Faculty of Pharmacy

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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
    ;
    Marija Hiljadnikova-Bajro
    ;
    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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    Biomolecular laboratory markers in cancer management
    (2017)
    The laboratory analysis is a compulsory supplement to clinical evaluation in making decisions upon diagnosis and treatment of cancer, one of the leading causes of death worldwide. The traditional biochemical laboratory protocols employed in diagnosis, prognosis and monitoring of malignant diseases include testing of soluble macromolecules as tumor markers and certain common parameters corresponding to the specific type of malignancy, but their limited reliability urges the necessity of identifying new biomarkers with higher specificity, sensitivity and predictability. Biomolecular/genetic testing is an emerging field within the scope of laboratory analysis with high clinical potential based on the assumption that revealing the genetic profile unique to each individual cancer may help predict the prognosis and select an appropriate treatment to target the changes in the specific tumor. This work reviews the currently available genomic laboratory tests and highlights their clinical and scientific relevance. Implication of aberrant transcripts BCR-ABL and PML-RAR for the management of leukemias, detection of genetic and epigenetic aberrations associated with familial cancer syndromes (MMR gene defects in Lynch Syndrome), pharmacogenetic assays for HER2, EGFR, ALK, KRAS, BRAF, UGT1A1 testing for selection of appropriate most efficient and least toxic treatment of particular cancer types will be addressed, along with novel, recently identified markers with anticipated clinical impact. The rapid development of high throughput technologies shifting singleplex towards multiplex testing, such as the next generation sequencing paired with bioinformatics which enable fast and affordable sequencing of the entire genome of an individual, will inevitably empower accelerated establishment of new biomolecular markers associated with the process of cancer initiation and progression. A comparative overview of the contemporary methodologies will be presented in the lecture. Multidisciplinary efforts should be made to implement the benefits from the technological advancement in the scientific process of new biomarker identification and translation of the research results into clinical practice, in order to provide best treatment for cancer patients in accordance with the principles of the precision medicine.
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    Pharmacogenetic testing in optimization of treatment with statins
    (2018-10)
    Statins are a class of drugs that have been widely prescribed nowadays for treating hypercholesterolemia and thus prevent the risk of atherosclerotic cardiovascular events and consecutive mortality. Unfortunate ly, the patient’s compliance with treatment is frequently compromised by the high incidence of adverse effects including hepatotoxicity, myotoxicity, increased risk for diabetes mellitus etc. The expansion of the precision medicine concept in pharmacology has introduced pharmacogenetic testing as a potential predictive strategy in statins pharmacotherapy. A thorough literature survey was performed using the PubMed database on the published data in English language in the period 2000-2017, regarding genotype-phenotype associations in statin-induced toxicity, identifying a growing body of evidence supporting the need for pharmacogenetic approach in treatment with statins. Polymorphisms in the genes coding for the CYP450 enzymes: CYP2D6, DYP2D9, CYP3A4 and drug transporter genes like ABCB1, ABCG2 and SLCO1B1 appear to be responsible for the variable re sponse and toxicity of statins. But, many studies highlight the importance of drug interactions and epi genetics in modifying the response towards this class of drugs metabolized via pathways shared by the majority of pharmaceutical agents. With the rapid development of molecular techniques accompanied by a dramatic cost reduction in genetic testing, it can be easily anticipated that pharmacogenetic patient profiling will soon become standard of care in designing the optimal statin treatment either as a monotherapy or in combination with other phar maceuticals.
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    Ethical issues in (pharmaco)genetics
    (2019-10)
    Apart from genetic testing for diagnostic purposes, application of genetics in human medicine encompasses genetic interventions and pharmacogenetical testing which are becoming more frequently utilized in clinical practice, as well as genetic studies employed in the process of research and drug development. It’s been widely known and accepted that application of a drug in equal dosing regimens for treatment of the same diagnosis in different patients, doesn’t produce equal results regarding achievement of a therapeutic effect and/or occurrence of side effects. Investigating the genetic cause for interindividual variations in patients’ drug response and toxicity, pharmacogenetics holds valuable prognostic and predictive value in tailoring the pharmacological treatment of various diseases according to the principles of precision medicine. But, just as any other medical testing, genetic analyses impose ethical risks which in this case are even more serious due to the following specific features of these tests and the obtained data: the “mutual” ownership of the genetic information by individuals from the same family, the lack of precise phenotype-genotype correlation and the influence of epigenetic and environmental factors on the phenotypic expression of genetic information, the balance between the right of an individual “to know” and the right “to not know” as well as the enormous potential for discrimination. The rapid advancement of high throughput technologies delivering a mass of detailed data on an individual’s genome introduces a lot of advantages in scientific and clinical applications, but also threatens with a tremendous risk for misuse of these data in various settings. The lecture discusses the fundamental ethical principles applicable to genetic analyses/studies including respect of the individual’s autonomy and privacy and commitment to providing confidentiality, beneficence and justice. The informed consent as well as the levels of anonymization in genetic testing as measures to satisfy the above mentioned principles will be addressed. Special emphasis will be placed on the ethical issues regarding orphan and rescued drugs emerging in the pharmacogenetical testing within clinical studies in drug research and development. Philosophers of science claim that science is morally neutral, it is actually the use and implementation of science that can have positive or negative impact. Hence, it is crucial to understand that achievement of our aim for humane application of (pharmaco)genetics can only be accomplished if technological and clinical advances in this field advance at a similar rate with the corresponding ethical considerations.
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    Nanostructured lipid carriers loaded with Salvia off. extract for intranasal delivery
    (2018-03-19)
    Taneska, Lea
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    Kostovska, Monika
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    Markova, Elena
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    Cambuleva, Ljubica
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    Shalabalija, Dushko
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    Influence of the surface properties of nanoliposomes on protein corona formation
    (2018-06-16)
    Shalabalija, Dushko
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    Cambuleva, Ljubica
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    Protein binding capacity of nanostructured lipid carriers loaded with Salvia off. Extract
    (2018-06-16)
    Markova, Elena
    ;
    Kostovska, Monika
    ;
    Taneska, Lea
    ;
    Cambuleva, Ljubica
    ;
    Shalabalija, Dushko