Faculty of Pharmacy

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Start date: 2012End date: 2019

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    Development and validation of automated SPE‐LC‐MS/MS method for determination of indapamide in human whole blood and its application to real study samples
    (Wiley, 2013-06-24)
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    Mladenovska, K.
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    Labacevski, N.
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    Dimovski, A.
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    Petkovska, R.
    A fast and simple liquid chromatography–electrospray ionization tandem mass spectrometry method for determination of indapamide in human whole blood was developed and validated. The sample extraction of indapamide from human whole blood was achieved using automated solid-phase extraction. Chromatographic separation was performed on Kinetex C18 column (100 × 2.1 mm, 1.7 µm particle size) using acetonitrile and 2 mm ammonium formate in ratio 90:10 (v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode using positive electrospray ionization for indapamide and the internal standard (zolpidem tartarate). The total run time was 2.5 min. The present method was found to be linear in the concentration range of 1–50 ng/mL with the coefficient of determination 0.9987. The absolute recoveries of indapamide were 90.51–93.90%. The method was validated according the recommendations for validation of bioanalytical methods of European Medicines Agency guideline and was successfully used to analyze human whole blood samples for application in a pharmacokinetic study.
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    Design and biological response of doxycycline loaded chitosan microparticles for periodontal disease treatment
    (Elsevier BV, 2018-04-15)
    Gjoseva, Silvana
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    Sazdovska, Simona Dimchevska
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    Popeski-Dimovski, Riste
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    Petruševski, Gjorgji
    The aim of this study was to develop chitosan (CS) microparticulated mucoadhesive drug delivery system (DDS) with improved therapeutic performance and biological responce. Ionotropic gelation/spray drying process was used for preparation of doxycycline hyclate (DOXY) loaded low and medium molecular weight (LMw and MMw) CS/sodium tripolyphosphate microparticles (CS/TPP MPs), further coated with ethyl cellulose (EC) using coacervation/solvent displacement technique. The relevant physico-chemical and biopharmaceutical properties were optimized using experimental design approach. Both coated and uncoated CS/TPP MPs showed high mucoadhesive potential and did not affect the viability of the tested epithelial cell line. The MPs induced slow and gradual apoptotic response in murine macrophage cell line RAW 264.7 and the observed effect depended upon formulation type and MP concentration. Biological effect of the CS-based MPs observed in our experiments point to synergism of the biological response of the carrier with the anti-inflammatory effect of DOXY.
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    Rational development of nanomedicines for molecular targeting in periodontal disease
    (Elsevier BV, 2018-09)
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    Sazdovska, Simona Dimchevska
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    Gjosheva, Silvana
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    Recent advances in understanding the etiology and pathogenesis of periodontal disease and polymicrobial synergy in the dysbiotic oral microbial community endorsed novel therapeutic targets and assured further improvement in periodontal disease treatment. Moreover, understanding of the events at the molecular level inspired the researchers to alleviate the stress from the disease by applying the bottom-up approach and delivering the drugs at the site of action, using nanoscale medicines. This review is focused on promising strategies for rational design of nanopaharmaceuticals for periodontal disease treatment based on novel therapeutic targets and the potential of advanced concepts for inflammation cascade targeting. Due to their size, nanomedicines are capable to interact with the elements of the immune system through cell receptor binding and to subsequently influence specific intracellular signaling pathways activation. They might also interfere with different signaling molecules continuously involved in the disease progression, in order to abolish cell activation and block the production of proinflammatory substances. Different biomacromolecules can be trafficked to the site of action using nanomedicines for gene targeting: i) decoy oligodeoxynucleotide (ODN) for suppression of NF-κB transcription activity, ii) DNA therapeutics for modulation of cell inflammatory response and iii) siRNA for cytokine production silencing. However, despite the potential of the nanotechnology for improvement of periodontal disease treatment, the translation of nano-drug delivery systems to clinical therapy is hindered by the lack of standard procedures for proper safety and efficacy profile evaluation.
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    MDM2309 (rs2279744) polymorphisms and risk for HPV persistence and cervical intraepithelial lesions and cervical cancer development in Macedonian women
    (2018)
    SotirijaDuvlis, Drage Dabeski, Ljube Ivkovski, Marija Hiljadnikova-Bajro, Dijana Plaseska Karanfilska
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    Association of p53Pro72Arg (rs1042522) and MDM2309 (rs2279744) polymorphisms with risk for cervical intraepthelial lesions and cervical cancer development in Macedonian women
    (2016)
    Sotirija Duvlis
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    Marija Hiljadnikova-Bajro
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    Dijana Plaseska Karanfilska
    High risk Human Papillomavirus (HPV) is an important etiological factor in initiation of squamous intraepithelial lesions (SIL), but not enough for malignant progression to cervical cancer (CCa). Single nucleotide polymorphisms (SNPs): rs1042522 within the codon 72 of p53 and rs2279744 within MDM2 promoter gene are plausible factors for development of SIL or CCa conferring increased attenuation of p53 pathway. We investigated the association of these SNPs with the HPV positive SIL and CCa among women from the Republic of Macedonia. Using a multiplex PCR SNaPShot analysis we genotyped rs1042522 and rs2279744 in 131 HPV positive women with SIL or CCa and 110 HPV and cytologicaly negative controls subject. No significant difference in either genotype or allelic frequencies for rs1042522 and rs2279744 between cases and control was found. The stratification of patients on the basis of the lesion grade revealed lower frequency of CC genotype and C allele of rs1042522 in HSIL and CCa compared to LSIL [GG vs CC; p=0.001, OR=0.4; CG vs CC; p=0.04, OR=0.03 and CG+ GG vs CC; p=0.004, OR=0.2]. Additionally TT genotype and T allele of MDM2 309 showed significantly lower frequency in HSIL and CCa group then in LSIL [G vs T p=0.02, OR=0.52; GG vs TT; p=0.04, OR=0.29; ТТ vs ТG+GG; p=0.007, OR=0.34].The Arg variant of rs1042522 and T allele/TT genotype of rs2279744 are associated with progression to LSIL to HSIL or CCa and may be used as prediction markers in CCa management, but the clinical relevant warrants further validation in large and well-designed studies.
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    Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia
    (2014-12)
    Kapedanovska Nestorovska, A
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    Jakovski, K
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    Naumovska, Z
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    Hiljadnikova Bajro, M
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    Sterjev, Z
    Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry.