109 results on '"A. Mikov"'
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2. Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study
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Zaklan, Dragana, Nešić, Dušan, Mitrović, Darko, Lazarević, Slavica, Đanić, Maja, Mikov, Momir, and Pavlović, Nebojša
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Background and Objective : Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico. Methods : After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (P
app ) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin. Results: Both CA and DCA at the highest studied concentration of 100 μM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids. Conclusions : The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.- Published
- 2024
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3. Quality of life and mental health of volunteers during COVID-19 pandemic: a cross-sectional survey in Serbia.
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IGIĆ, N., ZVEKIĆ-SVORCAN, J., MIKOV, J., BOŠKOVIĆ, K., MIKIĆ, A., KAŠIKOVIĆ-LEĆIĆ, S., CRNOBRNJA, V., and KUSTURICA, M. PAUT
- Abstract
OBJECTIVE: There is a paucity of information on the COVID-19 pandemic's impact on young volunteers. Therefore, the aim of this survey was to examine the QoL and mental health of young volunteers of the Novi Sad Voluntary Service during the COVID-19 pandemic. PATIENTS AND METHODS: This cross-sectional prospective study included 255 members of the Novi Sad Voluntary Service, Serbia. The survey instrument probed into the respondents' demographic characteristics and was followed by the anonymous WHOQOL-BREF questionnaire that measured their quality of life during the COVID-19 pandemic and DASS-21 scale. All statistical analyses were carried out using IBM SPSS Statistics for Windows, vers. 24.0. RESULTS: The study sample consisted of 255 young volunteers (71.4% females, 28.6% males), 62.0% of whom were aged 18-25 years, and 52.2% were students. Lower Physical Capacity scores could be predicted by female gender (p < 0.01) and COVID-19 infection among friends (p < 0.05). Male gender (p < 0.05) and being employed (p < 0.05) predicted greater QoL in the Psychological domain. The only predictor of a lower QoL in the Social Relationships domain was the internet as the main COVID-19-related information source (p < 0.05). On the other hand, being female (p < 0.05) and having COVID-19-positive household members (p = 0.01) predicted lower environment domain scores. For the lower overall DASS-21 score, having COVID-19-positive household members was the only significant predictor (p < 0.01). CONCLUSIONS: Mental health support should pursue strategies to improve all domains of QoL, especially for vulnerable sub-groups of the population, such as young females and the unemployed. Bearing in mind the importance of public engagement and community support in pandemic circumstances, as well as generally in public health, these results are relevant for interventions far beyond the current pandemic. [ABSTRACT FROM AUTHOR]
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- 2023
4. Impact of winter savory extract (Satureja montana L.) on biochemical parameters in serum and oxidative status of liver with application of the principal component analysis in extraction solvent selection.
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MILIJAŠEVIĆ, B., STEINBACH, M., MIKOV, M., RAŠKOVIĆ, A., ČAPO, I., ŽIVKOVIĆ, J., BORIŠEV, I., PANIĆ, J. ĆANJI, TEOFILOVIĆ, B., VUJĆIĆ, M., and POPOVIĆ, M. L.
- Abstract
OBJECTIVE: Satureja montana L. is traditionally used as spice and for treatment various diseases. Many studies have shown antioxidative effect of Satureja species. Our thorough study in an animal model was performed through measurement of biochemical parameters in the serum, histology analysis and determination of oxidative status of the liver, coupled with investigation of extraction solvent selection using principal component analysis (PCA). MATERIALS AND METHODS: Winter savory dry extract (500 mg/kg) dispersion and saline solution were given to Wistar rats for 7 days after exposure to oxidative stress using toxic doses of paracetamol (600 mg/kg). Rats were sacrificed, after which a complete autopsy was performed, the blood obtained was used to determine biochemical parameters, and the liver was sliced for histological analysis and determination of oxidative stress enzymes. RESULTS: Indicators of hepatic and kidney functions, as well as the concentration of oxidative stress enzymes, were statistically significantly lower in animals treated with Satureja montana L. extract compared to the paracetamol group alone before the toxic dose of paracetamol. Liver enzymes were unaltered by pre-treatment with the extract, but the level of lipid peroxidase was decreased, and the level of catalase, glutathione reductase and superoxide dismutase increased proving in vivo antioxidant effect. In addition, the number of inflammatory cells is decreased coupled with activity of CYP2E1 enzymes proving hepatoprotective effect. CONCLUSIONS: Satureja montana L. extract in our research has shown hepatoprotective, anti-inflammatory and antioxidative effect. PCA analyses indicated that extraction mediums have a great impact on the antioxidative effect. [ABSTRACT FROM AUTHOR]
- Published
- 2022
5. Biotechnological Effects of Advanced Smart‐Bile Acid Cyclodextrin‐Based Nanogels for Ear Delivery and Treatment of Hearing Loss
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Kovacevic, Bozica, Wagle, Susbin Raj, Ionescu, Corina Mihaela, Foster, Thomas, Đanić, Maja, Mikov, Momir, Mooranian, Armin, and Al‐Salami, Hani
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Inner ear delivery requires safe and effective drug delivery vehicles incorporating high‐viscosity formulations with permeation enhancers. This study designs novel thermoresponsive‐smart polymer‐bile acid and cyclodextrin‐based nanogels for inner ear delivery. Nanogels are examined for their rheological and physical properties. The biocompatibility studies will be assessed on auditory and macrophage cell lines by investigating the impact of nanogels on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, inflammatory profile, and macrophage polarization. Novel ther nanogels based on bile acid and beta‐cyclodextrin show preserved porous nanogels' inner structure, exhibit non‐Newtonian, shear‐thinning fluid behavior, have fast gelation at 37 °C and minimal albumin adsorption on the surface. The nanogels have minimal impact on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, and inflammatory profile of the auditory cell line House Ear Institute‐Organ of Corti 1 after 24 h incubation. Nanogel exposure of 24 h to macrophage cell line RAW264.7 leads to decreased viability, mitochondrial dysfunction, and increased intracellular ROS and inflammatory cytokines. However, polarization changes from M2 anti‐inflammatory to M1 pro‐inflammatory macrophages are minimal, and inflammatory products of RAW264.7 macrophages do not overly disrupt the survivability of HEI‐OC1 cells. Based on these results, thermoresponsive bile acid and cyclodextrin nanogels can be potential drug delivery vehicles for inner ear drug delivery. This study explores novel thermoresponsive‐smart polymer‐bile acid and cyclodextrin‐based nanogels for inner ear drug delivery. The nanogels exhibit unique rheological properties and minimal cellular impact on auditory and macrophage cell lines. The nanogels show promise as safe drug delivery vehicles for inner ear treatment, hinting at exciting possibilities for targeted therapy.
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- 2024
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6. Polymer-Based Nanoparticles with Probucol and Lithocholic Acid: A Novel Therapeutic Approach for Oxidative Stress-Induced Retinopathies
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Wagle, Susbin Raj, Kovacevic, Bozica, Ionescu, Corina Mihaela, Foster, Thomas, Lim, Patrick, Brunet, Alicia, McLenachan, Samuel, Carvalho, Livia, Mikov, Momir, Mooranian, Armin, and Al-Salami, Hani
- Abstract
Oxidative stress is pivotal in retinal disease progression, causing dysfunction in various retinal components. An effective antioxidant, such as probucol (PB), is vital to counteract oxidative stress and emerges as a potential candidate for treating retinal degeneration. However, the challenges associated with delivering lipophilic drugs such as PB to the posterior segment of the eye, specifically targeting photoreceptor cells, necessitate innovative solutions. This study uses formulation-based spray dry encapsulation technology to develop polymer-based PB-lithocholic acid (LCA) nanoparticles and assesses their efficacy in the 661W photoreceptor-like cell line. Incorporating LCA enhances nanoparticles’ biological efficacy without compromising PB stability. In vitrostudies demonstrate that PB-LCA nanoparticles prevent reactive oxygen species (ROS)-induced oxidative stress by improving cellular viability through the nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. These findings propose PB-LCA nanoparticles as a promising therapeutic strategy for oxidative stress-induced retinopathies.
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- 2024
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7. A second-generation micro/nano capsules of an endogenous primary un-metabolised bile acid, stabilized by Eudragit-alginate complex with antioxidant compounds.
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Mooranian, Armin, Zamani, Nassim, Mikov, Momir, Goločorbin-Kon, Svetlana, Stojanovic, Goran, Arfuso, Frank, Kovacevic, Bozica, and Al-Salami, Hani
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Bile acids (BAs) are amphiphilic compounds and of recently have demonstrated wide range of formulation stabilizing effects. A recent study showed that primary un-metabolised bile acids (PUBAs) have β-cell protective effects, and synergistic antidiabetic effects when combined with antioxidant and anti-inflammatory drugs, such as probucol (PB). Thus, this study aimed to design and test microcapsules containing a PUBA incorporated with PB and an alginate-Eudragit matrix. Six types of microcapsules were developed without (control) or with (test) PUBA, and tested for internal and external features and β-cell protective effects. The incorporation of PB-alginate-Eudragit with PUBA produced stable microcapsules but did not exert consistent positive effects on cell viability in the hyperglycaemic state, which suggests that PUBA in alginate-Eudragit matrices did not exhibit synergistic effects with PB nor exerted antidiabetic effects. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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8. Plasma Distribution of Methotrexate and Its Polyglutamates in Pediatric Acute Lymphoblastic Leukemia: Preliminary Insights
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Rajšić, Ivana, Lazarević, Slavica, Đanić, Maja, Al-Salami, Hani, Mooranian, Armin, Vukmirović, Saša, Mikov, Momir, and Goločorbin-Kon, Svetlana
- Abstract
Background and Objective: High-dose methotrexate (HD-MTX) is the mainstream therapy of current acute lymphoblastic leukemia (ALL) regimens, but frequent intra- and interindividual differences in the clinical response to HD-MTX lead to chemotherapeutic interruption or discontinuation. The exact mechanism of transport across the cell membrane and the disposition of active methotrexate metabolites—methotrexate polyglutamates (MTXPGs)—are not well described in the literature. The aim of this study was to gain more insight into the plasma distribution of methotrexate and MTXPGs in pediatric patients with ALL and to clarify the obscure pathways of MTXPGs. Methods: We prospectively measured the concentrations of MTXPG
1–7 in plasma samples from three male pediatric patients treated with HD-MTX and leucovorin rescue according to the IC-BFM 2009 protocol using liquid chromatography–mass spectrometry (LC-MS). Blood samples were obtained at 24, 36, 42, and 48 h after the start of HD-MTX treatment. Results: Noticeable plasma concentrations of MTXPGs with a 2.2-fold interpatient variability were detected. The highest interindividual variability in total plasma MTXPG concentration was observed at 36 h, and ranged from 13.78 to 30.82 μmol/L. Among all patients, the predominant polyglutamate types in relation to the total plasma MTXPG concentration at each time point were MTXPG3 (16.71–30.02%) and MTXPG5 (26.23–38.60%), while MTXPG7 was the least abundant MTXPG (3.22–5.02%). Conclusion: The presence of MTXPGs in plasma of patients with ALL could be related to the action of ABC efflux transporters on blood cells and hepatocytes resulting from the administration of high doses of methotrexate. This study may not draw definitive conclusions, but it does reduce uncertainty about the dynamics of methotrexate and its active metabolites, which may be of vital importance for achieving a clinical response.- Published
- 2021
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9. Oral gavage of nano-encapsulated conjugated acrylic acid-bile acid formulation in type 1 diabetes altered pharmacological profile of bile acids, and improved glycaemia and suppressed inflammation
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Mooranian, Armin, Zamani, Nassim, Ionescu, Corina M., Takechi, Ryu, Luna, Giuseppe, Mikov, Momir, Goločorbin-Kon, Svetlana, Kovačević, Božica, and Al-Salami, Hani
- Abstract
Background: Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid, metabolised in the gut, by microbiota. UDCA is currently prescribed for primary biliary cirrhosis, and of recently has shown β-cell protective effects, which suggests potential antidiabetic effects. Thus, this study aimed to design targeted-delivery microcapsules for oral uptake of UDCA and test its effects in type 1 diabetes (T1D). Methods: UDCA microcapsules were produced using alginate-NM30 matrix. Three equal groups of mice (6–7 mice per group) were gavaged daily UDCA powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced by alloxan injection and treatments continued until mice had to be euthanised due to weight loss > 10% or severe symptoms develop. Plasma, tissues, and faeces were collected and analysed for bile acids’ concentrations. Results: UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. Conclusion: The findings suggest that UDCA exerted direct protective effects on pancreatic β-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues. Graphic abstract: Three equal groups of mice were gavaged daily UDCA (ursodeoxycholic acid) powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced and treatments continued until mice had to be euthanised. UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. The findings suggest that UDCA exerted direct protective effects on pancreatic β-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues.
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- 2020
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10. DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment
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Mikov, Momir, Pavlović, Nebojša, Stanimirov, Bojan, Đanić, Maja, Goločorbin-Kon, Svetlana, Stankov, Karmen, and Al-Salami, Hani
- Abstract
The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.
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- 2020
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11. Modulatory Nano/Micro Effects of Diabetes Development on Pharmacology of Primary and Secondary Bile Acids Concentrations
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Mooranian, Armin, Zamani, Nassim, Takechi, Ryu, Luna, Giuseppe, Mikov, Momir, Goločorbin-Kon, Svetlana, Kovacevic, Bozica, Arfuso, Frank, and Al-Salami, Hani
- Abstract
Background: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut. Introduction: This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). Methods: T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly divided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces samples were collected for bile acid measurements. Results: Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice. Conclusion: Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D.
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- 2020
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12. In silicoDiscovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders
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Pavlović, Nebojša, Đanić, Maja, Stanimirov, Bojan, Goločorbin-Kon, Svetlana, Stankov, Karmen, Lalić-Popović, Mladena, and Mikov, Momir
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Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.
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- 2019
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13. Imported malaria in Bulgaria, status and prognosis after eradication in 1965.
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Rainova, Iskra G., Harizanov, Rumen N., Kaftandjiev, Iskren T., Mikov, Ognyan D., and Tsvetkova, Nina D.
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Background This retrospective analysis assessed all recorded malaria cases in Bulgaria after 1965, when the country was certified as malaria-free by the World Health Organization (WHO), and evaluated the readiness of the public health system to interrupt an outbreak of local transmission in case of infection importation. Methods The cases were analyzed according to causative species; geographic origin of the imported case; and the citizenship, age, and gender of the infected individuals. Results In the 50-year study period (1966–2015), there were a total of 3011 cases of malaria imported to Bulgaria from different regions of the world. The majority of the cases originating in Africa were caused by Plasmodium falciparum (65.5%), while most of these originating in Asia were caused by P. vivax (80.9%). The potential season for malaria transmission in Bulgaria is from April to October, and 58.5% of the malaria cases were imported during that time of the year. Conclusions The increasing movement of people to and from areas endemic for malaria requires the health authorities of countries with appropriate conditions for reintroduction to conduct enhanced measures for surveillance and control of this potentially deadly disease. [ABSTRACT FROM AUTHOR]
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- 2018
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14. Cross-linked guar gum and sodium borate based microspheres as colon-targeted anticancer drug delivery systems for 5-fluorouracil.
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Kamal, Tehsin, Sarfraz, Muhammad, Arafat, Mosab, Mikov, Momir, and Nisar-ur-Rahman
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The aim was to prepare cross linked polymer of 5-fluorouracil loaded microspheres containing guar gum and sodium borate for colon-targeted drug delivery systems. Micro spheres were prepared using emulsification cross linking method. The influence of drug polymer ratio, cross linker agent concentrations and cross linking timing on in vitro drug release and characteristics in terms of drug loading, entrapment efficiency and yielding percentage were investigated. The optimum drug loading, entrapment efficiency and percent yield were obtained from formulations with the lowest content of cross linker agent over 2 h of cross linking timing but with the highest drug to polymer ratio 1:11. The optimum in vitro drug release was obvious upon decreasing drug to polymer ratio up to 1:09, resulting in 81.5% drug release over 24 h. In conclusion, micro spheres composed of gaur gum and sodium borate can delay and control the release of 5-fluorouracil over 24 h. Thus, further in vivo studies are suggested for final assessment. [ABSTRACT FROM AUTHOR]
- Published
- 2017
15. Twenty‐four–hour normothermic perfusion of discarded human kidneys with urine recirculation
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Weissenbacher, Annemarie, Lo Faro, Letizia, Boubriak, Olga, Soares, Maria F., Roberts, Ian S., Hunter, James P., Voyce, Daniel, Mikov, Nikolay, Cook, Andrew, Ploeg, Rutger J., Coussios, Constantin C., and Friend, Peter J.
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Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer’s lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P= .44). Biomarkers, neutrophil gelatinase–associated lipocalin, and kidney injury molecule‐1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P< .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis. Normothermic machine perfusion of human kidneys for 24 hours is feasible, and urine recirculation facilitates maintenance of perfusate volume and homeostasis.
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- 2019
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16. Twenty-four–hour normothermic perfusion of discarded human kidneys with urine recirculation
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Weissenbacher, Annemarie, Lo Faro, Letizia, Boubriak, Olga, Soares, Maria F., Roberts, Ian S., Hunter, James P., Voyce, Daniel, Mikov, Nikolay, Cook, Andrew, Ploeg, Rutger J., Coussios, Constantin C., and Friend, Peter J.
- Abstract
Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer’s lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P= .44). Biomarkers, neutrophil gelatinase–associated lipocalin, and kidney injury molecule-1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P< .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis.
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- 2019
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17. The Effect of Diabetes and Hypertension on the Placental Permeation of the Hydrophilic Drug, Ranitidine.
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Lalic-Popovic, Mladena, Paunkovic, Jovana, Grujic, Zorica, Golocorbin-Kon, Svetlana, Vasovic, Velibor, Al-Salami, Hani, and Mikov, Momir
- Subjects
GESTATIONAL diabetes ,HYPERTENSION in pregnancy ,MATERNAL-fetal exchange ,PLACENTA ,RANITIDINE ,H2 receptor antagonists - Abstract
Introduction: Ranitidine is a hydrophilic weak base and an H2-receptor antagonist which is commonly used for gastroesophageal reflux, including during pregnancy. It has limited placental permeation and can be used as a pre-anesthetic antacid to prevent aspiration of acidic stomach contents. Recent studies suggest that diabetes and hypertension may influence placental permeation of hydrophilic drugs. Thus, this study aimed to investigate the influence of diabetes and hypertension on ranitidine's placental permeation in pregnant women.Methods: Forty one pregnant women all scheduled for elective cesarean section entered the study: healthy control (n = 15), with hypertension (n = 16) and with gestational diabetes (n = 10). All women received 50 mg of ranitidine intravenously. Three samples of maternal plasma (after ranitidine application, at delivery and after delivery), and two umbilical cord samples (arterial and venous blood) were collected and analyzed for ranitidine concentrations. Maternal pharmacokinetic parameter were calculated as well as feto:maternal and umbilical cord arterial to venous concentration ratios.Results: Ranitidine maternal and umbilical cord (arterial and venous) concentrations were similar in all three groups and there were no difference between feto:maternal ratios nor volume of distribution, clearance and half life between the groups.Discussion: Fetal concentrations are dependent on maternal concentrations in healthy and hypertensive women but not in diabetic women. Hypertension and diabetes did not affect fetal handling of ranitidine. Though hypertension and diabetes did not influence ranitidine placental permeation, it appears they altered time needed to achieve unity between maternal and fetal plasma. [ABSTRACT FROM AUTHOR]- Published
- 2016
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18. Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study
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Dragojević-Simić, Viktorija, Kovačević, Aleksandra, Jaćević, Vesna, Rančić, Nemanja, Djordjević, Snežana, Kilibarda, Vesna, Mikov, Momir, and Bokonjić, Dubravko
- Abstract
ABSTRACTBackground: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations.Research design and methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC0-72h, AUC0-∝, Cmax, Tmax, T1/2and Kel.Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC0-72h.Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, the 90% CI for this parameter for itraconazole was 93.49–133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15–138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events.Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.
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- 2018
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19. Evaluation of gender-based limited sampling methods for tacrolimus exposure after renal transplantation using the Monte Carlo simulation
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Catić-Đorđević, A., Pavlović, I., Pavlović, D., Stefanović, N., Mikov, M., Cvetković, T., and Veličković-Radovanović, R.
- Abstract
Numerous adverse and toxic effects of tacrolimus (Tac) are linked with a marked variability in its pharmacokinetics. New focus in this area is finding optimal measuring concentration points of Tac in order to predict area under the concentration-time curve (AUC). Currently, there is no consensus on the optimal strategies for the best AUC predictable concentrations. Potential introduction of the Monte Carlo (MC) method in clinical investigations is very important in the assessment of the most expecting numerical results for vulnerable transplant patients according to the derived analytical models. The study aimed to evaluate the best predictable concentration of Tac in order to predict body drug exposure after renal transplantation performing MC simulation with respect to gender. First part was presented as experimental measurements of Tac as well developed mathematical models for correlation of AUC and Tac concentrations. The second part was application of MC method in order to calculate AUC and compare new obtained results with previous data. For optimal determination of the AUC in female population: according to regression model the samples should be taken after two and twelve hours, while MC simulation suggested that sampling should be done after one and eight hours. In male population, eight hours after administration was the best sampling time according to both, regression and MC. The findings of MC simulation emphasized the gender differences in Tac pharmacokinetics and gender-based clinical approach. Monte Carlo simulation approach suggested two sampling points in female patients, one and eight hours, and one sampling point in male patients, eight hours after oral administration, for prediction of Tac exposure in renal transplant recipients.
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- 2018
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20. Potential Applications of Gliclazide in Treating Type 1 Diabetes Mellitus: Formulation with Bile Acids and Probiotics
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Mikov, Momir, Đanić, Maja, Pavlović, Nebojša, Stanimirov, Bojan, Goločorbin-Kon, Svetlana, Stankov, Karmen, and Al-Salami, Hani
- Abstract
A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM.
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- 2018
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21. Pharmacokinetic Profiling of Some Carbohydrate Derivatives and Their Structure Activity Relationship Evaluation
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Trifunovic, Jovana, Borcic, Vladan, Vukmirovic, Sasa, and Mikov, Momir
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Background: Carbohydrates are of great interest for the synthesis of novel ribonucleosides and C-Nucleosides which often show different pharmacological potential including antiinflammatory and antineoplastic characteristics. Introduction: In this research twelve aldopentose derivatives were examined and their chromatographic properties were used to describe their pharmacokinetic profiles. Methods: Thin layer chromatography was performed using three mobile phases: acetone–water (φ = 0.5–0.7 v/v), dioxane–water (φ = 0.5–0.7 v/v) and methanol–water (φ = 0.5–0.7 v/v). Multiple linear regression was performed to examine correlation between lipophilicity and pharmacokinetic descriptors of the examined molecules. Results: Good oral absorption can be expected for all investigated compounds. Moderate volume of distribution indicates low to moderate probability of their accumulation in body tissues. All investigated molecules show good pharmacokinetic characteristics but compounds 2, 3, 5, 6 and 7 demonstrated the best biological potential and biochemical activity such as inhibition of protease and kinase (compound 7) and possibility to be a ligand for GPCR. Conclusion: Among the best candidates authors would emphasize structure 7 as the most promising molecule regarding its pharmacological potential.
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- 2018
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22. High-Loading Dose of Microencapsulated Gliclazide Formulation Exerted a Hypoglycaemic Effect on Type 1 Diabetic Rats and Incorporation of a Primary Deconjugated Bile Acid, Diminished the Hypoglycaemic Antidiabetic Effect
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Golocorbin-Kon, Svetlana, Calasan, Jelena, Milijasevic, Boris, Vukmirovic, Sasa, Lalic-Popovic, Mladena, Mikov, Momir, and Al-Salami, Hani
- Abstract
Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.
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- 2017
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23. The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes
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Mikov, Momir, Đanić, Maja, Pavlović, Nebojša, Stanimirov, Bojan, Goločorbin-Kon, Svetlana, Stankov, Karmen, and Al-Salami, Hani
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Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug–drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects. However, the testing of the role of metabolites in CYP inhibition is still not routinely performed during the process of drug development, although the evaluation of time-dependent CYP inhibition during the clinical candidate selection process may provide information on possible effects of metabolites in CYP inhibition. Due to large number of compounds to be tested in the early stages of drug discovery, the experimental approaches for assessment of CYP-mediated metabolic profiles are particularly resource demanding. Consequently, a large number of in silico or computational tools have been developed as useful complement to experimental approaches. In summary, circulating metabolites may be recognized as significant CYP inhibitors. Current data may suggest the need for an optimized effort to characterize the inhibitory potential of parent drugs metabolites on CYP, as well as the necessity to develop the advanced in vitro models that would allow a better quantitative predictive value of in vivo studies.
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- 2017
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24. EP04.02-006 Burn-Out Syndrome: Neglected Syndrome Among Health Care Professionals Managing Lung Cancer Patients
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Kovacevic, T., Zaric, B., Bokan, D., and Mikov, I.
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- 2022
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25. Docking-based preliminary study on the interactions of bile acids with drugs at the transporter level in intestinal bacteria.
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DJANIC, M., PAVLOVIC, N., STANIMIROV, B., STOJANCEVIC, T., GOLOCORBIN-KON, S., BOJIC, G., and MIKOV, M.
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OBJECTIVE: The aim of this study was to estimate the binding-affinities of different bile acids towards drug transporters in Lactobacillus acidophilus and Bifidobacterium longum in order to predict the influence of bile acids and probiotics interactions on drug pharmacokinetics. MATERIALS AND METHODS: In order to study interactions of bile acids with transporters of intestinal bacteria, molecular-docking step was performed, using SwissDock web-service. For the purpose of comparison, two natural bile acids, cholic acid (CA) and deoxycholic acid (DCA), and one semi-synthetic bile acid, 12- monoketocholic acid (MKC), were studied in parallel. The free-binding energy was used as the main criterion for ranking ligands. RESULTS: Studied bile acids exhibited different binding affinities towards bacterial transporters with MKC showing the most prominent effect. For the majority of studied transporters, the estimated affinities of bile acids decreased in the following order: MKC–CA–DCA. Namely, 38.7% of examined transport proteins gave the lowest free-binding energy with MKC. The weak inverse relationship between numbers of hydrogen bonds and estimated free-binding energies was revealed. CONCLUSIONS: The predominant effect of MKC for the majority of studied transport proteins suggests that keto group at carbon 12 of the steroid core has a significant influence on the properties of MKC and consequently, on interactions with membrane transporters. Present findings might have a role in the prediction of potential influence of bile acids and probiotics on drug pharmacokinetics. [ABSTRACT FROM AUTHOR]
- Published
- 2016
26. Mixed Micelles Loaded with Bile Salt: An Approach to Enhance Intestinal Transport of the BCS Class III Drug Cefotaxime in Rats
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Arafat, Mosab, Kirchhoefer, Cathrin, and Mikov, Momir
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Cefotaxime is a class III drug according to the Biopharmaceutical Classification System due to low intestinal permeability based on poor oral bioavailability. Bile salt compounds have been shown to be effective additive for drug permeation through several biological membranes. The main purpose of this study was to investigate the ability of a mixed micelles made of phosphatidylcholine, sodium deoxycholate, and loaded with a cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex to enhance the oral bioavailability of cefotaxime in rats. Thin-film hydration method was used to prepare cefotaxime-loaded mixed micelles using different bile salt concentrations (0.87–25 mM of sodium deoxycholate). Overall, micelle sizes ranging from 86.9 to 155.6 nm were produced with negative zeta potential values from −15.9 to −19.5 mV and drug loading from 10.5 to 18.9 %. The oral bioavailability of cefotaxime in mixed micellar formulation was assessed and the pharmacokinetic parameters were compared with cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex and cefotaxime aqueous solution. 24 Male Wistar rats were randomly allocated into four groups (n= 6, per group) to receive the following: (1) a single intravenous dose of cefotaxime (25 mg/kg) in sterilized normal saline solution for injection; (2) a single oral dose of mixed micelles (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (3) a single oral dose of cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (4) a single oral dose of free cefotaxime (100 mg/kg) in aqueous solution administered by oral gavage. Blood samples were collected for up to 24 h and cefotaxime analyzed using a validated HPLC assay. Pharmacokinetic data showed that the oral bioavailability of cefotaxime in mixed micelles was found to be 4.91 % higher compared to the cefotaxime in aqueous solution (1.30 %). Maximum concentration (Cmax) of cefotaxime in mixed micellar formulation was higher (1.08 ± 0.1 µg/ml) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (0.69 ± 0.1 µg/ml) and cefotaxime in aqueous solution (0.52 ± 0.1 µg/ml). Similarly, the mean values for area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) of cefotaxime in the mixed micellar formulation was higher (3.89 ± 0.9 μg·h/mL) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (1.52 ± 0.2 μg·h/mL) and cefotaxime in aqueous solution (1.03 ± 0.4 μg·h/mL), respectively. The mixed micellar formulation was able to increase the oral bioavailability of the BCS Class III drug cefotaxime up to fourfold by enhancing drug permeation through the mucosal membrane of the small intestine.
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- 2017
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27. Bile Acids as Novel Pharmacological Agents: The Interplay Between Gene Polymorphisms, Epigenetic Factors and Drug Response
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Pavlovic, Nebojsa, Stanimirov, Bojan, and Mikov, Momir
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Background: The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging. Methods: The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome. Results: Most effects of bile acids are mediated by both nuclear and G protein-coupled receptors. Three natural bile acids have already been registered for the use in humans, but various semi-synthetic bile acid analogues with improved pharmacokinetic and pharmacodynamic properties have been developed, which opens up new avenues in pharmacotherapy. Many efforts have been made to evaluate the impact of nuclear receptors on inter-individual variation in responses to drugs, since nuclear receptors are significant mediators between environmental stimuli and pharmacokinetics. Genetic variation of bile acid-activated receptors is associated with both benign and malignant diseases, in terms of disease risk and severity, but also with pharmacokinetics and therapy outcome. Furthermore, the activity of these receptors may be masked or amplified by epigenetic modifications. Conclusion: Both genetic and epigenetic factors may alter complex and intricate network of bile acid signaling pathways, contributing to the development of several metabolic and non-metabolic diseases and altered activities of drug-metabolizing enzymes and transporters. These polymorphisms and epigenetic modifications may also impact the effectiveness and pharmacokinetics of bile acid analogues, which must be taken into account during the development of these compounds as novel therapeutic agents.
- Published
- 2017
28. Epidemiological and clinical characteristics of imported malaria in Bulgaria: A retrospective study of а 21-year period.
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Kaftandjiev, Iskren, Harizanov, Rumen, Rainova, Iskra, Mikov, Ognyan, Tsvetkova, Nina, Borisova, Raina, and Kaneva, Eleonora
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Bulgaria, with a high endemicity for malaria in the past, was declared by the WHO as a malaria-free country in 1965. We intended to analyze the epidemiological and clinical implications of imported malaria cases in Bulgaria. This is a retrospective cross-sectional analysis of all recorded cases of imported malaria in Bulgaria over a 21-year period (2000–2020). Patients' clinical records and information gathered from the epidemiological survey of each recorded malaria case were reviewed. A total of 232 cases of imported malaria were reported, 147 (63.4%) were Bulgarian citizens (BC) and 85 (36.6%) were foreign nationals (FN). Two thirds (66.4%) of cases were diagnosed from April to October. Most BCs had travelled for work (66.6%) to Africa (93.9%) and were infected with P. falciparum (83.3%), while most FNs were migrants (54.7%), exposed in Asia (63.5%) with P. vivax infection (62.4%). Clinical complications and a fatal outcome were noted in 14.7% (n = 34) and 3.5% (n = 8) of cases respectively. All complicated cases were in BNs with P. falciparum infection. Bulgaria experiences a steady import of malaria. Efforts to improve diagnosis, management and prevention of malaria, as well as maintenance of a high degree of epidemiological vigilance are needed. • Efforts are being made in Europe to prevent reestablishment of malaria transmission. • For the period 2000–2020 in Bulgaria were imported 232 cases of malaria. • During the potential malaria season were recorded 66.37% of all cases. • Тhere is a risk of locally acquired cases due to imports. [ABSTRACT FROM AUTHOR]
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- 2022
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29. Analgesic effects of rosemary essential oil and its interactions with codeine and paracetamol in mice.
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RASKOVIC, A., MILANOVIC, I., PAVLOVIC, N., MILIJASEVIC, B., UBAVIC, M., and MIKOV, M.
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OBJECTIVE: The use of herbal medicinal products in the management of pain has been increasing steadily in recent years, often in combination with conventional analgesics, which can induce significant interactions. In traditional medicine, rosemary was used as mild analgesic, for relieving renal colic pain and dysmenorrhea. The aim of our study was to examine analgesic effects of rosemary essential oil and its pharmacodynamic interactions with codeine and paracetamol in mice. MATERIALS AND METHODS: The identification and quantification of chemical constituents of the essential oil isolated from air-dried aerial parts of rosemary were carried out by GC/FID and GC/MS. The hot plate test was performed on NMRI mice by placing them individually on hot plate and assessing their response to the thermal stimulus. RESULTS: In this research, we identified 29 chemical compounds of the studied rosemary essential oil, and the main constituents were 1,8-cineole, camphor, and α-pinene. Administration of investigated essential oil increased significantly the latency time of animal response to heat-induced pain between 20
th and 50th minute of the test, when compared to saline-treated group. Rosemary essential oil in the dose of 20 mg/kg was shown to be more efficient than in the dose of 10 mg/kg, in combinations with both codeine and paracetamol. CONCLUSIONS: Our findings support the use of rosemary in the management of pain and indicate a therapeutic potential of rosemary essential oil in combination with analgesic drugs. The mechanisms involved in analgesic effects of rosemary essential oil and the potential influence on cytochromes and drug metabolism should be more in-depth investigated. [ABSTRACT FROM AUTHOR]- Published
- 2015
30. Effect of Simultaneous Exposure to Benzene and Ethanol on Urinary Thioether Excretion
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Mikov, Ivan, Stankov, Karmen, Vasovic, Velibor, Mikov, Aleksandra, Golocorbin-Kon, Svetlana, and Mikov, Momir
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AbstractThe toxicity of benzene is not an issue of the past, especially in developing countries. Bone marrow toxicity is demonstrated among workers. In this study, the effect of simultaneous exposure to benzene and ethanol on benzene metabolism in mice was investigated by measuring the excretion of thioethers in urine. Urinary thioether excretion significantly decreased in the mice receiving both benzene and ethanol compared with the animals receiving benzene only. The assay of determining thioethers in urine samples in this study is a simple and low-cost method, thus suitable for routine use, especially in developing countries, not only for benzene, but also for other alkilating agents, which can be found during occupational exposure. Our results suggest that further research is needed to elucidate the mechanisms of decreased urinary excretion of thioether after simultaneous exposure to benzene and ethanol.
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- 2012
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31. Influence of bile acid derivates on tramadol analgesic effect in mice
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Vasovic, V., Vukmirovic, Sasa, Pjevic, M., Mikov, I., Mikov, M., and Jakovljevic, V.
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Abstract: Influence of two newly synthesized bile acids derivates, namely sodium salt of monoketocholic acid MKH-Na and methyl ester of monoketocholic acid MKH-Me on tramadol (12.5 mg/kg oral and intramuscular) analgesic effect was examined in this research. Analgesic effect was measured by antinociceptive hot plate method. Interaction was estimated by detection of changes in analgesic effect of tramadol combined with bile acids (subcutaneous administration of 4 mg/kg 20 min before tramadol) compared to analgesic effect of the same dose of tramadol given alone. Hydrosoluble sodium salt of monoketocholic acid did not show interaction with tramadol, regardless of the route of administration of tramadol. However, methyl ester of monoketocholic acid increased the analgesic effect of tramadol when it was given intramuscularly. After oral administration of tramadol, methyl ester of monoketocholic acid decreased the analgesic effect of tramadol. According to the time point when interaction reached statistically significant difference, it can be presumed that after intramuscular administration of tramadol, methyl ester of monoketocholic acid increases tramadol absorption and transport to brain and in that way increases its analgesic effect. The analgesic effect of tramadol after oral administration was decreased, which could be explained by the induction of tramadol metabolism in the liver, but should be examined in more details.
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- 2010
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32. Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats
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Al-Salami, Hani, Butt, Grant, Tucker, Ian, Fawcett, Paul J, Golo-Corbin-Kon, Svetlana, Mikov, Ivan, and Mikov, Momir
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The aim is to investigate the influence of the antidiabetic drug gliclazide on the ileal permeation of the semisynthetic bile acid, MKC, in tissues from healthy and diabetic rats. Sixteen Wistar rats (350±50 g) were randomly allocated into four groups (4 rats per group, 8 chambers per rat i.e. n=32) two of which were made diabetic (given alloxan i.v.30 mg/kg). Group 1 was used to measure the permeation of MKC (50 μg/ml) alone (control) while group 2 to measure MKC permeation in the presence of gliclazide (200μg/ml). The diabetic groups 3 (gliclazide) and 4 (MKC+gliclazide) were treated in the same way. Rats were sacrificed and tissues were mounted into the Ussing chamber for the measurement of MKC mucosal to serosal (absorptive) and serosal to mucosal (secretory) fluxes. In healthy tissues, gliclazide reduced MKC absorptive flux (p<0.01) and increased its secretory flux (p<0.01). In diabetic tissues, gliclazide had no effect on either the absorptive or the secretory fluxes of MKC. The lack of effect of gliclazide on MKC permeation in diabetic tissues suggests the absence or suppressed drug transporters. Furthermore, gliclazide inhibition of MKC absorptive flux and induction of MKC secretory flux in healthy tissues may result from the selective inhibition of an efflux drug transporter.
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- 2009
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33. Cefotaxime pharmacokinetics after oral application in the form of 3α,7α-dihydroxy-12-keto-5β-cholanate microvesicles in rat
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Golocorbin-Kon, Svetlana, Mikov, Momir, Arafat, Mousab, Lepojevic, Zika, Mikov, Ivan, Sahman-Zaimovic, Majda, and Tomic, Zdenko
- Abstract
The aim of ths study was to investigate the pharmacokinetics of cefotaxime sodium (CEF) pharmacokinetics after oral application in the form of sodium 3α,7α-dihydroxy-12-keto-5β-cholanate (MKC) microvesicles (MV) in rat. Thirty Male Wister rats were divided into six groups (n=5 per group). Groups were treated orally with: i. CEF (15 mg/kg) saline solution (15 mg/kg); ii. CEF (15 mg/kg) saline solution with MKC (2 mg/kg); iii. CEF saline solution mixed with blank microvesicles; iv. CEF (15 mg/kg) encapsulated in microvesicles with saline solution; v. CEF saline solution (15 mg/kg) mixed with blank MKC microvesicules; vi. CEF (15 mg/kg) encapsulated in MKC microvesicules with saline solution. Data were analyzed using noncompartmental model. CEF oral bioavailability was increased twofold when coadministered with MKC and when encapsulated in microvesicles and ninefold when encap-sulated in MKC microvesicles compared to the same CEF dose administered orally as saline solution. The increased bioavailability of CEF resulting from CEF encapsulation in microvesicules with MKC suggests that this formulation can extend the application of CEF from parenteral only to oral application.
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- 2009
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34. Introgression of common wheat lines with genetic material of Agropyron glaucum
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Davoyan, R., Bebyakina, I., Davoyan, E., Zinchenco, A., Zubanova, Y., and Mikov, D.
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Grey wheatgrass Agropyron glaucum(Desf. ex DC) Roem. & Schult is a valuable source of genes for resistance to diseases, frost resistance, and salt tolerance. An unstable 76-chromosomal amphidiploid combining genomes A and B of common wheat variety Avrora, six chromosomes of genome D of the same variety, and a full set of Ag. glaucum(2n= 42) chromosomes was used as an intermediate to transfer the genetic material from the wild donor to this wheat variety. A large set of wheat introgression lines differing in a variety of morphological characters was developed. For effective employment of the developed lines in breeding, cytological and molecular-genetic analyses of the lines were conducted, and their pest resistance and grain technological properties were evaluated. We report the investigation of 25 common wheat introgression lines with genetic material from Ag. glaucum, not studied before. All lines except D43 formed 21 bivalents in MI meiosis. In lines D3, D21, and D23, the genetic material of Ag. glaucumwas present as a translocation segment. Lines D7, D43, and D49 carried substituted chromosomes and, presumably, translocations. One pair of wheat chromosomes was substituted in 18 lines. For the identification of translocations and substituted chromosomes, microsatellite analysis was done with markers specific to D genome chromosomes. The introgression touched all D genome chromosomes except 3D and 4D. The lines under the study differed in protein and gluten contents, gluten quality, and bread-making quality. The study of gliadin spectra revealed changes in the gliadin formula in 7 of the 12 lines with reference to the recipient Avrora variety. Thus, the results obtained point to the genetic diversity of the investigated introgression lines and their value for common wheat breeding.
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- 2016
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35. RealTrac technology at the EvAAL-2013 competition
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Moschevikin, Alex, Galov, Aleksandr, Volkov, Alexander, Mikov, Alexander, Reginya, Sergey, Voronov, Roman, Reut, Oleg, Serezhina, Maria, Zaitsev, Alexey, Lunkov, Pavel, Malodushev, Sergey, Kirienko, Dmitry, Fedorov, Alexander, Sementsov, Alexey, Podryadchikov, Sergey, Spiridonov, Konstantin, Tershukov, Ivan, Yushev, Artem, Nuikin, Alexander, Gostev, Kirill, Pashinsky, Sergey, and Soloviev, Alexei
- Abstract
In this paper, we examine the results of the EvAAL-2013 localization competition. We present a comprehensive description of RealTrac™ technology, the winner of this competition. Focused on real-time location technology, RealTrac hardware includes a server, access points (gateways and repeaters), and mobile devices (voice intercoms and tags). A location calculation engine is based on Bayesian algorithms fusing data from time-of-flight and received signal strength measurements, inertial measurement units, building structure, and optionally, from context events. The peculiarity of the embedded navigation system is that it works effectively independent of the place where the mobile tag is actually attached, i.e., it could be mounted on one’s foot, carried freely in a jacket pocket, held in one’s hand, or even hung on a shoestring. The RealTrac system can easily be combined with third-party systems via the Real Time Location System Communication Protocol that consists of an open API and uses a common Keyhole Markup Language format for geo-data presentation. Furthermore, in this paper, we show that the scores obtained in the competition regarding positioning accuracy might be significantly higher when the applied particle filter is appropriately configured and a probability-based approach for area-of-interest determination is introduced.
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- 2015
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36. Use of molecular markers in wheat breeding for resistance to leaf rust at the Lukyanenko Research Institute of Agriculture
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Davoyan, E., Bespalova, L., Davoyan, R., Zubanova, Yu., Mikov, D., Filobok, V., and Khudokormova, J.
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Wheat accessions were genotyped with molecular markers linked to wheat leaf rust resistance genes Lr9, Lr10, Lr19, Lr24, Lr26, Lr34, and Lr37. They included 1920 wheat plants and 46 commercial varieties bred at the Lukyanenko Institute. Basically, the analyzed varieties had the inefficient gene Lr10, poorly efficient Lr26and Lr34, or their combinations. The highly efficient genes Lr9and Lr24were not detected. The Lr19gene, effective in the Krasnodar region, was identified in varieties Pallada and Yara. The resistance gene Lr37was found in the Morozko variety. Within a short time, the F2and F3plants with the introgression of genes Lr9, Lr19, Lr24, and Lr37were obtained. Accessions with combinations Lr24+Lr37, Lr24+ Lr19, Lr24+ Lr9, Lr19+ Lr37, Lr37+ Lr9, and Lr19+ Lr9were identified. Seven plants with the combination of three genes Lr37+ Lr19+ Lr9and one with Lr37+ Lr24+ Lr9were selected.
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- 2015
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37. Gender-dependent predictable pharmacokinetic method for tacrolimus exposure monitoring in kidney transplant patients
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Velickovic-Radovanovic, Radmila, Mikov, Momir, Catic-Djordjevic, Aleksandra, Stefanovic, Nikola, Mitic, Branka, Paunovic, Goran, and Cvetkovic, Tatjana
- Abstract
Tacrolimus (Tac) is an immunosuppressive drug with a narrow therapeutic width and highly variable pharmacokinetics. Therefore, monitoring of Tac blood concentrations is of utmost importance in the management of renal transplant recipients. The occurrence and intensity of adverse effects depend on blood concentration and total exposure of the organism to this drug. This implies finding a new gender-dependent predictable method for Tac exposure monitoring based on determination of the area under the time concentration curve (AUC). The primary aim of this study was to investigate gender differences in systemic body exposure to Tac in renal transplant patients after the first oral dose and in a steady state by determining 12-h AUC (AUC0–12). The secondary objective was to find the best sampling time in which measured Tac concentration best predicts AUC value with respect to gender. Tac pharmacokinetic study was conducted in 20 kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first oral Tac dose (0.05 mg/kg) was given on the fifth day post-transplant. After reaching steady state, regimen stabilized and dosage was adjusted in accordance with the level of Tac. Blood concentrations were measured by microparticle enzyme immunoassay method. AUC0–12for each patient was calculated after the first oral Tac dose and in the steady state from a plot of Tac concentration versus time from 0 to 12 h using the trapezoid rule. Associations between each sampling time point of concentrations within 12 h after the administration and AUC0–12were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. Statistically significant difference was found in AUC0–12between male and female patients after the first oral dose (p< 0.01), but this difference was lost in a steady state. In female recipients C2seemed to be good indicator of total body exposure to Tac after the first oral dose and this was also confirmed in a steady state. The three-point sampling method was required for calculating AUC after the first oral dose in male patients, whereas in the steady state, concentration of C8seemed to be a good indicator of abbreviated AUC for a Tac monitoring strategy in male patients. Non-compartment Tac pharmacokinetic and regression analysis showed gender difference in total Tac exposure and determined the best predictable Tac concentrations after the first oral dose. Our study confirmed gender-dependent pharmacokinetics in a steady state in terms of best sampling time in which measured Tac concentration best predicts AUC value.
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- 2015
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38. Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases
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Stanimirov, Bojan, Stankov, Karmen, and Mikov, Momir
- Abstract
The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases.
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- 2015
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39. The influence of comedication on tacrolimus blood concentration in patients subjected to kidney transplantation: a retrospective study
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Vavic, Neven, Rancic, Nemanja, Dragojevic-Simic, Viktorija, Draskovic-Pavlovic, Biljana, Bokonjic, Dubravko, Ignjatovic, Ljiljana, and Mikov, Momir
- Abstract
Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers, diuretics and proton pump inhibitors (PPIs) significantly affected TTC (p< 0.001). PPIs significantly increased the number of examinations in which the TTC were in the recommended therapeutic range (from 5 to 15 ng/ml), as well as over the therapeutic range (p< 0.0001). When calcium channel blockers were added to PPIs, even more pronounced effect was obtained in comparison to triple-drug therapy only (p< 0.0001). In case a diuretic was given with a PPI, a significantly increased number of examinations with subtherapeutic TTC was observed when compared with PPI only (p= 0.0203). The combination of calcium channel blockers, diuretics and PPIs resulted in the number of examinations with TTC in the recommended therapeutic range not being different from the number of examinations with TTC in the triple-drug therapy only (p= 0.3829). β-adrenergic antagonists can be administered without fear of affecting the tacrolimus optimal therapeutic concentrations. This was confirmed with all combinations of the examined drugs used in patients subjected to kidney transplantation concomitantly with β blockers.
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- 2014
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40. Tacrolimus as a Part of Immunosuppressive Treatment in Kidney Transplantation Patients: Sex Differences.
- Author
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Velickovic-Radovanovic, Radmila, Mikov, Momir, Catic-Djordjevic, Aleksandra, Stefanovic, Nikola, Stojanovic, Mariola, Jokanovic, Milan, and Cvetkovic, Tatjana
- Abstract
Abstract: Background: Metabolism interaction between corticosteroids and tacrolimus (Tac) exists and can be an important factor in providing rational pharmacotherapy in kidney transplantation patients. Both Tac and corticosteroids can induce adverse metabolic effects, such as hyperglycemia, post-transplantation diabetes mellitus, and dyslipidemia. Objective: The main goal of this study was to detect corticosteroid dose influence on Tac level within the first 6 months of immunosuppressive therapy. The secondary goal of this research was to investigate sex differences on Tac−corticosteroid interaction. We also monitored biochemical-parameter changes, which are related to immunosuppressive treatment. Methods: This retrospective pharmacokinetic study included 30 Serbian patients after kidney transplantation. Patients received a quaternary immunosuppressive regimen including Tac, mycophenolate, mofetil, basiliximab, and corticosteroids. To compare dose-normalized level and dose of Tac in different days after transplantation, we performed the Friedman test and Wilcoxon matched-pairs signed rank sum test. Mann-Whitney test was performed to compare differences in dose of Tac, level of Tac, and dose-normalized level of Tac between male and female patient groups. We used the Friedman test to compare biological and clinical data. Results: Obtained results show statistical significance between dose of Tac on day 180 post transplantation and dose on days 7, 14, 21, and 60 post transplantation. There was a statistical difference in dose-normalized level of Tac between days 7 and 21 post transplantation (P < 0.01), days 7 and 60 (P < 0.01), and between days 7 and 180 (P < 0.05). There is a statistical significance between male and female levels of Tac on day 21 after transplantation (P < 0.01). Significance also exists on day 60 after transplantation between male and female dose-normalized levels (P < 0.05). There is also a statistical difference in glucose, cholesterol, triglyceride, serum creatinine, and urea level and activity of alanine aminotransferase and alkaline phosphatase before and after operation. Conclusion: Our study shows that dose of corticosteroid affects Tac level in kidney transplantation patients. Tac dose and level changes showed that corticosteroid−Tac interaction has more influence on male than female patients. According to biochemical monitoring, the immunosuppressive therapy used at present is quite well tolerated. [Copyright &y& Elsevier]
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- 2012
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41. Cancer Incidence in a Population Living Near a Petrochemical Facility and Oil Refinery.
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Bulat, Petar, Ivić, Milka L. Avramov, Jovanović, Mića B., Petrović, Slobodan D., Miljuš, Dragan, Todorović, Tanja, Miladinov-Mikov, Marica M., and Bogdanović, Milka
- Subjects
CANCER risk factors ,DISEASE incidence ,PETROLEUM chemicals industry ,PETROLEUM refineries ,AIR pollution ,ENVIRONMENTAL exposure ,BENZENE ,POPULATION - Abstract
Copyright of Collegium Antropologicum is the property of Croatian Anthropological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2011
42. Gender Differences in Pharmacokinetics of Tacrolimus and Their Clinical Significance in Kidney Transplant Recipients.
- Author
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Velicković-Radovanović, Radmila, Mikov, Momir, Paunović, Goran, Djordjević, Vidojko, Stojanović, Mariola, Cvetković, Tatjana, and Djordjević, Aleksandra Catić-
- Abstract
Abstract: Background: The possible influence of gender on tacrolimus disposition and response in kidney transplant recipients is an issue of medical importance. Objective: The aim of this study was to detect interpatient pharmacokinetic variability of tacrolimus due to patients'' gender and to assess the predictability of individual tacrolimus concentrations using abbreviated AUC measurements. The secondary objective was to find the best sampling time to predict the exposure of tacrolimus in kidney transplant recipients. Methods: Gender-related first oral dose tacrolimus pharmacokinetics studies were conducted in 20 Serbian kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first tacrolimus oral dose (0.05 mg/kg) was given on day 5 post-transplant. Blood concentrations were measured by microparticle enzyme immunoassay method. Associations between each sampling time point of concentrations and 12 hours after the administration AUC (AUC
0–12 ) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. Results: AUC0–12 showed remarkable interindividual variations after the first tacrolimus oral dose. There were significantly lower values of AUC in women than men (P < 0.05). The most important time point influencing AUC0–12 was the concentration of tacrolimus measured 2 hours after administration(C2 ) in women, whereas in men the most important time points were the concentrations at 1 (C1 ), 4 (C4 ), and 12 (C12 ) hours as an abbreviated AUC. Conclusion: Our results show significant differences between men and women. C2 seems to be indicator of total body exposure to tacrolimus in the early period after kidney transplant in women. The three-point sampling method seems to be a good indicator of abbreviated AUC for a tacrolimus monitoring strategy in men. [Copyright &y& Elsevier]- Published
- 2011
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43. CULTURAL AND HISTORICAL PROFILE OF CLOCK TOWERS IN THE BULGARIAN LANDS (17th-19th CENTURIES).
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MIKOV, Lyubomir
- Abstract
This article discusses the history of clock towers in Bulgaria between the 17th and 19th centuries when this building type became so popular and the sign of the Bulgarian economic and urban development. The author analyzes the cultural, religious and economic factors which underlie the architectural evolution of the Bulgarian clock towers of this period mostly its shift from a Turkish-Muslim model to a lay-Bulgarian style reflecting the decline of the Ottoman Empire and the strengthening of the non-Muslim population in Bulgaria. Accordingly, the shift from the use of clock towers for time management serving Islamic religious purposes together with minarets reminding prayers times to lay purposes to regulate business hours in the newly developing urban centers, is discussed.
- Published
- 2010
44. BULGARİSTAN'DA TÜRK HALK TASAVVUFU (DÖRT TÜRBE VE EVLİYALARINA İLİŞKİN MATERYALLERE GÖRE).
- Author
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Mikov, Lyubomir
- Subjects
TURKISH history ,OTTOMAN architecture ,BEKTASHI - Abstract
Copyright of Turkish Culture & Haci Bektas Veli Research Quarterly is the property of Turkish Cultur & Haci Bektas Veli Research Quarterly and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2009
45. Could Foreign Policy Failures Sink Macedonia's Government in Elections Next Month?
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Mikov, Paul
- Subjects
MACEDONIAN politics & government ,ELECTIONS & international relations ,MEMBERSHIP - Abstract
The article discusses the impact of foreign policy failures on Macedonia's Government in December 2016 elections. According to the ruling government, its foreign policy has been successful. It reflects on Macedonia's relations with its neighbors, its efforts to progress toward membership in North Atlantic Treaty Organization and the European Union and its international reputation.
- Published
- 2016
46. C-KIT Signaling in Cancer Treatment
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Stankov, Karmen, Popovic, Stevan, and Mikov, Momir
- Abstract
Tumor progression is strongly associated with the activity of receptor tyrosine kinases (RTKs) and their intracellular signal transduction pathways, which regulate several cell functions including proliferation, apoptosis, motility, adhesion and angiogenesis. Detailed structural and functional studies of RTKs, including the stem cell factor receptor c-KIT, revealed the complexity of these receptor systems and contributed to development of targeted clinical approaches with relevance in both prognosis and therapy. C-KIT signaling network has been the subject of intense research and pharmaceutical strategies to identify novel target-based approaches for cancer treatment. Evidence that c-KIT signaling promotes cell proliferation and survival, along with the frequency in which this pathway is aberrantly activated in cancer, support the current efforts to identify approaches for its efficient inhibition. C-KIT mutations are associatied with several human malignancies, such as gastrointestinal stromal tumors, acute myeloid leukemia, mast cell leukemia, and melanoma. Novel therapies are developed that target some of the identified genetic defects. It is therefore anticipated that newly-identified genetic markers will acquire a predictive value, that is, the ability to predict differential efficacy of a therapy. This review describes the evolving understanding of c-KIT/SCF axis and their downstream signaling in cancer, and the strategies for c-KIT-directed targeted cancer therapy.
- Published
- 2014
47. Application of bile acids in drug formulation and delivery
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Stojančević, Maja, Pavlović, Nebojša, Goločorbin-Kon, Svetlana, and Mikov, Momir
- Abstract
Bile acids are naturally produced in humans and are known to provide human health benefits through their endocrinological, microfloral, metabolic and other åffects that are still to be elucidated. In recent years, there has been a growing interest in using bile acids as absorption enhancers for drug delivery. Bile acids are amphiphilic molecules with a unique ability to facilitate and promote drug permeation through biological membranes. The role of bile acids in promoting drug permeation has been experimentally illustrated in various pharmaceutical formulations including oral, nasal, ocular, buccal, pulmonary and rectal delivery as well as through the blood–brain barrier. Recently, bile acids have drawn attention in the field of drug delivery due to their ability to act as a drug carrier system in the form of mixed micelles, bilosomes and chemical conjugates with drug molecules. Bile acids have demonstrated a unique ability to enhance the epithelial transport of hydrophilic drugs through the paracellular route and that of hydrophobic compounds through both paracellular and transcellular routes. The aim of this review is to discuss various chemical and pharmaceutical aspects of BAs and their potential applications in drug formulation and delivery.
- Published
- 2013
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48. Probiotics decreased the bioavailability of the bile acid analog, monoketocholic acid, when coadministered with gliclazide, in healthy but not diabetic rats
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Al-Salami, Hani, Butt, Grant, Tucker, Ian, Golocorbin-Kon, Svetlana, and Mikov, Momir
- Abstract
Abstract: In recent studies we showed that gliclazide has no hypoglycemic effect on type 1 diabetic (T1D) rats while MKC does, and their combination exerted a better hypoglycemic effect than MKC alone. We also showed that the most hypoglycemic effect was noticed when T1D rats were treated with probiotics then gavaged with MKC + gliclazide (blood glucose decreased from 24 ± 3 to 10 ± 2 mmol/l). The aim of this study is to investigate the influence of probiotics on MKC pharmacokinetics when coadministered with gliclazide, in T1D rats. 80 male Wistar rats (weight 350 ± 50 g) were randomly allocated into 8 groups (10 rats/group), 4 of which were injected with alloxan (30 mg/kg) to induce T1D. Group 1 was healthy and group 2 was diabetic. Groups 3 (healthy) and 4 (diabetic) were gavaged with probiotics (75 mg/kg) every 12 h for 3 days and 12 h later all groups received a single oral dose of MKC + gliclazide (4 and 20 mg/kg respectively). The remaining 4 groups were treated in the same way but administered MKC + gliclazide via the i.v. route. Blood samples collected from T1D rats prior to MKC + gliclazide revealed that probiotic treatment alone reduced blood glucose levels twofold. When coadministered with gliclazide, the bioavailability of MKC was reduced in healthy rats treated with probiotics but remained the same in diabetic pretreated rats. The decrease in MKC bioavailability, when administered with gliclazide, caused by probiotic treatment in healthy but not diabetic rats suggests that probiotic treatment induced MKC metabolism or impaired its absorption, only in healthy animals. The different MKC bioavailability in healthy and diabetic rats could be explained by different induction of presystemic elimination of MKC in the gut by probiotic treatment.
- Published
- 2012
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49. 850nm VCSEL with a liquid crystal overlay
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Nair, Veena M., Panajotov, Krassimir, Petrov, Mikov, Thienpont, Hugo, Xie, Yi, Beeckman, Jeroen, and Neyts, Kristiaan
- Abstract
We developed an in- house technology to overlay liquid crystal (LC) on top of a 850nm Vertical Cavity Surface Emitting Laser (VCSEL) creating a so-called LC-VCSEL. Prior to this, the effect of the cell thickness on the planar alignment of the E7 LC is investigated. It is observed that the LC orientation is planar, uniformly aligned over the whole cell with an average pre-tilt of 22.50in a thin a cell of 13m thickness; such alignment uniformity is not observed in a thick cell of 125m. Nevertheless, several domains of good uniformity are still present. Further, the polarization resolved LI characteristics of LC-VCSEL are investigated with and without the insertion of LC in a cell glued directly onto VCSEL package. Before filling in the LC, the VCSEL emits linearly polarized light and this linear polarization is lost after LC filling. The output intensity as a function of polarizer angle shows partial planar alignment of the E7 LC, which is very important for the further advancement of the LC-VCSEL integrated system.
- Published
- 2012
- Full Text
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50. An Insight on Differences in Availability and Reimbursement of Orphan Medicines Among Serbia, Bulgaria and Sweden
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Pavlović, Nebojša, Stanimirov, Bojan, Stojančević, Maja, Paut-Kusturica, Milica, Stoimenova, Assena, Goločorbin-Kon, Svetlana, and Mikov, Momir
- Abstract
ABSTRACTIn the European Union (EU), rare diseases are defined as life-threatening or chronically debilitating diseases with prevalence lower than five in 10,000 inhabitants. Although individually rare, together, rare diseases affect a significant part of the population (27–36 million people in the EU). Therefore, patient access to orphan medicines is receiving increasing political attention in the EU.In order to assess the differences in availability of reimbursed orphan medicines among Serbia, Bulgaria and Sweden, National Reimbursement Lists were reviewed and identified orphan medicines were crossed with the List of orphan drugs in Europe, published in July 2011, available from Orphanet. The analysis of regulatory traits was based mainly on a review of the official documents setting out legislation regarding rare diseases and orphan medicines in the studied countries.Only 6.5% (4 out of 61) of the authorised orphan medicines in Europe with prior orphan designation and 25.0% (17 out of 68) without prior orphan designation were available and reimbursed in Serbia. In the Bulgarian Positive Drug List 44.3% (27 out of 61) of the drugs with prior orphan designation and 50.0% (34 out of 68) without prior orphan designation were identified. The share of reimbursed orphan medicines was the highest in Sweden among the observed countries—52.5% (32 out of 61) of the medicines with orphan designation and 60.3% (41 out of 61) without prior orphan designation. According to the first level of the ATC Classification System, most of the reimbursed orphan medicines in the three studied countries belonged to the group L: “Antineoplastic and immunomodulating agents”, while the most common indications for authorised and reimbursed orphan medicines were “Neoplasms” (C00-D48), with 19 available orphan drugs in Serbia, 26 in Sweden and 31 in Bulgaria.Inequities in the access to orphan medicines among Serbia, Bulgaria and Sweden may be explained by the differences in the approaches for registration, pricing and reimbursement of orphan medicines. The low share of reimbursed orphan drugs in Serbia may be due to incomplete compliance with EU legislation and existence of domestic procedure for authorisation as well. The EU legislation and policy on treatment of rare diseases obviously facilitate the penetration of orphan drugs on the EU market, but apparently there is also considerable budget impact on the availability of reimbursed orphan medicines.
- Published
- 2012
- Full Text
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