TY  - JOUR
AU  - Nastić, Katarina
AU  - Pecikoza, Uroš
AU  - Labudović-Borović, Milica
AU  - Kotur-Stevuljević, Jelena
AU  - Micov, Ana
AU  - Jovanović, Aleksandar
AU  - Tomić, Maja
AU  - Stepanović-Petrović, Radica
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5018
AB  - Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive disorders, which can be exacerbated by osteoarthritis or drugs used for its treatment. Here, we examined the behavioral and cardiac effects of the novel antidepressant vortioxetine in an osteoarthritis model, and compared them to duloxetine (an established osteoarthritis treatment). Osteoarthritis was induced in male and female rats with an intraarticular sodium-monoiodoacetate injection. Antidepressants were orally administered for 28 days following induction. During this period the acetone, burrowing and novel-object-recognition tests (NORT) were used to assess the effects of antidepressants on pain hypersensitivity (cold allodynia), animal well-being and cognitive performance, respectively. Following behavioral experiments, heart muscles were collected for assessment of redox status/histology. Antidepressant treatment dose-dependently reduced cold allodynia in rats with osteoarthritis. Duloxetine (but not vortioxetine) depressed burrowing behavior in osteoarthritic rats in a dose-related manner. Osteoarthritis induction reduced cognitive performance in NORT, which was dose-dependently alleviated by vortioxetine (duloxetine improved performance only in female rats). Furthermore, duloxetine (but not vortioxetine) increased oxidative stress parameters in the heart muscles of female (but not male) rats and induced histological changes in cardiomyocytes indicative of oxidative damage. Vortioxetine displayed comparable efficacy to duloxetine in reducing pain hypersensitivity. Furthermore, vortioxetine (unlike duloxetine) dose-dependently improved cognitive performance and had no adverse effect on burrowing behavior (animal surrogate of well-being) and cardiac redox status/histology. Our results indicate that vortioxetine could be a potential osteoarthritis treatment (with better characteristics compared to duloxetine).
PB  - Elsevier Masson
T2  - Biomedicine and Pharmacotherapy
T1  - The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis
VL  - 166
DO  - 10.1016/j.biopha.2023.115360
ER  - 

@article{
author = "Nastić, Katarina and Pecikoza, Uroš and Labudović-Borović, Milica and Kotur-Stevuljević, Jelena and Micov, Ana and Jovanović, Aleksandar and Tomić, Maja and Stepanović-Petrović, Radica",
year = "2023",
abstract = "Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive disorders, which can be exacerbated by osteoarthritis or drugs used for its treatment. Here, we examined the behavioral and cardiac effects of the novel antidepressant vortioxetine in an osteoarthritis model, and compared them to duloxetine (an established osteoarthritis treatment). Osteoarthritis was induced in male and female rats with an intraarticular sodium-monoiodoacetate injection. Antidepressants were orally administered for 28 days following induction. During this period the acetone, burrowing and novel-object-recognition tests (NORT) were used to assess the effects of antidepressants on pain hypersensitivity (cold allodynia), animal well-being and cognitive performance, respectively. Following behavioral experiments, heart muscles were collected for assessment of redox status/histology. Antidepressant treatment dose-dependently reduced cold allodynia in rats with osteoarthritis. Duloxetine (but not vortioxetine) depressed burrowing behavior in osteoarthritic rats in a dose-related manner. Osteoarthritis induction reduced cognitive performance in NORT, which was dose-dependently alleviated by vortioxetine (duloxetine improved performance only in female rats). Furthermore, duloxetine (but not vortioxetine) increased oxidative stress parameters in the heart muscles of female (but not male) rats and induced histological changes in cardiomyocytes indicative of oxidative damage. Vortioxetine displayed comparable efficacy to duloxetine in reducing pain hypersensitivity. Furthermore, vortioxetine (unlike duloxetine) dose-dependently improved cognitive performance and had no adverse effect on burrowing behavior (animal surrogate of well-being) and cardiac redox status/histology. Our results indicate that vortioxetine could be a potential osteoarthritis treatment (with better characteristics compared to duloxetine).",
publisher = "Elsevier Masson",
journal = "Biomedicine and Pharmacotherapy",
title = "The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis",
volume = "166",
doi = "10.1016/j.biopha.2023.115360"
}

Nastić, K., Pecikoza, U., Labudović-Borović, M., Kotur-Stevuljević, J., Micov, A., Jovanović, A., Tomić, M.,& Stepanović-Petrović, R.. (2023). The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis. in Biomedicine and Pharmacotherapy
Elsevier Masson., 166.
https://doi.org/10.1016/j.biopha.2023.115360

Nastić K, Pecikoza U, Labudović-Borović M, Kotur-Stevuljević J, Micov A, Jovanović A, Tomić M, Stepanović-Petrović R. The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis. in Biomedicine and Pharmacotherapy. 2023;166.
doi:10.1016/j.biopha.2023.115360 .

Nastić, Katarina, Pecikoza, Uroš, Labudović-Borović, Milica, Kotur-Stevuljević, Jelena, Micov, Ana, Jovanović, Aleksandar, Tomić, Maja, Stepanović-Petrović, Radica, "The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis" in Biomedicine and Pharmacotherapy, 166 (2023),
https://doi.org/10.1016/j.biopha.2023.115360 . .

TY  - CONF
AU  - Nastić, Katarina
AU  - Pecikoza, Uroš
AU  - Micov, Ana
AU  - Tomić, Maja
AU  - Jovanović, Aleksandar
AU  - Stepanović-Petrović, Radica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4525
AB  - Osteoarthritis is the most common rheumatic degenerative condition, with chronic
joint pain being the major source of disability. Currently, available treatment options for
alleviating pain are often ineffective and/or associated with unfavorable safety profiles (1).
Vortioxetine is a novel multimodal antidepressant, an inhibitor of serotonin reuptake, but
also an agonist, partial agonist, or antagonist of several serotonin (5-HT) receptors subtypes
involved in pain modulation (2). The study aimed to examine the efficacy of vortioxetine
compared to duloxetine, an antidepressant recommended for the treatment of osteoarthritis,
in the rat model of osteoarthritis. Osteoarthritis was induced by intra-articular injection of
monosodium iodoacetate (MIA; 2 mg/25 μL) in the right knee of male Wistar rats.
Vortioxetine/duloxetine was administered orally for 28 days following MIA injection. The
antinociceptive effect of vortioxetine/duloxetine was assessed using von Frey, acetone, and
weight-bearing test. The influence of treatments on animals’ well-being and motor
performance was examined in the burrowing and rotarod test, respectively. Vortioxetine (2
and 10 mg/kg) and duloxetine (15 and 25 mg/kg) significantly reduced mechanical and cold
allodynia, and improved weight borne on the ipsilateral hind paw in von Frey, acetone, and
weight-bearing test, respectively. Vortioxetine had no significant effect on burrowing
behavior, whereas duloxetine significantly reduced this inherent rodent activity. The rotarod
test did not demonstrate a significant effect of treatment on motor performance/sedation.
This study suggests comparable antinociceptive efficacy of vortioxetine with duloxetine, a
referent drug, as well as a better impact on the animals’ well-being of vortioxetine.
AB  - Osteoartritis predstavlja najčešće reumatsko degenerativno oboljenje, praćeno
hroničnim bolom, glavnim uzrokom onesposobljenosti pacijenata. Postojeće terapijske opcije
za otklanjanje bola su neretko nedovoljno efikasne i/ili udružene sa brojnim neželjenim
efektima (1). Vortioksetin je noviji antidepresiv multimodalnog mehanizma dejstva; inhibira
transporter za preuzimanje serotonina, a deluje i kao agonist, parcijalni agonist ili antagonist
različitih podtipova serotoninskih (5-HT) receptora uključenih u modulaciju bola (2). Cilj
ovog rada je bio ispitati efikasnost vortioksetina u poređenju sa duloksetinom,
antidepresivom preporučenim za lečenje osteoartritisa, u modelu osteoartritisa kod pacova.
Osteoartritis je indukovan intraartikularnom injekcijom natrijum-monojodacetata (MIA; 2
mg/25 μL) u desno koleno mužjaka pacova Wistar soja. Vortioksetin/duloksetin je
primenjivan oralno svakodnevno tokom 28 dana nakon injekcije MIA. Procena
antinociceptivne efikasnosti vortioksetina/duloksetina ispitivana je korišćenjem von Frey,
aceton testa i testa raspodele težine (eng. weight‐bearing). Uticaj tretmana na dobrobit
životinja (eng. well‐being), kao i motornu spretnost ispitivan je u testu kopanja i rotarod
testu, redom. Vortioksetin (2 i 10 mg/kg) i duloksetin (15 i 25 mg/kg) su značajno smanjili
mehaničku i hladnu alodiniju, i poboljšali oslanjanje životinja na ipsilateralnu šapu u von
Frey, aceton i testu raspodele težine, redom. Vortioksetin nije imao značajan uticaj na
aktivnost životinja u testu kopanja, dok je duloksetin značajno smanjio ovu inherentnu
aktivnost glodara. U rotarod testu nije pokazan značajan uticaj tretmana na motorne
performanse/sedaciju životinja. Ova studija je pokazala da su antinociceptivni efekti
vortioksetina i referentnog leka duloksetina uporedivi, kao i povoljniji uticaj vortioksetina
na opštu dobrobit životinja.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Efficacy of vortioxetine in the osteoarthritis rat model
T1  - Efikasnost vortioksetina u modelu osteoartritisa kod pacova
VL  - 72
IS  - 4 suplement
SP  - S245
EP  - S246
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4525
ER  - 

@conference{
author = "Nastić, Katarina and Pecikoza, Uroš and Micov, Ana and Tomić, Maja and Jovanović, Aleksandar and Stepanović-Petrović, Radica",
year = "2022",
abstract = "Osteoarthritis is the most common rheumatic degenerative condition, with chronic
joint pain being the major source of disability. Currently, available treatment options for
alleviating pain are often ineffective and/or associated with unfavorable safety profiles (1).
Vortioxetine is a novel multimodal antidepressant, an inhibitor of serotonin reuptake, but
also an agonist, partial agonist, or antagonist of several serotonin (5-HT) receptors subtypes
involved in pain modulation (2). The study aimed to examine the efficacy of vortioxetine
compared to duloxetine, an antidepressant recommended for the treatment of osteoarthritis,
in the rat model of osteoarthritis. Osteoarthritis was induced by intra-articular injection of
monosodium iodoacetate (MIA; 2 mg/25 μL) in the right knee of male Wistar rats.
Vortioxetine/duloxetine was administered orally for 28 days following MIA injection. The
antinociceptive effect of vortioxetine/duloxetine was assessed using von Frey, acetone, and
weight-bearing test. The influence of treatments on animals’ well-being and motor
performance was examined in the burrowing and rotarod test, respectively. Vortioxetine (2
and 10 mg/kg) and duloxetine (15 and 25 mg/kg) significantly reduced mechanical and cold
allodynia, and improved weight borne on the ipsilateral hind paw in von Frey, acetone, and
weight-bearing test, respectively. Vortioxetine had no significant effect on burrowing
behavior, whereas duloxetine significantly reduced this inherent rodent activity. The rotarod
test did not demonstrate a significant effect of treatment on motor performance/sedation.
This study suggests comparable antinociceptive efficacy of vortioxetine with duloxetine, a
referent drug, as well as a better impact on the animals’ well-being of vortioxetine., Osteoartritis predstavlja najčešće reumatsko degenerativno oboljenje, praćeno
hroničnim bolom, glavnim uzrokom onesposobljenosti pacijenata. Postojeće terapijske opcije
za otklanjanje bola su neretko nedovoljno efikasne i/ili udružene sa brojnim neželjenim
efektima (1). Vortioksetin je noviji antidepresiv multimodalnog mehanizma dejstva; inhibira
transporter za preuzimanje serotonina, a deluje i kao agonist, parcijalni agonist ili antagonist
različitih podtipova serotoninskih (5-HT) receptora uključenih u modulaciju bola (2). Cilj
ovog rada je bio ispitati efikasnost vortioksetina u poređenju sa duloksetinom,
antidepresivom preporučenim za lečenje osteoartritisa, u modelu osteoartritisa kod pacova.
Osteoartritis je indukovan intraartikularnom injekcijom natrijum-monojodacetata (MIA; 2
mg/25 μL) u desno koleno mužjaka pacova Wistar soja. Vortioksetin/duloksetin je
primenjivan oralno svakodnevno tokom 28 dana nakon injekcije MIA. Procena
antinociceptivne efikasnosti vortioksetina/duloksetina ispitivana je korišćenjem von Frey,
aceton testa i testa raspodele težine (eng. weight‐bearing). Uticaj tretmana na dobrobit
životinja (eng. well‐being), kao i motornu spretnost ispitivan je u testu kopanja i rotarod
testu, redom. Vortioksetin (2 i 10 mg/kg) i duloksetin (15 i 25 mg/kg) su značajno smanjili
mehaničku i hladnu alodiniju, i poboljšali oslanjanje životinja na ipsilateralnu šapu u von
Frey, aceton i testu raspodele težine, redom. Vortioksetin nije imao značajan uticaj na
aktivnost životinja u testu kopanja, dok je duloksetin značajno smanjio ovu inherentnu
aktivnost glodara. U rotarod testu nije pokazan značajan uticaj tretmana na motorne
performanse/sedaciju životinja. Ova studija je pokazala da su antinociceptivni efekti
vortioksetina i referentnog leka duloksetina uporedivi, kao i povoljniji uticaj vortioksetina
na opštu dobrobit životinja.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Efficacy of vortioxetine in the osteoarthritis rat model, Efikasnost vortioksetina u modelu osteoartritisa kod pacova",
volume = "72",
number = "4 suplement",
pages = "S245-S246",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4525"
}

Nastić, K., Pecikoza, U., Micov, A., Tomić, M., Jovanović, A.,& Stepanović-Petrović, R.. (2022). Efficacy of vortioxetine in the osteoarthritis rat model. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S245-S246.
https://hdl.handle.net/21.15107/rcub_farfar_4525

Nastić K, Pecikoza U, Micov A, Tomić M, Jovanović A, Stepanović-Petrović R. Efficacy of vortioxetine in the osteoarthritis rat model. in Arhiv za farmaciju. 2022;72(4 suplement):S245-S246.
https://hdl.handle.net/21.15107/rcub_farfar_4525 .

Nastić, Katarina, Pecikoza, Uroš, Micov, Ana, Tomić, Maja, Jovanović, Aleksandar, Stepanović-Petrović, Radica, "Efficacy of vortioxetine in the osteoarthritis rat model" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S245-S246,
https://hdl.handle.net/21.15107/rcub_farfar_4525 .

TY  - CONF
AU  - Stepanović-Petrović, Radica
AU  - Tomić, Maja
AU  - Jovanović, Aleksandar
AU  - Pecikoza, Uroš
AU  - Micov, Ana
AU  - Nastić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4486
AB  - Osteoarthritis (OA) is the most common rheumatic disease, affecting over 300 million
people worldwide. It causes chronic pain, disability and is commonly associated with
comorbid diseases (CMD) that cause worse health outcomes, more complex management,
and increased healthcare costs. Current treatments (typical/atypical analgesics) have limited
efficacy and/or tolerability and usually do not affect or can even worse CMD. In era of longer
life expectancy, extended professional life and reduced pension funds in Serbia and Europe,
there is a compelling need for maintaining functionality and working capability of older
population. Our aim is to search for novel treatments that could concomitantly treat chronic
pain and its major CMD: depression, cognitive impairment and/or cardiovascular disease
(CVD). It was planned to test the effects of vortioxetine, a novel antidepressant with
multimodal mechanism of action, on pain, depressive and cognitive-impairment behaviour
and CV status in rat model of knee OA. Its effects will be compared to the effects of
duloxetine, the only antidepressant used for pain relief in OA. Next, we will test the effects of
2-component combinations of vortioxetine/duloxetine with adjuvant treatments (regular
exercise/metformin/nicotinamide), that showed the potential to alleviate pain, depression,
reduced cognition and/or CVD in preclinical/clinical research. If proved effective and well
tolerated, new treatment(s) could be implemented in clinical practice much faster and with
significantly less investment, than those required to develop brand new drug, as they consist
of drugs already approved for human use and safe, widely available and inexpensive non-
pharmacologic measures.
AB  - Osteoartritis (OA) je najčešć a reumatska bolest, koja pogađa preko 300 miliona ljudi
širom sveta. Prouzrokuje hronični bol, invaliditet i obično je povezan sa komorbiditetima koji
dovode do lošijih zdravstvenih ishoda, složenijeg lečenja i povećanja troškova zdravstvene
zaštite. Trenutno dostupne terapijske opcije (tipični/atipični analgetici) imaju ograničenu
efikasnost i/ili lošu podnošljivost, i obično ne utiču ili čak mogu pogoršati komorbiditete. U
vremenu kada su ljudski i radni vek produženi, a penzioni fondovi u Srbiji i Evropi smanjeni,
postoji velika potreba za održavanjem funkcionalnosti i radne sposobnosti starije populacije.
Naš cilj je da pronađemo nove terapijske opcije koje bi istovremeno mogle da leče hronični
bol i njegove glavne komorbiditete: depresiju, kognitivno oštećenje i/ili kardiovaskularne
bolesti (KVB). Planirano je ispitivanje efekata vortioksetina, novog antidepresiva sa
multimodalnim mehanizmom delovanja, na bol, depresivno ponašanje, kognitivno ošteć enje i
kardiovaskularni status pacova u modelu OA kolena. Efekti vortioksetina biće poređeni sa
efektima duloksetina, jedinog antidepresiva koji se koristi za ublažavanje bola kod OA. Zatim
će biti ispitani efekti dvokomponentnih kombinacija vortioksetina/duloksetina sa
adjuvantnim tretmanima (redovna fizička aktivnost/metformin/nikotinamid), koji su
pokazali efikasnost u ublažavanju bola, depresije, narušene kognicije i/ili KVB u
pretkliničkim/kliničkim istraživanjima. Ukoliko se pokaže da su efikasne i da se dobro
tolerišu, nove terapijske opcije bi se mogle implementirati u kliničku praksu mnogo brže i sa
znatno manje finansijskih ulaganja u poređenju sa vremenom i ulaganjima koja su potrebna
za razvoj novog leka, jer se sastoje od lekova koji su već odobreni za ljudsku upotrebu i
bezbednih, široko dostupnih i ekonomski povoljnih nefarmakoloških mera.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Multimodal control of chronic pain and comorbidities with atypical analgesics – “two birds with one stone”
T1  - Multimodalna kontrola hroničnog bola i komorbiditeta sa atipičnim analgeticima ‐,,više muva jednim udarcem“
VL  - 72
IS  - 4 suplement
SP  - S172
EP  - S173
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4486
ER  - 

@conference{
author = "Stepanović-Petrović, Radica and Tomić, Maja and Jovanović, Aleksandar and Pecikoza, Uroš and Micov, Ana and Nastić, Katarina",
year = "2022",
abstract = "Osteoarthritis (OA) is the most common rheumatic disease, affecting over 300 million
people worldwide. It causes chronic pain, disability and is commonly associated with
comorbid diseases (CMD) that cause worse health outcomes, more complex management,
and increased healthcare costs. Current treatments (typical/atypical analgesics) have limited
efficacy and/or tolerability and usually do not affect or can even worse CMD. In era of longer
life expectancy, extended professional life and reduced pension funds in Serbia and Europe,
there is a compelling need for maintaining functionality and working capability of older
population. Our aim is to search for novel treatments that could concomitantly treat chronic
pain and its major CMD: depression, cognitive impairment and/or cardiovascular disease
(CVD). It was planned to test the effects of vortioxetine, a novel antidepressant with
multimodal mechanism of action, on pain, depressive and cognitive-impairment behaviour
and CV status in rat model of knee OA. Its effects will be compared to the effects of
duloxetine, the only antidepressant used for pain relief in OA. Next, we will test the effects of
2-component combinations of vortioxetine/duloxetine with adjuvant treatments (regular
exercise/metformin/nicotinamide), that showed the potential to alleviate pain, depression,
reduced cognition and/or CVD in preclinical/clinical research. If proved effective and well
tolerated, new treatment(s) could be implemented in clinical practice much faster and with
significantly less investment, than those required to develop brand new drug, as they consist
of drugs already approved for human use and safe, widely available and inexpensive non-
pharmacologic measures., Osteoartritis (OA) je najčešć a reumatska bolest, koja pogađa preko 300 miliona ljudi
širom sveta. Prouzrokuje hronični bol, invaliditet i obično je povezan sa komorbiditetima koji
dovode do lošijih zdravstvenih ishoda, složenijeg lečenja i povećanja troškova zdravstvene
zaštite. Trenutno dostupne terapijske opcije (tipični/atipični analgetici) imaju ograničenu
efikasnost i/ili lošu podnošljivost, i obično ne utiču ili čak mogu pogoršati komorbiditete. U
vremenu kada su ljudski i radni vek produženi, a penzioni fondovi u Srbiji i Evropi smanjeni,
postoji velika potreba za održavanjem funkcionalnosti i radne sposobnosti starije populacije.
Naš cilj je da pronađemo nove terapijske opcije koje bi istovremeno mogle da leče hronični
bol i njegove glavne komorbiditete: depresiju, kognitivno oštećenje i/ili kardiovaskularne
bolesti (KVB). Planirano je ispitivanje efekata vortioksetina, novog antidepresiva sa
multimodalnim mehanizmom delovanja, na bol, depresivno ponašanje, kognitivno ošteć enje i
kardiovaskularni status pacova u modelu OA kolena. Efekti vortioksetina biće poređeni sa
efektima duloksetina, jedinog antidepresiva koji se koristi za ublažavanje bola kod OA. Zatim
će biti ispitani efekti dvokomponentnih kombinacija vortioksetina/duloksetina sa
adjuvantnim tretmanima (redovna fizička aktivnost/metformin/nikotinamid), koji su
pokazali efikasnost u ublažavanju bola, depresije, narušene kognicije i/ili KVB u
pretkliničkim/kliničkim istraživanjima. Ukoliko se pokaže da su efikasne i da se dobro
tolerišu, nove terapijske opcije bi se mogle implementirati u kliničku praksu mnogo brže i sa
znatno manje finansijskih ulaganja u poređenju sa vremenom i ulaganjima koja su potrebna
za razvoj novog leka, jer se sastoje od lekova koji su već odobreni za ljudsku upotrebu i
bezbednih, široko dostupnih i ekonomski povoljnih nefarmakoloških mera.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Multimodal control of chronic pain and comorbidities with atypical analgesics – “two birds with one stone”, Multimodalna kontrola hroničnog bola i komorbiditeta sa atipičnim analgeticima ‐,,više muva jednim udarcem“",
volume = "72",
number = "4 suplement",
pages = "S172-S173",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4486"
}

Stepanović-Petrović, R., Tomić, M., Jovanović, A., Pecikoza, U., Micov, A.,& Nastić, K.. (2022). Multimodal control of chronic pain and comorbidities with atypical analgesics – “two birds with one stone”. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S172-S173.
https://hdl.handle.net/21.15107/rcub_farfar_4486

Stepanović-Petrović R, Tomić M, Jovanović A, Pecikoza U, Micov A, Nastić K. Multimodal control of chronic pain and comorbidities with atypical analgesics – “two birds with one stone”. in Arhiv za farmaciju. 2022;72(4 suplement):S172-S173.
https://hdl.handle.net/21.15107/rcub_farfar_4486 .

Stepanović-Petrović, Radica, Tomić, Maja, Jovanović, Aleksandar, Pecikoza, Uroš, Micov, Ana, Nastić, Katarina, "Multimodal control of chronic pain and comorbidities with atypical analgesics – “two birds with one stone”" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S172-S173,
https://hdl.handle.net/21.15107/rcub_farfar_4486 .

TY  - JOUR
AU  - Pecikoza, Uroš
AU  - Tomić, Maja
AU  - Nastić, Katarina
AU  - Micov, Ana
AU  - Stepanović-Petrović, Radica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4253
AB  - Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy
(PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of
interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in
relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in
mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged
7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a
single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments,
metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of
their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced
dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and
local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose-
dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises
with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In
conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and pe-
ripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia.
Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer)
analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief
and mitigate metformin-induced vitamin B12 deficiency.
PB  - Elsevier Masson s.r.l.
T2  - Biomedicine and Pharmacotherapy
T1  - Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy
VL  - 153
DO  - 10.1016/j.biopha.2022.113441
ER  - 

@article{
author = "Pecikoza, Uroš and Tomić, Maja and Nastić, Katarina and Micov, Ana and Stepanović-Petrović, Radica",
year = "2022",
abstract = "Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy
(PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of
interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in
relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in
mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged
7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a
single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments,
metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of
their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced
dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and
local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose-
dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises
with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In
conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and pe-
ripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia.
Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer)
analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief
and mitigate metformin-induced vitamin B12 deficiency.",
publisher = "Elsevier Masson s.r.l.",
journal = "Biomedicine and Pharmacotherapy",
title = "Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy",
volume = "153",
doi = "10.1016/j.biopha.2022.113441"
}

Pecikoza, U., Tomić, M., Nastić, K., Micov, A.,& Stepanović-Petrović, R.. (2022). Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy. in Biomedicine and Pharmacotherapy
Elsevier Masson s.r.l.., 153.
https://doi.org/10.1016/j.biopha.2022.113441

Pecikoza U, Tomić M, Nastić K, Micov A, Stepanović-Petrović R. Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy. in Biomedicine and Pharmacotherapy. 2022;153.
doi:10.1016/j.biopha.2022.113441 .

Pecikoza, Uroš, Tomić, Maja, Nastić, Katarina, Micov, Ana, Stepanović-Petrović, Radica, "Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy" in Biomedicine and Pharmacotherapy, 153 (2022),
https://doi.org/10.1016/j.biopha.2022.113441 . .

TY  - CONF
AU  - Lasica, Anđelka
AU  - Tomić, Maja
AU  - Nastić, Katarina
AU  - Pecikoza, Uroš
AU  - Micov, Ana
AU  - Stepanović-Petrović, Radica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4578
AB  - Metformin, a well-known antidiabetic drug, has been shown to possess analgesic
properties in inflammatory pain models, but the mechanisms of its antinociceptive effects
are not completely understood (1,2). We aimed to examine the involvement of serotonergic
mechanisms in metformin-induced antinociception in a model of inflammatory pain, using
the formalin test in mice. Firstly, we examined the antinociceptive effects of intraperitoneally
administered metformin in the first and second phase of the test. Then, the involvement of
serotonergic receptors was evaluated by intraperitoneally pretreating mice with a 5-HT1B/1D
(GR127935) or 5-HT1A receptor antagonist (WAY100635). Further, we examined the effect of
metformin after depletion of endogenous serotonin with a tryptophan-hydroxylase inhibitor
(PCPA; applied intraperitoneally for 4 days). Additionally, to avoid misinterpretation of
motor incoordination, we performed the rotarod test with the highest tested metformin
dose. Metformin (50-200 mg/kg) produced significant and dose-dependent antinociceptive
effects (17-81%) in the second (inflammatory) phase of the test. Pretreatment with
antagonists significantly reduced the antinociceptive effect of metformin (150 mg/kg).
GR127935 inhibited the effects of metformin by 67% (1 mg/kg) and 100% (3 mg/kg),
whereas the inhibitory effects for WAY100635 were 19% (1 mg/kg) and 68% (3 mg/kg).
Depletion of serotonin with PCPA (100 mg/kg/day) significantly reduced the antinociceptive
effects of higher metformin doses (150 and 200 mg/kg). Metformin (200 mg/kg) had no
influence on rotarod performance. This study demonstrates that 5-HT1B/1D and 5-HT1A
receptors are involved in metformin’s antinociceptive effects and that metformin’s action on
these receptors seems to be indirect (mediated by endogenous serotonin released by
metformin).
AB  - Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička
svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog
dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće
serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom
modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani
antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi
testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene
antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku
eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina,
primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4
dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi
se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200
mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj
(inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat
metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i
100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg).
Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila
antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg).
Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu.
Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu
metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom
oslobađanja endogenog serotonina od strane metformina).
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - The involvement of serotonergic mechanisms in the antinociceptive effect of metformin
T1  - Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina
VL  - 72
IS  - 4 suplement
SP  - S448
EP  - S449
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4578
ER  - 

@conference{
author = "Lasica, Anđelka and Tomić, Maja and Nastić, Katarina and Pecikoza, Uroš and Micov, Ana and Stepanović-Petrović, Radica",
year = "2022",
abstract = "Metformin, a well-known antidiabetic drug, has been shown to possess analgesic
properties in inflammatory pain models, but the mechanisms of its antinociceptive effects
are not completely understood (1,2). We aimed to examine the involvement of serotonergic
mechanisms in metformin-induced antinociception in a model of inflammatory pain, using
the formalin test in mice. Firstly, we examined the antinociceptive effects of intraperitoneally
administered metformin in the first and second phase of the test. Then, the involvement of
serotonergic receptors was evaluated by intraperitoneally pretreating mice with a 5-HT1B/1D
(GR127935) or 5-HT1A receptor antagonist (WAY100635). Further, we examined the effect of
metformin after depletion of endogenous serotonin with a tryptophan-hydroxylase inhibitor
(PCPA; applied intraperitoneally for 4 days). Additionally, to avoid misinterpretation of
motor incoordination, we performed the rotarod test with the highest tested metformin
dose. Metformin (50-200 mg/kg) produced significant and dose-dependent antinociceptive
effects (17-81%) in the second (inflammatory) phase of the test. Pretreatment with
antagonists significantly reduced the antinociceptive effect of metformin (150 mg/kg).
GR127935 inhibited the effects of metformin by 67% (1 mg/kg) and 100% (3 mg/kg),
whereas the inhibitory effects for WAY100635 were 19% (1 mg/kg) and 68% (3 mg/kg).
Depletion of serotonin with PCPA (100 mg/kg/day) significantly reduced the antinociceptive
effects of higher metformin doses (150 and 200 mg/kg). Metformin (200 mg/kg) had no
influence on rotarod performance. This study demonstrates that 5-HT1B/1D and 5-HT1A
receptors are involved in metformin’s antinociceptive effects and that metformin’s action on
these receptors seems to be indirect (mediated by endogenous serotonin released by
metformin)., Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička
svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog
dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće
serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom
modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani
antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi
testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene
antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku
eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina,
primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4
dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi
se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200
mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj
(inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat
metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i
100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg).
Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila
antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg).
Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu.
Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu
metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom
oslobađanja endogenog serotonina od strane metformina).",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "The involvement of serotonergic mechanisms in the antinociceptive effect of metformin, Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina",
volume = "72",
number = "4 suplement",
pages = "S448-S449",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4578"
}

Lasica, A., Tomić, M., Nastić, K., Pecikoza, U., Micov, A.,& Stepanović-Petrović, R.. (2022). The involvement of serotonergic mechanisms in the antinociceptive effect of metformin. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S448-S449.
https://hdl.handle.net/21.15107/rcub_farfar_4578

Lasica A, Tomić M, Nastić K, Pecikoza U, Micov A, Stepanović-Petrović R. The involvement of serotonergic mechanisms in the antinociceptive effect of metformin. in Arhiv za farmaciju. 2022;72(4 suplement):S448-S449.
https://hdl.handle.net/21.15107/rcub_farfar_4578 .

Lasica, Anđelka, Tomić, Maja, Nastić, Katarina, Pecikoza, Uroš, Micov, Ana, Stepanović-Petrović, Radica, "The involvement of serotonergic mechanisms in the antinociceptive effect of metformin" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S448-S449,
https://hdl.handle.net/21.15107/rcub_farfar_4578 .

TY  - CONF
AU  - Pecikoza, Uroš
AU  - Lasica, Anđelka
AU  - Tomić, Maja
AU  - Micov, Ana
AU  - Nastić, Katarina
AU  - Stepanović-Petrović, Radica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4577
AB  - Several lines of (pre)clinical evidence have emerged that the antidiabetic drug
metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not
completely understood, there are reports that metformin can affect neurotransmitters
involved in pain modulation, such as its ability to increase peripheral serotonin release (2).
Here, we evaluated metformin’s efficacy following local peripheral administration in an
inflammatory pain model and examined the potential involvement of serotonin receptors.
We used the formalin test in mice, where we measured duration of nociceptive behavior in
the first and second phase of the test. First, we examined the metformin’s antinociceptive
effects following intraplantar administration. Additionally, the highest tested metformin
dose was applied contralateral to the formalin-injected side, to exclude possible systemic
effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D
antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin
(antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2
mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the
second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no
significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive
effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive
effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas
GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This
study demonstrates that peripheral metformin application can produce antinociceptive
effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D
receptors contributes to these effects.
AB  - Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe
antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije
u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere
uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na
periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne
primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih
receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u
nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti
metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je
primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili
mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A
(WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne,
efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa
metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan
antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna
primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni
antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni
inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5
μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24%
(3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina
proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5-
HT1B/1D receptora doprinosi ovom efektu.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin
T1  - Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina
VL  - 72
IS  - 4 suplement
SP  - S446
EP  - S447
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4577
ER  - 

@conference{
author = "Pecikoza, Uroš and Lasica, Anđelka and Tomić, Maja and Micov, Ana and Nastić, Katarina and Stepanović-Petrović, Radica",
year = "2022",
abstract = "Several lines of (pre)clinical evidence have emerged that the antidiabetic drug
metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not
completely understood, there are reports that metformin can affect neurotransmitters
involved in pain modulation, such as its ability to increase peripheral serotonin release (2).
Here, we evaluated metformin’s efficacy following local peripheral administration in an
inflammatory pain model and examined the potential involvement of serotonin receptors.
We used the formalin test in mice, where we measured duration of nociceptive behavior in
the first and second phase of the test. First, we examined the metformin’s antinociceptive
effects following intraplantar administration. Additionally, the highest tested metformin
dose was applied contralateral to the formalin-injected side, to exclude possible systemic
effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D
antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin
(antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2
mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the
second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no
significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive
effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive
effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas
GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This
study demonstrates that peripheral metformin application can produce antinociceptive
effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D
receptors contributes to these effects., Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe
antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije
u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere
uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na
periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne
primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih
receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u
nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti
metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je
primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili
mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A
(WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne,
efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa
metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan
antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna
primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni
antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni
inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5
μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24%
(3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina
proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5-
HT1B/1D receptora doprinosi ovom efektu.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin, Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina",
volume = "72",
number = "4 suplement",
pages = "S446-S447",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4577"
}

Pecikoza, U., Lasica, A., Tomić, M., Micov, A., Nastić, K.,& Stepanović-Petrović, R.. (2022). Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S446-S447.
https://hdl.handle.net/21.15107/rcub_farfar_4577

Pecikoza U, Lasica A, Tomić M, Micov A, Nastić K, Stepanović-Petrović R. Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin. in Arhiv za farmaciju. 2022;72(4 suplement):S446-S447.
https://hdl.handle.net/21.15107/rcub_farfar_4577 .

Pecikoza, Uroš, Lasica, Anđelka, Tomić, Maja, Micov, Ana, Nastić, Katarina, Stepanović-Petrović, Radica, "Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S446-S447,
https://hdl.handle.net/21.15107/rcub_farfar_4577 .

TY  - JOUR
AU  - Todorović, Marija
AU  - Micov, Ana
AU  - Nastić, Katarina
AU  - Tomić, Maja
AU  - Pecikoza, Uroš
AU  - Vuković, Milja
AU  - Stepanović-Petrović, Radica
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4009
AB  - Vortioxetine is a novel atypical antidepressant with multimodal activity that has recently demonstrated efficacy against neuropathic pain. There is no published data about its analgesic properties in models characterized by peripheral inflammation and consequent pain pathway sensitization, nor data on its mechanism of antinociceptive action. This study aimed to investigate vortioxetine's antinociceptive/antihyperalgesic effects in trigeminal, visceral, and somatic inflammatory pain models, and provide evidence on its mechanism of action in the modulation of trigeminal nociception. Vortioxetine's effects on the nociceptive behavior in orofacial formalin test (OFT) and acetic acid-writhing test in mice and on mechanical hyperalgesia in carrageenan-induced paw inflammation in rats were examined following peroral single administration. The involvement of serotonergic/adrenergic/cholinergic/cannabinoid/adenosine receptors was evaluated in OFT by intraperitoneally treating mice with an appropriate antagonist immediately after vortioxetine application. We used antagonists of 5-HT1B/1D serotonergic (GR 127935), α1-adrenergic (prazosin), α2-adrenergic (yohimbine), β1-adrenergic (metoprolol), muscarinic (atropine), α7 nicotinic (methyllycaconitine), CB1/CB2 cannabinoid (AM251 and AM630), and adenosine A1 (DPCPX) receptors. Vortioxetine dose-dependently reduced pain behavior in OFT and acetic acid writhing test, as well as inflammatory hyperalgesia in paw pressure test. All examined antagonists except prazosin dose-dependently inhibited vortioxetine's antinociceptive effects. In conclusion, vortioxetine exerted analgesic efficacy in trigeminal, visceral, and somatic inflammatory pain. The effect is at least in part mediated by 5-HT1B/1D serotonergic, α2/β1-adrenergic, muscarinic and nicotinic cholinergic, CB1/CB2 cannabinoid, and adenosine A1 receptors. These findings contribute to better understanding of the analgesic effect of vortioxetine and suggest its potential usefulness for inflammatory pain treatment.
PB  - John Wiley and Sons Inc
T2  - Fundamental and Clinical Pharmacology
T1  - Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action
VL  - 36
IS  - 2
SP  - 237
EP  - 249
DO  - 10.1111/fcp.12737
ER  - 

@article{
author = "Todorović, Marija and Micov, Ana and Nastić, Katarina and Tomić, Maja and Pecikoza, Uroš and Vuković, Milja and Stepanović-Petrović, Radica",
year = "2021",
abstract = "Vortioxetine is a novel atypical antidepressant with multimodal activity that has recently demonstrated efficacy against neuropathic pain. There is no published data about its analgesic properties in models characterized by peripheral inflammation and consequent pain pathway sensitization, nor data on its mechanism of antinociceptive action. This study aimed to investigate vortioxetine's antinociceptive/antihyperalgesic effects in trigeminal, visceral, and somatic inflammatory pain models, and provide evidence on its mechanism of action in the modulation of trigeminal nociception. Vortioxetine's effects on the nociceptive behavior in orofacial formalin test (OFT) and acetic acid-writhing test in mice and on mechanical hyperalgesia in carrageenan-induced paw inflammation in rats were examined following peroral single administration. The involvement of serotonergic/adrenergic/cholinergic/cannabinoid/adenosine receptors was evaluated in OFT by intraperitoneally treating mice with an appropriate antagonist immediately after vortioxetine application. We used antagonists of 5-HT1B/1D serotonergic (GR 127935), α1-adrenergic (prazosin), α2-adrenergic (yohimbine), β1-adrenergic (metoprolol), muscarinic (atropine), α7 nicotinic (methyllycaconitine), CB1/CB2 cannabinoid (AM251 and AM630), and adenosine A1 (DPCPX) receptors. Vortioxetine dose-dependently reduced pain behavior in OFT and acetic acid writhing test, as well as inflammatory hyperalgesia in paw pressure test. All examined antagonists except prazosin dose-dependently inhibited vortioxetine's antinociceptive effects. In conclusion, vortioxetine exerted analgesic efficacy in trigeminal, visceral, and somatic inflammatory pain. The effect is at least in part mediated by 5-HT1B/1D serotonergic, α2/β1-adrenergic, muscarinic and nicotinic cholinergic, CB1/CB2 cannabinoid, and adenosine A1 receptors. These findings contribute to better understanding of the analgesic effect of vortioxetine and suggest its potential usefulness for inflammatory pain treatment.",
publisher = "John Wiley and Sons Inc",
journal = "Fundamental and Clinical Pharmacology",
title = "Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action",
volume = "36",
number = "2",
pages = "237-249",
doi = "10.1111/fcp.12737"
}

Todorović, M., Micov, A., Nastić, K., Tomić, M., Pecikoza, U., Vuković, M.,& Stepanović-Petrović, R.. (2021). Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action. in Fundamental and Clinical Pharmacology
John Wiley and Sons Inc., 36(2), 237-249.
https://doi.org/10.1111/fcp.12737

Todorović M, Micov A, Nastić K, Tomić M, Pecikoza U, Vuković M, Stepanović-Petrović R. Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action. in Fundamental and Clinical Pharmacology. 2021;36(2):237-249.
doi:10.1111/fcp.12737 .

Todorović, Marija, Micov, Ana, Nastić, Katarina, Tomić, Maja, Pecikoza, Uroš, Vuković, Milja, Stepanović-Petrović, Radica, "Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action" in Fundamental and Clinical Pharmacology, 36, no. 2 (2021):237-249,
https://doi.org/10.1111/fcp.12737 . .

TY  - JOUR
AU  - Stepanović-Petrović, Radica
AU  - Nastić, Katarina
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3745
AB  - Thromboembolic events are the leading cause of morbidity and mortality worldwide. From the second half of the 20th century, vitamin K antagonists (VKAs), warfarin and acenocoumarol, were the only anticoagulants taken orally. The major reform in anticoagulation therapy was made by  the  advent  of  direct  oral  anticoagulants  (DOACs),  about  10  years  ago.  Direct  thrombin inhibitor (dabigatran) and direct inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban, and betrixaban) have demonstrated favorable risk/benefit ratio. Compared to warfarin, DOACs are associated  with  a  predictable  pharmacokinetic  profile,  lower  severe  bleeding  complications, particularly intracranial hemorrhages, and minimal drug interactions. Moreover, DOACs achieve a rapid onset of action and have shown comparable efficacy with warfarin and low molecular weight heparin (LMWH) in clinical trials. As a result, DOACs are now replacing VKAs and LMWH for many indications including stroke and systemic embolism prevention in nonvalvular atrial fibrillation, prevention, and treatment of venous thromboembolism and thromboprophylaxis following  total  knee/hip  replacement  surgery.  In  addition,  rivaroxaban  (in  combination  with aspirin alone or aspirin and clopidogrel) is used in the prevention of atherothrombotic events following acute coronary syndrome with elevated cardiac biomarkers. In case of severe bleeding complications  under  DOACs  treatment,  antidotes  are  available;  idarucizumab  for  dabigatran reversal and andexanet alfa for rivaroxaban and apixaban.
AB  - Tromboembolijski događaji predstavljaju vodeći uzrok morbiditeta i mortaliteta širom sveta. Od druge polovine 20. veka, antagonisti vitamina K (VKA), varfarin i acenokumarol bili su jedini dostupni oralni antikoagulantni lekovi. Pojava direktnih oralnih antikoagulanasa (DOAK), od pre 10-tak godina, donela je veliku promenu u antikoagulantnoj terapiji. Direktni inhibitor trombina (dabigatran) i direktni inhibitori faktora Xa (rivaroksaban, apiksaban, edoksaban i betriksaban) su pokazali povoljan odnos koristi i rizika. U poređenju sa varfarinom, DOAK pokazuju predvidljiv farmakokinetički profil, nižu incidencu ozbiljnog krvarenja posebno intrakranijalnog krvarenja i stupaju u mali broj interakcija sa drugim lekovima. Pored toga, DOAK imaju brz nastup dejstva i pokazali su komparabilnu efikasnost u poređenju sa varfarinom i niskomolekularnim heparinima (LMWH) u kliničkim ispitivanjima. Posledično, DOAK postepeno zamenjuju VKA i LMWH u mnogim indikacijama uključujući prevenciju moždanog udara i sistemskog embolizma kod pacijenata sa nevalvularnom atrijalnom fibrilacijom, prevenciju i terapiju venskog tromboembolizma, kao i tromboprofilaksu nakon ugradnje veštačkog kolena/kuka. Dodatno, rivaroksaban (sa aspirinom ili kombinacijom aspirina i klopidogrela) je indikovan u prevenciji aterotrombotičnih događaja posle akutnog koronarnog sindroma, kod pacijenata sa povećanim srčanim biomarkerima. U slučaju pojave ozbiljnog krvarenja, dostupni su antidoti; idarucizumab za dabigatran i andeksanet alfa za rivaroksaban i apiksaban.
PB  - Beograd : Savez farmaceutskih udruženja Srbije
T2  - Arhiv za farmaciju
T1  - Direct oral anticoagulants – a new chapter in anticoagulation therapy
T1  - Direktni oralni antikoagulansi - novo poglavlje u antikoagulantnoj terapiji
VL  - 70
IS  - 5
SP  - 249
EP  - 268
DO  - 10.5937/arhfarm2005249S
ER  - 

@article{
author = "Stepanović-Petrović, Radica and Nastić, Katarina",
year = "2020",
abstract = "Thromboembolic events are the leading cause of morbidity and mortality worldwide. From the second half of the 20th century, vitamin K antagonists (VKAs), warfarin and acenocoumarol, were the only anticoagulants taken orally. The major reform in anticoagulation therapy was made by  the  advent  of  direct  oral  anticoagulants  (DOACs),  about  10  years  ago.  Direct  thrombin inhibitor (dabigatran) and direct inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban, and betrixaban) have demonstrated favorable risk/benefit ratio. Compared to warfarin, DOACs are associated  with  a  predictable  pharmacokinetic  profile,  lower  severe  bleeding  complications, particularly intracranial hemorrhages, and minimal drug interactions. Moreover, DOACs achieve a rapid onset of action and have shown comparable efficacy with warfarin and low molecular weight heparin (LMWH) in clinical trials. As a result, DOACs are now replacing VKAs and LMWH for many indications including stroke and systemic embolism prevention in nonvalvular atrial fibrillation, prevention, and treatment of venous thromboembolism and thromboprophylaxis following  total  knee/hip  replacement  surgery.  In  addition,  rivaroxaban  (in  combination  with aspirin alone or aspirin and clopidogrel) is used in the prevention of atherothrombotic events following acute coronary syndrome with elevated cardiac biomarkers. In case of severe bleeding complications  under  DOACs  treatment,  antidotes  are  available;  idarucizumab  for  dabigatran reversal and andexanet alfa for rivaroxaban and apixaban., Tromboembolijski događaji predstavljaju vodeći uzrok morbiditeta i mortaliteta širom sveta. Od druge polovine 20. veka, antagonisti vitamina K (VKA), varfarin i acenokumarol bili su jedini dostupni oralni antikoagulantni lekovi. Pojava direktnih oralnih antikoagulanasa (DOAK), od pre 10-tak godina, donela je veliku promenu u antikoagulantnoj terapiji. Direktni inhibitor trombina (dabigatran) i direktni inhibitori faktora Xa (rivaroksaban, apiksaban, edoksaban i betriksaban) su pokazali povoljan odnos koristi i rizika. U poređenju sa varfarinom, DOAK pokazuju predvidljiv farmakokinetički profil, nižu incidencu ozbiljnog krvarenja posebno intrakranijalnog krvarenja i stupaju u mali broj interakcija sa drugim lekovima. Pored toga, DOAK imaju brz nastup dejstva i pokazali su komparabilnu efikasnost u poređenju sa varfarinom i niskomolekularnim heparinima (LMWH) u kliničkim ispitivanjima. Posledično, DOAK postepeno zamenjuju VKA i LMWH u mnogim indikacijama uključujući prevenciju moždanog udara i sistemskog embolizma kod pacijenata sa nevalvularnom atrijalnom fibrilacijom, prevenciju i terapiju venskog tromboembolizma, kao i tromboprofilaksu nakon ugradnje veštačkog kolena/kuka. Dodatno, rivaroksaban (sa aspirinom ili kombinacijom aspirina i klopidogrela) je indikovan u prevenciji aterotrombotičnih događaja posle akutnog koronarnog sindroma, kod pacijenata sa povećanim srčanim biomarkerima. U slučaju pojave ozbiljnog krvarenja, dostupni su antidoti; idarucizumab za dabigatran i andeksanet alfa za rivaroksaban i apiksaban.",
publisher = "Beograd : Savez farmaceutskih udruženja Srbije",
journal = "Arhiv za farmaciju",
title = "Direct oral anticoagulants – a new chapter in anticoagulation therapy, Direktni oralni antikoagulansi - novo poglavlje u antikoagulantnoj terapiji",
volume = "70",
number = "5",
pages = "249-268",
doi = "10.5937/arhfarm2005249S"
}

Stepanović-Petrović, R.,& Nastić, K.. (2020). Direct oral anticoagulants – a new chapter in anticoagulation therapy. in Arhiv za farmaciju
Beograd : Savez farmaceutskih udruženja Srbije., 70(5), 249-268.
https://doi.org/10.5937/arhfarm2005249S

Stepanović-Petrović R, Nastić K. Direct oral anticoagulants – a new chapter in anticoagulation therapy. in Arhiv za farmaciju. 2020;70(5):249-268.
doi:10.5937/arhfarm2005249S .

Stepanović-Petrović, Radica, Nastić, Katarina, "Direct oral anticoagulants – a new chapter in anticoagulation therapy" in Arhiv za farmaciju, 70, no. 5 (2020):249-268,
https://doi.org/10.5937/arhfarm2005249S . .