TY  - JOUR
AU  - Mitrović, Jelena
AU  - Bjelošević Žiberna, Maja
AU  - Vukadinović, Aleksandar
AU  - Knutson, Daniel E.
AU  - Sharmin, Dishary
AU  - Kremenović, Aleksandar
AU  - Ahlin Grabnar, Pegi
AU  - Planinšek, Odon
AU  - Lunter, Dominique
AU  - Cook, James M
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11440
AB  - Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7‑methoxy-2-(4‑methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 μm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.
T2  - European Journal of Pharmaceutical Sciences
T1  - Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study
VL  - 189
DO  - 10.1016/j.ejps.2023.106557
ER  - 

@article{
author = "Mitrović, Jelena and Bjelošević Žiberna, Maja and Vukadinović, Aleksandar and Knutson, Daniel E. and Sharmin, Dishary and Kremenović, Aleksandar and Ahlin Grabnar, Pegi and Planinšek, Odon and Lunter, Dominique and Cook, James M and Savić, Miroslav and Savić, Snežana",
year = "2023",
abstract = "Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7‑methoxy-2-(4‑methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 μm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study",
volume = "189",
doi = "10.1016/j.ejps.2023.106557"
}

Mitrović, J., Bjelošević Žiberna, M., Vukadinović, A., Knutson, D. E., Sharmin, D., Kremenović, A., Ahlin Grabnar, P., Planinšek, O., Lunter, D., Cook, J. M., Savić, M.,& Savić, S.. (2023). Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study. in European Journal of Pharmaceutical Sciences, 189.
https://doi.org/10.1016/j.ejps.2023.106557

Mitrović J, Bjelošević Žiberna M, Vukadinović A, Knutson DE, Sharmin D, Kremenović A, Ahlin Grabnar P, Planinšek O, Lunter D, Cook JM, Savić M, Savić S. Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study. in European Journal of Pharmaceutical Sciences. 2023;189.
doi:10.1016/j.ejps.2023.106557 .

Mitrović, Jelena, Bjelošević Žiberna, Maja, Vukadinović, Aleksandar, Knutson, Daniel E., Sharmin, Dishary, Kremenović, Aleksandar, Ahlin Grabnar, Pegi, Planinšek, Odon, Lunter, Dominique, Cook, James M, Savić, Miroslav, Savić, Snežana, "Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study" in European Journal of Pharmaceutical Sciences, 189 (2023),
https://doi.org/10.1016/j.ejps.2023.106557 . .

TY  - JOUR
AU  - Aranđelović, Jovana
AU  - Santrač, Anja
AU  - Batinić, Bojan
AU  - Todorović, Lidija
AU  - Stevanović, Vladimir
AU  - Tiruveedhula, Veera Venkata Naga Phani Babu
AU  - Sharmin, Dishary
AU  - Rashid, Farjana
AU  - Stanojević, Boban
AU  - Cook, James M.
AU  - Savić, Miroslav M.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10360
AB  - Aims GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.
T2  - CNS Neuroscience & Therapeutics
T2  - CNS Neuroscience & Therapeutics
T1  - Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease
VL  - 28
IS  - 11
SP  - 1767
EP  - 1778
DO  - 10.1111/cns.13914
ER  - 

@article{
author = "Aranđelović, Jovana and Santrač, Anja and Batinić, Bojan and Todorović, Lidija and Stevanović, Vladimir and Tiruveedhula, Veera Venkata Naga Phani Babu and Sharmin, Dishary and Rashid, Farjana and Stanojević, Boban and Cook, James M. and Savić, Miroslav M.",
year = "2022",
abstract = "Aims GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.",
journal = "CNS Neuroscience & Therapeutics, CNS Neuroscience & Therapeutics",
title = "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease",
volume = "28",
number = "11",
pages = "1767-1778",
doi = "10.1111/cns.13914"
}

Aranđelović, J., Santrač, A., Batinić, B., Todorović, L., Stevanović, V., Tiruveedhula, V. V. N. P. B., Sharmin, D., Rashid, F., Stanojević, B., Cook, J. M.,& Savić, M. M.. (2022). Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics, 28(11), 1767-1778.
https://doi.org/10.1111/cns.13914

Aranđelović J, Santrač A, Batinić B, Todorović L, Stevanović V, Tiruveedhula VVNPB, Sharmin D, Rashid F, Stanojević B, Cook JM, Savić MM. Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics. 2022;28(11):1767-1778.
doi:10.1111/cns.13914 .

Aranđelović, Jovana, Santrač, Anja, Batinić, Bojan, Todorović, Lidija, Stevanović, Vladimir, Tiruveedhula, Veera Venkata Naga Phani Babu, Sharmin, Dishary, Rashid, Farjana, Stanojević, Boban, Cook, James M., Savić, Miroslav M., "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease" in CNS Neuroscience & Therapeutics, 28, no. 11 (2022):1767-1778,
https://doi.org/10.1111/cns.13914 . .

TY  - JOUR
AU  - Gajić-Bojić, Milica
AU  - Todorović, Lidija
AU  - Santrač, Anja
AU  - Mian, Md Yeunus
AU  - Sharmin, Dishary
AU  - Cook, James M.
AU  - Savić, Miroslav M.
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9163
AB  - Different subtypes of GABAA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABAA receptors are expressed on blood vessels, through which positive allosteric modulators of GABAA receptors exhibit vasodilatory effects. This study involved two parts: one to determine the presence of α1-6 subunit GABAA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABAA receptor modulators: zolpidem (α1-selective), XHe–III–074 (α4-selective), MP–III–022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective). Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue bath assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe–III–074, MP–III–022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10−7 M and 3 × 10−7 M). The present work suggests that the observed vasoactivity is due to modulation of “vascular” GABAA receptors, which after further detailed research may provide a therapeutic target. © 2021 Elsevier B.V.
T2  - European Journal of Pharmacology
T1  - Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta
VL  - 899
SP  - 174023
DO  - 10.1016/j.ejphar.2021.174023
ER  - 

@article{
author = "Gajić-Bojić, Milica and Todorović, Lidija and Santrač, Anja and Mian, Md Yeunus and Sharmin, Dishary and Cook, James M. and Savić, Miroslav M.",
year = "2021",
abstract = "Different subtypes of GABAA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABAA receptors are expressed on blood vessels, through which positive allosteric modulators of GABAA receptors exhibit vasodilatory effects. This study involved two parts: one to determine the presence of α1-6 subunit GABAA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABAA receptor modulators: zolpidem (α1-selective), XHe–III–074 (α4-selective), MP–III–022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective). Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue bath assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe–III–074, MP–III–022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10−7 M and 3 × 10−7 M). The present work suggests that the observed vasoactivity is due to modulation of “vascular” GABAA receptors, which after further detailed research may provide a therapeutic target. © 2021 Elsevier B.V.",
journal = "European Journal of Pharmacology",
title = "Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta",
volume = "899",
pages = "174023",
doi = "10.1016/j.ejphar.2021.174023"
}

Gajić-Bojić, M., Todorović, L., Santrač, A., Mian, M. Y., Sharmin, D., Cook, J. M.,& Savić, M. M.. (2021). Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta. in European Journal of Pharmacology, 899, 174023.
https://doi.org/10.1016/j.ejphar.2021.174023

Gajić-Bojić M, Todorović L, Santrač A, Mian MY, Sharmin D, Cook JM, Savić MM. Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta. in European Journal of Pharmacology. 2021;899:174023.
doi:10.1016/j.ejphar.2021.174023 .

Gajić-Bojić, Milica, Todorović, Lidija, Santrač, Anja, Mian, Md Yeunus, Sharmin, Dishary, Cook, James M., Savić, Miroslav M., "Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta" in European Journal of Pharmacology, 899 (2021):174023,
https://doi.org/10.1016/j.ejphar.2021.174023 . .