature hinder their systematic comparison, and thus slows the advances in brain-targeting by lipid-based nanoparticles. This review provides an overview of the methods most commonly utilized during the preclinical testing of liposomes, nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers intended for the treatment of various CNS disorders via the parenteral route. In order to fully elucidate the structure, stability, safety profiles, biodistribution, metabolism, pharmacokinetics and immunological effects of such lipid-based nanoparticles, a transdisciplinary approach to preclinical characterization is mandatory, covering a comprehensive set of physical, chemical, in vitro and in vivo biological testing.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation",
volume = "15",
number = "2",
doi = "10.3390/pharmaceutics15020443"
}

Ilić, T., Đoković, J., Nikolić, I., Mitrović, J., Pantelić, I., Savić, S.,& Savić, M.. (2023). Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation. in Pharmaceutics
MDPI., 15(2).
https://doi.org/10.3390/pharmaceutics15020443

Ilić T, Đoković J, Nikolić I, Mitrović J, Pantelić I, Savić S, Savić M. Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation. in Pharmaceutics. 2023;15(2).
doi:10.3390/pharmaceutics15020443 .

Ilić, Tanja, Đoković, Jelena, Nikolić, Ines, Mitrović, Jelena, Pantelić, Ivana, Savić, Snežana, Savić, Miroslav, "Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation" in Pharmaceutics, 15, no. 2 (2023),
https://doi.org/10.3390/pharmaceutics15020443 . .

TY  - CONF
AU  - Aranđelović, Jovana
AU  - Kojić, Jana
AU  - Mirković, Kristina
AU  - Jančić, Ivan
AU  - Todorović, Lidija
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5520
AB  - Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.
PB  - European College of Neuropsychopharmacology (ECNP)
C3  - 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
T1  - Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5520
ER  - 

@conference{
author = "Aranđelović, Jovana and Kojić, Jana and Mirković, Kristina and Jančić, Ivan and Todorović, Lidija and Savić, Miroslav",
year = "2023",
abstract = "Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.",
publisher = "European College of Neuropsychopharmacology (ECNP)",
journal = "36th ECPN congress, 7th -10th October 2023, Barcelona, Spain",
title = "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5520"
}

Aranđelović, J., Kojić, J., Mirković, K., Jančić, I., Todorović, L.,& Savić, M.. (2023). Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
European College of Neuropsychopharmacology (ECNP)..
https://hdl.handle.net/21.15107/rcub_farfar_5520

Aranđelović J, Kojić J, Mirković K, Jančić I, Todorović L, Savić M. Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5520 .

Aranđelović, Jovana, Kojić, Jana, Mirković, Kristina, Jančić, Ivan, Todorović, Lidija, Savić, Miroslav, "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats" in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5520 .

TY  - CONF
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5116
AB  - Neuro pharmacokinetics: the secret life of - old and novel - psychopharmacological drugs
Miroslav Savić
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia
In the 21st century, the pace of development of new pharmacological treatments for general medical and psychiatric disorders is remarkably different. While successes for the former are frequent, new drugs for mental, behavioral and neurodevelopmental disorders are sporadic. Many factors contribute to this discrepancy. Probably the most important is the complexity of etiology and manifestations of mood, psychotic, anxiety, neurocognitive and other disorders that are commonly treated with psycho pharmacological drugs. Although this factor cannot be directly addressed in drug development, optimization of drug exposure in brain tissue can certainly help to balance the efficacy and safety of both widely used and novel psycho pharmacological drugs. While drug exposure of various organs and tissues can be easily assessed from free (unbound) blood concentrations, the central nervous system (CNS) has a number of barriers, most notably the blood-brain barrier (BBB) that separates nervous tissue from the periphery. Optimised CNS exposure of a drug to its target site over a desired time period is critical to triggering its therapeutic effect. The presence of the BBB readily leads to an asymmetry of drug (unbound) exposure in the brain and in the systemic circulation, which prohibits the use of unbound drug concentration in plasma as a surrogate for unbound drug concentration in the brain. Comprehensive pharmacokinetic/pharmacodynamic studies of marketed CNS drugs have shown that the concentration of unbound drug in brain interstitial fluid is an appropriate measure of CNS exposure in the context of cell membrane targets of action. The more recent concept of brain-plasma partition coefficient, Kp,uu, as a parameter describing the relationship between the concentration of unbound drug in brain interstitial fluid and the concentration of unbound drug in plasma, is assumed to be the most important means of assessing brain exposure. Experimental assessment of Kp,uu requires either measurement of the brain unbound drug concentration in the interstitial fluid by microdialysis in vivo or estimation of the fraction of unbound drug in the whole brain homogenate (fu,brain) by equilibrium dialysis in vitro. Kp,uu can be calculated by dividing either the area under the curve (AUC) of the profile of the concentration of unbound drug in brain and plasma after a single administration or the steady-state unbound concentrations of drug in brain interstitial fluid and plasma. Although many marketed psychotropic drugs have Kp,uu values as low as 0.1-0.2, it is theorized that the most successful small molecule CNS drugs should have Kp,uu values near 1. The neuropharmacokinetic behavior of benzodiazepine compounds, both widely used and those in preclinical and clinical development, is presented as a showcase. Given the variety of receptor subpopulations at which these drugs act as positive allosteric modulators of GABAA receptors, the complexity of linking brain exposure data to the corresponding pharmacodynamic effect is explained.
PB  - International Association of Physical Chemists
C3  - 10th IACP conference, World Conferences on Physico Chemical Methods in Drug Discovery and Development and on ADMET and DMPK; September 4th - 6th, Belgrade, Serbia
T1  - Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5116
ER  - 

@conference{
author = "Savić, Miroslav",
year = "2023",
abstract = "Neuro pharmacokinetics: the secret life of - old and novel - psychopharmacological drugs
Miroslav Savić
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia
In the 21st century, the pace of development of new pharmacological treatments for general medical and psychiatric disorders is remarkably different. While successes for the former are frequent, new drugs for mental, behavioral and neurodevelopmental disorders are sporadic. Many factors contribute to this discrepancy. Probably the most important is the complexity of etiology and manifestations of mood, psychotic, anxiety, neurocognitive and other disorders that are commonly treated with psycho pharmacological drugs. Although this factor cannot be directly addressed in drug development, optimization of drug exposure in brain tissue can certainly help to balance the efficacy and safety of both widely used and novel psycho pharmacological drugs. While drug exposure of various organs and tissues can be easily assessed from free (unbound) blood concentrations, the central nervous system (CNS) has a number of barriers, most notably the blood-brain barrier (BBB) that separates nervous tissue from the periphery. Optimised CNS exposure of a drug to its target site over a desired time period is critical to triggering its therapeutic effect. The presence of the BBB readily leads to an asymmetry of drug (unbound) exposure in the brain and in the systemic circulation, which prohibits the use of unbound drug concentration in plasma as a surrogate for unbound drug concentration in the brain. Comprehensive pharmacokinetic/pharmacodynamic studies of marketed CNS drugs have shown that the concentration of unbound drug in brain interstitial fluid is an appropriate measure of CNS exposure in the context of cell membrane targets of action. The more recent concept of brain-plasma partition coefficient, Kp,uu, as a parameter describing the relationship between the concentration of unbound drug in brain interstitial fluid and the concentration of unbound drug in plasma, is assumed to be the most important means of assessing brain exposure. Experimental assessment of Kp,uu requires either measurement of the brain unbound drug concentration in the interstitial fluid by microdialysis in vivo or estimation of the fraction of unbound drug in the whole brain homogenate (fu,brain) by equilibrium dialysis in vitro. Kp,uu can be calculated by dividing either the area under the curve (AUC) of the profile of the concentration of unbound drug in brain and plasma after a single administration or the steady-state unbound concentrations of drug in brain interstitial fluid and plasma. Although many marketed psychotropic drugs have Kp,uu values as low as 0.1-0.2, it is theorized that the most successful small molecule CNS drugs should have Kp,uu values near 1. The neuropharmacokinetic behavior of benzodiazepine compounds, both widely used and those in preclinical and clinical development, is presented as a showcase. Given the variety of receptor subpopulations at which these drugs act as positive allosteric modulators of GABAA receptors, the complexity of linking brain exposure data to the corresponding pharmacodynamic effect is explained.",
publisher = "International Association of Physical Chemists",
journal = "10th IACP conference, World Conferences on Physico Chemical Methods in Drug Discovery and Development and on ADMET and DMPK; September 4th - 6th, Belgrade, Serbia",
title = "Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5116"
}

Savić, M.. (2023). Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs. in 10th IACP conference, World Conferences on Physico Chemical Methods in Drug Discovery and Development and on ADMET and DMPK; September 4th - 6th, Belgrade, Serbia
International Association of Physical Chemists..
https://hdl.handle.net/21.15107/rcub_farfar_5116

Savić M. Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs. in 10th IACP conference, World Conferences on Physico Chemical Methods in Drug Discovery and Development and on ADMET and DMPK; September 4th - 6th, Belgrade, Serbia. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5116 .

Savić, Miroslav, "Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs" in 10th IACP conference, World Conferences on Physico Chemical Methods in Drug Discovery and Development and on ADMET and DMPK; September 4th - 6th, Belgrade, Serbia (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5116 .

TY  - JOUR
AU  - Mirković, Duško
AU  - Beletić, Anđelo
AU  - Savić, Miroslav
AU  - Milinković, Neda
AU  - Sarić-Matutinović, Marija
AU  - Jančić, Ivan
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4910
AB  - Occupational and environmental toxicology specialists find catecholamine fluctuations in brain tissue relevant for research of neurotoxicity, such as that induced by manganese or zinc, pesticides, industrial solvents, plastic, air pollution, or irradiation. Considering that catecholamine tissue concentrations are generally very low, their extraction requires a reliable and optimal method that will achieve maximum recovery and minimise other interferences. This study aimed to evaluate whether the aluminium (III) oxide (Al2O3, alumina) based cartridges designed for catecholamine isolation from plasma could be used for solid-phase extraction (SPE) of catecholamine from the brain tissue. To do that, we homogenised Wistar rat brain tissue with perchloric acid and compared three extraction techniques: SPE, the routine filtration through a 0.22 µm membrane filter, and their combination. In the extracts, we compared relative chromatographic catecholamine mobility measured with high performance liquid chromatography with electrochemical detection. Chromatographic patterns for norepinephrine and epinephrine were similar regardless of the extraction technique, which indicates that the alumina cartridge is good enough to isolate them from brain tissue. However, the dopamine pattern was unsatisfactory, and further experiments are needed to identify the issue and optimise the protocol. © 2023 Duško Mirković et al., published by Sciendo.  Promjene razine katekolamina (KAT) u moždanom tkivu značajne su za brojna područja profesionalne toksikologije odnosno ekotoksikologije u kojima se istražuje neurotoksičnost izazvana različitim agensima poput mangana ili cinka, pesticida, industrijskih otapala, plastike, aerozagađenja ili zračenja. Niske koncentracije KAT-a u tkivu zahtijevaju pouzdanu i učinkovitu tehniku ekstrakcije kojom se postiže maksimalni „prinos“ katekolamina i minimalni sadržaj interferirajućih spojeva. Cilj istraživanja bio je procijeniti mogu li se kolone na bazi aluminijeva (III) oksida (Al2O3), dizajnirane za izolaciju KAT-a iz plazme, koristiti za ekstrakciju čvrstom fazom (eng. solid-phase extraction – SPE) KAT-a iz moždanoga tkiva. Nakon homogenizacije tkiva Sprague Dawley štakora upotrebom perklorne kiseline, primijenjene su tri tehnike ekstrakcije: SPE, filtracija kroz 0,22 µm membranski filtar, koji je zapravo rutinska tehnika za izolaciju KAT-a iz mozga, i kombinacija tih dviju tehnika. U ekstraktima je relativna kromatografska pokretljivost KAT-a analizirana HPLC metodom s elektrokemijskom detekcijom. Ponašanje norepinefrina i epinefrina tijekom kromatografije bilo je slično, bez obzira na tehniku ekstrakcije, što upućuje na to da aluminijev oksid ima zadovoljavajuća svojstva izolirati ta dva KAT-a iz moždanoga tkiva. Međutim, uočeni su problemi s ekstrakcijom dopamina, koji zahtijevaju dodatne eksperimente kako bi se otkrio njihov uzrok i osmislio protokol optimizacije. Author keywords aluminijev oksid; aluminium oxide; brain; catecholamines; ekstrakcija čvrste faze; katekolamini; mozak; solid phase extraction; tissue; tkivo   © This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine      1of1   Top of page Cited by 0 documents Inform me when this document is cited in Scopus: Related documents Find more related documents in Scopus based on: Authors Keywords
AB  - Promjene razine katekolamina (KAT) u moždanom tkivu značajne su za brojna područja profesionalne toksikologije odnosno ekotoksikologije u kojima se istražuje neurotoksičnost izazvana različitim agensima poput mangana ili cinka, pesticida, industrijskih otapala, plastike, aerozagađenja ili zračenja. Niske koncentracije KAT-a u tkivu zahtijevaju pouzdanu i učinkovitu tehniku ekstrakcije kojom se postiže maksimalni „prinos“ katekolamina i minimalni sadržaj interferirajućih spojeva. Cilj istraživanja bio je procijeniti mogu li se kolone na bazi aluminijeva (III) oksida (Al2 O 3), dizajnirane za izolaciju KAT-a iz plazme, koristiti za ekstrakciju čvrstom fazom (eng. solid-phase extraction – SPE) KAT-a iz moždanoga tkiva. Nakon homogenizacije tkiva Sprague Dawley štakora upotrebom perklorne kiseline, primijenjene su tri tehnike ekstrakcije: SPE, filtracija kroz 0,22 μm membranski filtar, koji je zapravo rutinska tehnika za izolaciju KAT-a iz mozga, i kombinacija tih dviju tehnika. U ekstraktima je relativna kromatografska pokretljivost KAT-a analizirana HPLC metodom s elektrokemijskom detekcijom. Ponašanje norepinefrina i epinefrina tijekom kromatografije bilo je slično, bez obzira na tehniku ekstrakcije, što upućuje na to da aluminijev oksid ima zadovoljavajuća svojstva izolirati ta dva KAT-a iz moždanoga tkiva. Međutim, uočeni su problemi s ekstrakcijom dopamina, koji zahtijevaju dodatne eksperimente kako bi se otkrio njihov uzrok i osmislio protokol optimizacije.
PB  - De Gruyter Poland
T2  - Arhiv za higijenu rada i toksikologiju
T1  - Is alumina suitable for solid phase extraction of catecholamines from brain tissue?
T1  - Je li aluminijev oksid pogodan za postupak ekstrakcije čvrste faze katekolamina iz moždanoga tkiva?
VL  - 74
IS  - 2
SP  - 120
EP  - 126
DO  - 10.2478/aiht-2023-74-3706
ER  - 

@article{
author = "Mirković, Duško and Beletić, Anđelo and Savić, Miroslav and Milinković, Neda and Sarić-Matutinović, Marija and Jančić, Ivan",
year = "2023",
abstract = "Occupational and environmental toxicology specialists find catecholamine fluctuations in brain tissue relevant for research of neurotoxicity, such as that induced by manganese or zinc, pesticides, industrial solvents, plastic, air pollution, or irradiation. Considering that catecholamine tissue concentrations are generally very low, their extraction requires a reliable and optimal method that will achieve maximum recovery and minimise other interferences. This study aimed to evaluate whether the aluminium (III) oxide (Al2O3, alumina) based cartridges designed for catecholamine isolation from plasma could be used for solid-phase extraction (SPE) of catecholamine from the brain tissue. To do that, we homogenised Wistar rat brain tissue with perchloric acid and compared three extraction techniques: SPE, the routine filtration through a 0.22 µm membrane filter, and their combination. In the extracts, we compared relative chromatographic catecholamine mobility measured with high performance liquid chromatography with electrochemical detection. Chromatographic patterns for norepinephrine and epinephrine were similar regardless of the extraction technique, which indicates that the alumina cartridge is good enough to isolate them from brain tissue. However, the dopamine pattern was unsatisfactory, and further experiments are needed to identify the issue and optimise the protocol. © 2023 Duško Mirković et al., published by Sciendo.  Promjene razine katekolamina (KAT) u moždanom tkivu značajne su za brojna područja profesionalne toksikologije odnosno ekotoksikologije u kojima se istražuje neurotoksičnost izazvana različitim agensima poput mangana ili cinka, pesticida, industrijskih otapala, plastike, aerozagađenja ili zračenja. Niske koncentracije KAT-a u tkivu zahtijevaju pouzdanu i učinkovitu tehniku ekstrakcije kojom se postiže maksimalni „prinos“ katekolamina i minimalni sadržaj interferirajućih spojeva. Cilj istraživanja bio je procijeniti mogu li se kolone na bazi aluminijeva (III) oksida (Al2O3), dizajnirane za izolaciju KAT-a iz plazme, koristiti za ekstrakciju čvrstom fazom (eng. solid-phase extraction – SPE) KAT-a iz moždanoga tkiva. Nakon homogenizacije tkiva Sprague Dawley štakora upotrebom perklorne kiseline, primijenjene su tri tehnike ekstrakcije: SPE, filtracija kroz 0,22 µm membranski filtar, koji je zapravo rutinska tehnika za izolaciju KAT-a iz mozga, i kombinacija tih dviju tehnika. U ekstraktima je relativna kromatografska pokretljivost KAT-a analizirana HPLC metodom s elektrokemijskom detekcijom. Ponašanje norepinefrina i epinefrina tijekom kromatografije bilo je slično, bez obzira na tehniku ekstrakcije, što upućuje na to da aluminijev oksid ima zadovoljavajuća svojstva izolirati ta dva KAT-a iz moždanoga tkiva. Međutim, uočeni su problemi s ekstrakcijom dopamina, koji zahtijevaju dodatne eksperimente kako bi se otkrio njihov uzrok i osmislio protokol optimizacije. Author keywords aluminijev oksid; aluminium oxide; brain; catecholamines; ekstrakcija čvrste faze; katekolamini; mozak; solid phase extraction; tissue; tkivo   © This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine      1of1   Top of page Cited by 0 documents Inform me when this document is cited in Scopus: Related documents Find more related documents in Scopus based on: Authors Keywords, Promjene razine katekolamina (KAT) u moždanom tkivu značajne su za brojna područja profesionalne toksikologije odnosno ekotoksikologije u kojima se istražuje neurotoksičnost izazvana različitim agensima poput mangana ili cinka, pesticida, industrijskih otapala, plastike, aerozagađenja ili zračenja. Niske koncentracije KAT-a u tkivu zahtijevaju pouzdanu i učinkovitu tehniku ekstrakcije kojom se postiže maksimalni „prinos“ katekolamina i minimalni sadržaj interferirajućih spojeva. Cilj istraživanja bio je procijeniti mogu li se kolone na bazi aluminijeva (III) oksida (Al2 O 3), dizajnirane za izolaciju KAT-a iz plazme, koristiti za ekstrakciju čvrstom fazom (eng. solid-phase extraction – SPE) KAT-a iz moždanoga tkiva. Nakon homogenizacije tkiva Sprague Dawley štakora upotrebom perklorne kiseline, primijenjene su tri tehnike ekstrakcije: SPE, filtracija kroz 0,22 μm membranski filtar, koji je zapravo rutinska tehnika za izolaciju KAT-a iz mozga, i kombinacija tih dviju tehnika. U ekstraktima je relativna kromatografska pokretljivost KAT-a analizirana HPLC metodom s elektrokemijskom detekcijom. Ponašanje norepinefrina i epinefrina tijekom kromatografije bilo je slično, bez obzira na tehniku ekstrakcije, što upućuje na to da aluminijev oksid ima zadovoljavajuća svojstva izolirati ta dva KAT-a iz moždanoga tkiva. Međutim, uočeni su problemi s ekstrakcijom dopamina, koji zahtijevaju dodatne eksperimente kako bi se otkrio njihov uzrok i osmislio protokol optimizacije.",
publisher = "De Gruyter Poland",
journal = "Arhiv za higijenu rada i toksikologiju",
title = "Is alumina suitable for solid phase extraction of catecholamines from brain tissue?, Je li aluminijev oksid pogodan za postupak ekstrakcije čvrste faze katekolamina iz moždanoga tkiva?",
volume = "74",
number = "2",
pages = "120-126",
doi = "10.2478/aiht-2023-74-3706"
}

Mirković, D., Beletić, A., Savić, M., Milinković, N., Sarić-Matutinović, M.,& Jančić, I.. (2023). Is alumina suitable for solid phase extraction of catecholamines from brain tissue?. in Arhiv za higijenu rada i toksikologiju
De Gruyter Poland., 74(2), 120-126.
https://doi.org/10.2478/aiht-2023-74-3706

Mirković D, Beletić A, Savić M, Milinković N, Sarić-Matutinović M, Jančić I. Is alumina suitable for solid phase extraction of catecholamines from brain tissue?. in Arhiv za higijenu rada i toksikologiju. 2023;74(2):120-126.
doi:10.2478/aiht-2023-74-3706 .

Mirković, Duško, Beletić, Anđelo, Savić, Miroslav, Milinković, Neda, Sarić-Matutinović, Marija, Jančić, Ivan, "Is alumina suitable for solid phase extraction of catecholamines from brain tissue?" in Arhiv za higijenu rada i toksikologiju, 74, no. 2 (2023):120-126,
https://doi.org/10.2478/aiht-2023-74-3706 . .

TY  - CONF
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4483
AB  - The adverse effects of pharmaceuticals on the central or peripheral nervous systems
are poorly predicted by the current in vitro and in vivo preclinical studies performed during
research and development process. Increasing the predictivity of the preclinical toolbox is a
clear need, and would benefit to human volunteers/patients (safer drugs) and
pharmaceutical industry (reduced attrition). The NeuroDeRisk Consortium consists of 18
academic, pharmaceutical industry and small and medium enterprise partners within the
Innovative Medicines Initiative project (2019-2022). University of Belgrade – Faculty of
Pharmacy is the partner that leads the work package devoted to preclinical prediction of
mood and cognitive adverse effects. The other two groups of challenging adverse effects
tackled by the project are seizures and peripheral neuropathies. By employing a plethora of
experimental techniques and numerous pharmaceuticals previously connected with each of
major adverse effects examined, the project looks for innovative tools, assays and protocols,
which cover in silico, in vitro, in vivo and ex vivo approaches. Besides widening the
knowledge on many widely used pharmaceuticals, the major goal of the project is to develop
an integrated platform for better risk-assessment in exploratory and regulatory studies in
the future.
AB  - Postojeće in vitro i in vivo prekliničke studije koje se sprovode tokom procesa
istraživanja i razvoja teško mogu predvideti neželjene efekte farmaceutika na centralni i
periferni nervni sistem. Postoji jasna potreba za povećanjem prediktivnosti prekliničkih
oruđa, što bi bilo korisno za humane volontere/pacijente (bezbedniji lekovi) i farmaceutsku
industriju (smanjena stopa neuspeha). NeuroDeRisk konzorcijum se sastoji od 18
akademskih institucija, kompanija farmaceutske industrije i malih i srednjih preduzeća u
okviru projekta Inicijative za inovativne lekove (2019-2022). Univerzitet u Beogradu –
Farmaceutski fakultet jeste partner koji predvodi radni parket posvećen prekliničkom
predviđanju neželjenih efekata na raspoloženje i kogniciju. Druge dve grupe izazovnih
neželjenih efekata koje projekat obrađuje jesu konvulzivni napadi i periferne neuropatije.
Korišćenjem mnoštva eksperimentalnih tehnika i brojnih farmaceutika koji su prethodno
povezani sa svakim od ispitivanih velikih neželjenih efekata, projekat traga za inovativnim
oruđima, esejima i protokolima, koji pokrivaju in silico, in vitro, in vivo i ex vivo pristupe.
Mimo širenja znanja o brojnim široko korišćenim farmaceuticima, glavni cilj projekta jeste
razvoj integrisane platforme za bolju procenu rizika u budućim eksploratornim i
regulatornim studijama.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Neurotoxicity De-Risking in Preclinical Drug Discovery
T1  - Prekliničko predviđanje neželjenih efekata lekova na nervni sistem
VL  - 72
IS  - 4 suplement
SP  - S163
EP  - S164
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4483
ER  - 

@conference{
author = "Savić, Miroslav",
year = "2022",
abstract = "The adverse effects of pharmaceuticals on the central or peripheral nervous systems
are poorly predicted by the current in vitro and in vivo preclinical studies performed during
research and development process. Increasing the predictivity of the preclinical toolbox is a
clear need, and would benefit to human volunteers/patients (safer drugs) and
pharmaceutical industry (reduced attrition). The NeuroDeRisk Consortium consists of 18
academic, pharmaceutical industry and small and medium enterprise partners within the
Innovative Medicines Initiative project (2019-2022). University of Belgrade – Faculty of
Pharmacy is the partner that leads the work package devoted to preclinical prediction of
mood and cognitive adverse effects. The other two groups of challenging adverse effects
tackled by the project are seizures and peripheral neuropathies. By employing a plethora of
experimental techniques and numerous pharmaceuticals previously connected with each of
major adverse effects examined, the project looks for innovative tools, assays and protocols,
which cover in silico, in vitro, in vivo and ex vivo approaches. Besides widening the
knowledge on many widely used pharmaceuticals, the major goal of the project is to develop
an integrated platform for better risk-assessment in exploratory and regulatory studies in
the future., Postojeće in vitro i in vivo prekliničke studije koje se sprovode tokom procesa
istraživanja i razvoja teško mogu predvideti neželjene efekte farmaceutika na centralni i
periferni nervni sistem. Postoji jasna potreba za povećanjem prediktivnosti prekliničkih
oruđa, što bi bilo korisno za humane volontere/pacijente (bezbedniji lekovi) i farmaceutsku
industriju (smanjena stopa neuspeha). NeuroDeRisk konzorcijum se sastoji od 18
akademskih institucija, kompanija farmaceutske industrije i malih i srednjih preduzeća u
okviru projekta Inicijative za inovativne lekove (2019-2022). Univerzitet u Beogradu –
Farmaceutski fakultet jeste partner koji predvodi radni parket posvećen prekliničkom
predviđanju neželjenih efekata na raspoloženje i kogniciju. Druge dve grupe izazovnih
neželjenih efekata koje projekat obrađuje jesu konvulzivni napadi i periferne neuropatije.
Korišćenjem mnoštva eksperimentalnih tehnika i brojnih farmaceutika koji su prethodno
povezani sa svakim od ispitivanih velikih neželjenih efekata, projekat traga za inovativnim
oruđima, esejima i protokolima, koji pokrivaju in silico, in vitro, in vivo i ex vivo pristupe.
Mimo širenja znanja o brojnim široko korišćenim farmaceuticima, glavni cilj projekta jeste
razvoj integrisane platforme za bolju procenu rizika u budućim eksploratornim i
regulatornim studijama.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Neurotoxicity De-Risking in Preclinical Drug Discovery, Prekliničko predviđanje neželjenih efekata lekova na nervni sistem",
volume = "72",
number = "4 suplement",
pages = "S163-S164",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4483"
}

Savić, M.. (2022). Neurotoxicity De-Risking in Preclinical Drug Discovery. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S163-S164.
https://hdl.handle.net/21.15107/rcub_farfar_4483

Savić M. Neurotoxicity De-Risking in Preclinical Drug Discovery. in Arhiv za farmaciju. 2022;72(4 suplement):S163-S164.
https://hdl.handle.net/21.15107/rcub_farfar_4483 .

Savić, Miroslav, "Neurotoxicity De-Risking in Preclinical Drug Discovery" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S163-S164,
https://hdl.handle.net/21.15107/rcub_farfar_4483 .

TY  - CONF
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4466
AB  - Throughout the process of drug discovery, development and commercialization,
impact of adverse effects on nervous system is second only to cardiovascular adverse effects.
Many of these effects are within the interconnected domains of mood and cognition, usually
with low incidence and thus more difficult to be revealed. While most of them have more or
less impact on quality of life, some are life-threating, directly (suicide ideation and behavior,
including completed suicide) or indirectly (cognitive impairment that affects driving
performance). Intriguingly, mood and cognitive adverse effects (MCAEs) are encountered
not only with low-molecular weight pharmaceuticals that readily pass the blood-brain
barrier, but also with biological drugs, most notably several monoclonal antibodies. Besides
a number of receptors, transporters and other elements involved in processes of
neurotransmission and neuronal plasticity, neuroimmunomodulation has taken a distinct
place in still limited understanding the mechanisms that induce MCAEs. The latter concept
corresponds with substantial data demonstrating that inflammatory signals generated both
in the central nervous system and in the peripheral tissues play an important role in
pathogenesis of various psychiatric and neurological disorders. It is possible that changes in
conventional immune components, such are interleukins, are linked with impaired
behavioral manifestations through metabolites of the kynurenine pathway and/or changes
in activity of non-neuronal glial cells. In clinical as well as experimental settings, recognition
of MCAEs is hindered by difficulties in differentiation between normal compared to
pathological changes in behavior – especially having in mind substantial variations in output
of behavioral parameters both in humans and experimental animals.
AB  - Tokom procesa otkrića, razvoja i komercijalizacije lekova, jedino su kardiovaskularni
neželjeni efekti češći nego oni koji su vezani za nervni sistem. Mnogi od ovih efekata se
nalaze u povezanim domenima raspoloženja i kognicije, često sa niskom učestalošću
javljanja, što otežava njihovo prepoznavanje. Dok većina ovih efekata ima veći ili manji uticaj
na kvalitet života, pojedini među njima i ugrožavaju život, direktno (suicidalna ideacija i
ponašanje, uključujući izvršeni suicid) ili indirektno (kognitivno oštećenje koje utiče na
sposobnost vožnje). Intrigantno, neželjeni efekti na raspoloženje i kogniciju (NERK) sreću se
ne samo sa farmaceuticima male molekulske mase, koji lako prolaze krvno-moždanu
barijeru, nego i sa biološkim lekovima, najistaknutije sa nekoliko monoklonskih antitela.
Pored pojedinih receptora, transportera i drugih elemenata uključenih u procese
neurotransmisije i neuronske plastičnosti, neuroimunomodulacija zauzima istaknuto mesto
u još uvek ograničenom razumevanju mehanizama koji dovode do NERK. Ovaj poslednji
koncept korespondira sa obimnim nalazima koji potvrđuju da u patogenezi različitih
psihijatrijskih i neuroloških poremećaja značajnu ulogu imaju inflamatorni signali koji se
generišu kako u centralnom nervnom sistemu, tako i u perifernim tkivima. Moguće je da
metaboliti kinureninskog puta i/ili promene u aktivnosti ne-neuronskih glijalnih ćelija
povezuju promene u konvencionalnim imunskim komponentama, kao što su interleukini, sa
manifestacijama oštećenog ponašanja. U kliničkim kao i u eksperimentalnim uslovima,
prepoznavanje NERK ograničavaju poteškoće u diferencijaciji između normalnih i patoloških
promena u ponašanju – posebno kada se uzmu u obzir znatne varijacije u vrednostima
parametara ponašanja kako kod ljudi tako i kod eksperimentalnih životinja.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Adverse effects of pharmaceuticals on mood, cognition and behavior
T1  - Neželjena dejstva lekova na raspoloženje, kogniciju i ponašanje
VL  - 72
IS  - 4 suplement
SP  - S122
EP  - S123
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4466
ER  - 

@conference{
author = "Savić, Miroslav",
year = "2022",
abstract = "Throughout the process of drug discovery, development and commercialization,
impact of adverse effects on nervous system is second only to cardiovascular adverse effects.
Many of these effects are within the interconnected domains of mood and cognition, usually
with low incidence and thus more difficult to be revealed. While most of them have more or
less impact on quality of life, some are life-threating, directly (suicide ideation and behavior,
including completed suicide) or indirectly (cognitive impairment that affects driving
performance). Intriguingly, mood and cognitive adverse effects (MCAEs) are encountered
not only with low-molecular weight pharmaceuticals that readily pass the blood-brain
barrier, but also with biological drugs, most notably several monoclonal antibodies. Besides
a number of receptors, transporters and other elements involved in processes of
neurotransmission and neuronal plasticity, neuroimmunomodulation has taken a distinct
place in still limited understanding the mechanisms that induce MCAEs. The latter concept
corresponds with substantial data demonstrating that inflammatory signals generated both
in the central nervous system and in the peripheral tissues play an important role in
pathogenesis of various psychiatric and neurological disorders. It is possible that changes in
conventional immune components, such are interleukins, are linked with impaired
behavioral manifestations through metabolites of the kynurenine pathway and/or changes
in activity of non-neuronal glial cells. In clinical as well as experimental settings, recognition
of MCAEs is hindered by difficulties in differentiation between normal compared to
pathological changes in behavior – especially having in mind substantial variations in output
of behavioral parameters both in humans and experimental animals., Tokom procesa otkrića, razvoja i komercijalizacije lekova, jedino su kardiovaskularni
neželjeni efekti češći nego oni koji su vezani za nervni sistem. Mnogi od ovih efekata se
nalaze u povezanim domenima raspoloženja i kognicije, često sa niskom učestalošću
javljanja, što otežava njihovo prepoznavanje. Dok većina ovih efekata ima veći ili manji uticaj
na kvalitet života, pojedini među njima i ugrožavaju život, direktno (suicidalna ideacija i
ponašanje, uključujući izvršeni suicid) ili indirektno (kognitivno oštećenje koje utiče na
sposobnost vožnje). Intrigantno, neželjeni efekti na raspoloženje i kogniciju (NERK) sreću se
ne samo sa farmaceuticima male molekulske mase, koji lako prolaze krvno-moždanu
barijeru, nego i sa biološkim lekovima, najistaknutije sa nekoliko monoklonskih antitela.
Pored pojedinih receptora, transportera i drugih elemenata uključenih u procese
neurotransmisije i neuronske plastičnosti, neuroimunomodulacija zauzima istaknuto mesto
u još uvek ograničenom razumevanju mehanizama koji dovode do NERK. Ovaj poslednji
koncept korespondira sa obimnim nalazima koji potvrđuju da u patogenezi različitih
psihijatrijskih i neuroloških poremećaja značajnu ulogu imaju inflamatorni signali koji se
generišu kako u centralnom nervnom sistemu, tako i u perifernim tkivima. Moguće je da
metaboliti kinureninskog puta i/ili promene u aktivnosti ne-neuronskih glijalnih ćelija
povezuju promene u konvencionalnim imunskim komponentama, kao što su interleukini, sa
manifestacijama oštećenog ponašanja. U kliničkim kao i u eksperimentalnim uslovima,
prepoznavanje NERK ograničavaju poteškoće u diferencijaciji između normalnih i patoloških
promena u ponašanju – posebno kada se uzmu u obzir znatne varijacije u vrednostima
parametara ponašanja kako kod ljudi tako i kod eksperimentalnih životinja.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Adverse effects of pharmaceuticals on mood, cognition and behavior, Neželjena dejstva lekova na raspoloženje, kogniciju i ponašanje",
volume = "72",
number = "4 suplement",
pages = "S122-S123",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4466"
}

Savić, M.. (2022). Adverse effects of pharmaceuticals on mood, cognition and behavior. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S122-S123.
https://hdl.handle.net/21.15107/rcub_farfar_4466

Savić M. Adverse effects of pharmaceuticals on mood, cognition and behavior. in Arhiv za farmaciju. 2022;72(4 suplement):S122-S123.
https://hdl.handle.net/21.15107/rcub_farfar_4466 .

Savić, Miroslav, "Adverse effects of pharmaceuticals on mood, cognition and behavior" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S122-S123,
https://hdl.handle.net/21.15107/rcub_farfar_4466 .

TY  - JOUR
AU  - Andronis, Christos
AU  - Silva, João
AU  - Lekka, Eftychia
AU  - Virvilis, Vassilis
AU  - Carmo, Helena
AU  - Bampali, Konstantina
AU  - Ernst, Margot
AU  - Hu, Yang
AU  - Loryan, Irena
AU  - Richard, Jacques
AU  - Carvalho, Félix
AU  - Savić, Miroslav
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3613
AB  - Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.
PB  - Springer Nature Switzerland
T2  - Archives of Toxicology
T1  - Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis
VL  - 94
IS  - 8
SP  - 2829
EP  - 2845
DO  - 10.1007/s00204-020-02788-1
ER  - 

@article{
author = "Andronis, Christos and Silva, João and Lekka, Eftychia and Virvilis, Vassilis and Carmo, Helena and Bampali, Konstantina and Ernst, Margot and Hu, Yang and Loryan, Irena and Richard, Jacques and Carvalho, Félix and Savić, Miroslav",
year = "2020",
abstract = "Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.",
publisher = "Springer Nature Switzerland",
journal = "Archives of Toxicology",
title = "Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis",
volume = "94",
number = "8",
pages = "2829-2845",
doi = "10.1007/s00204-020-02788-1"
}

Andronis, C., Silva, J., Lekka, E., Virvilis, V., Carmo, H., Bampali, K., Ernst, M., Hu, Y., Loryan, I., Richard, J., Carvalho, F.,& Savić, M.. (2020). Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis. in Archives of Toxicology
Springer Nature Switzerland., 94(8), 2829-2845.
https://doi.org/10.1007/s00204-020-02788-1

Andronis C, Silva J, Lekka E, Virvilis V, Carmo H, Bampali K, Ernst M, Hu Y, Loryan I, Richard J, Carvalho F, Savić M. Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis. in Archives of Toxicology. 2020;94(8):2829-2845.
doi:10.1007/s00204-020-02788-1 .

Andronis, Christos, Silva, João, Lekka, Eftychia, Virvilis, Vassilis, Carmo, Helena, Bampali, Konstantina, Ernst, Margot, Hu, Yang, Loryan, Irena, Richard, Jacques, Carvalho, Félix, Savić, Miroslav, "Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis" in Archives of Toxicology, 94, no. 8 (2020):2829-2845,
https://doi.org/10.1007/s00204-020-02788-1 . .