- Assoc. prof. at Department of Pharmacy, Faculty of Medical Sciences, University Goce Delcev - Stip, R. North Macedoni... moreAssoc. prof. at Department of Pharmacy, Faculty of Medical Sciences, University Goce Delcev - Stip, R. North Macedonia. Interest at variety of topics in the field of pharmaceutical sciences.edit
Research Interests:
Кај радиофармацевтиците, како и кај сите останати лекови, постои можност од појава на несакани ефекти. Пријавените несакани ефекти се во мал број, и повеќето од нив не се сериозни и животозагрозувачки. Текстот се однесува на најчесто... more
Кај радиофармацевтиците, како и кај сите останати лекови, постои можност од појава на несакани ефекти. Пријавените несакани ефекти се во мал број, и повеќето од нив не се сериозни и животозагрозувачки. Текстот се однесува на најчесто забележуваните несакани ефекти и нивен третман.
Research Interests:
The importance of well-established and recognized education in Radiopharmacy became a need all around the world as result of different national regulation, different system of education and mostly of the level of need, development and... more
The importance of well-established and recognized education in Radiopharmacy became a need all around the world as result of different national regulation, different system of education and mostly of the level of need, development and investment in clinical and research usage of radiopharmaceuticals. The substantial confusion and challenge in the same time is to define the appropriate and sufficient knowledge, understanding and competences corresponding to position of professionals in the working place, including the type and level of formal education.
Research Interests:
Трудот опфаќа дефиниција и поделба на функционалната храна од стручен аспект, опфаќајќи ги неколкуте видови функционална храна: збогатена храна, храна со намалено количество на нутриенти, храна која содржи супстанции од растително... more
Трудот опфаќа дефиниција и поделба на функционалната храна од стручен аспект, опфаќајќи ги неколкуте видови функционална храна: збогатена храна, храна со намалено количество на нутриенти, храна која содржи супстанции од растително потекло, фитоестрогени, храна со додадени состојки и храна која содржи пробиотици и пребиотици.
Една од значајните улоги на фармацевтската наука е истражувањето и развојот на нови лекови. Ова како цел не е едноставно, бидејќи само мал процент од синтетизираните хемиски соединенија може да станат лекови, додека повеќето соединенија... more
Една од значајните улоги на фармацевтската наука е истражувањето и развојот на нови лекови. Ова како цел не е едноставно, бидејќи само мал процент од синтетизираните хемиски соединенија може да станат лекови, додека повеќето соединенија се покажуваат како несоодветни во однос на нивната ефикасност, активност или токсичност. Сите фази на откривање и развој на лековите се долготрајни процеси кои можат да траат меѓу пет и десет години во просек, па и повеќе. Овде се вклучени истражувања од многу различни дисциплини, пред се врзани за идентификување целните болести, откривање соодветни хемиски компоненти кои имаат соодветни биолошки, хемиски и фармаколошко-токсиколошки својства. Кога потенцијалниот лек е избран за развој, се изведуваат сеопфатни студии за безбедност и предклинички и клинички студии кои се со цел да обезбедат доволно податоци за поднесување барање за регистрација на нов лек.
Трудот опфаќа дефиниција и поделба на функционалната храна од стручен аспект, опфаќајќи ги неколкуте видови функционална храна: збогатена храна, храна со намалено количество на нутриенти, храна која содржи супстанции од растително... more
Трудот опфаќа дефиниција и поделба на функционалната храна од стручен аспект, опфаќајќи ги неколкуте видови функционална храна: збогатена храна, храна со намалено количество на нутриенти, храна која содржи супстанции од растително потекло, фитоестрогени, храна со додадени состојки и храна која содржи пробиотици и пребиотици
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Областа на токсиколошките проучувања е комплексна и составена од различни подобласти кои опфаќаат широко поле на интерес. Централно место зазема „отровот“ – неговата идентификација, квантификација, утврдување механизам на дејство и... more
Областа на токсиколошките проучувања е комплексна и составена од различни подобласти кои опфаќаат широко поле на интерес. Централно место зазема „отровот“ – неговата идентификација, квантификација, утврдување механизам на дејство и дијагностика на настанато труење. Овој практикум е насочен кон практичните основи на лабораториските анализи на широк спектар ксенобиотици кои се предмет на испитување во токсиколошката хемија. Практичните аспекти заедно со теоретските основи ќе помогнат во подоброто разбирање на основните механизми и добивањето веродостојни резултати од анализите. Затоа, авторите на овој практикум се обидоа да обединат некои од постоечките протоколи и методологии за остварување на оваа цел. Намерата на авторите е со овде опфатените теми да им се даде насока и основа за започнување на какво било токсиколошко испитување на студентите по фармација кои штотуку навлегуваат во изучувањето на токсикологијата како предмет
Имунотерапијата на канцерот има за цел да ја искористи специфичноста и моќноста на имуниот систем за третман на најразлични видови малигнитети. Иако канцерните клетки се далеку помалку имуногени во однос на патогените, студиите покажале... more
Имунотерапијата на канцерот има за цел да ја искористи специфичноста и моќноста на имуниот систем за третман на најразлични видови малигнитети. Иако канцерните клетки се далеку помалку имуногени во однос на патогените, студиите покажале дека имуниот систем е способен за препознавање и елиминирање и на туморските клетки. Современиот пристап за развој на имунотретмански алтернативи за лекување на канцерни заболувања ги користи сознанијата на клеточната и молекуларната имунологија со цел постигнување на најсилен и најдолготраен, а во исто време и безбеден пристап за третман на канцер
1. Што е вакцина? Зошто се важни вакцините? 2. Зошто за сезонски грип е потребно вакцина секоја година, а за некои други болести само еднаш ја добиваме вакцината? 3. Можеме ли да заболиме од вакцината, која што требала да не заштити од... more
1. Што е вакцина? Зошто се важни вакцините? 2. Зошто за сезонски грип е потребно вакцина секоја година, а за некои други болести само еднаш ја добиваме вакцината? 3. Можеме ли да заболиме од вакцината, која што требала да не заштити од истата болест? 4. Дали може од вакцина да се добие аутизам? 5. Дали родителите треба да бидат загрижени кога треба да ги вакцинираат своите деца? 6. Дали луѓето треба да имаат избор за вакцинација? 7. На пример има пациент кој што вели дека не познава никој кој што е заболен од таа болест, и покрај тоа зошто е потребна вакцинација? 8. Дали се безбедни вакцините во Македонија, понекогаш има шпекулации дека квалитетот е на многу ниско ниво? 9. Многу луѓе мислат дека вакцинацијата најголем дел е наменета за деца, дали и возрасните треба да бидат вакцинирани? 10. Ако патувам во странство, кои вакцини треба да ги примам пред да заминам? 11. Кои се негативните ефекти од вакцините? Дали можат да доведат до некои посериозни и долготрајни последици? 12. Кои се...
Research Interests:
The revealed immunomodulating, antioxidant, chemopreventive and anticancer activity of the piperine, mayor alkaloid in fruits of the black pepper (Piper nigrum Linn.) and the long pepper (Piper Longum Linn.) which for many centuries are... more
The revealed immunomodulating, antioxidant, chemopreventive and anticancer activity of the piperine, mayor alkaloid in fruits of the black pepper (Piper nigrum Linn.) and the long pepper (Piper Longum Linn.) which for many centuries are broadly used both as spice and as remedy in culinary and traditional medicine, respectively spurs our interest on the research of enhancing its low bioavailability. On a purpose to study interactions between piperine and different pharmacotherapy classes of drugs and other natural compounds with both therapeutic and biological activity that differ by their molecular structures, our initial approach is to apply crystal engineering concept for growing single crystalline phases of cocrystallzed piperine with selected models of drug and natural compounds. Referring to the ternary amide structure of piperine which is formed between piperidine in chair conformation and piperic acid (5-(3,4-methylenedioxyphenyl)-2,4-pentadienoic acid), its side chain with c...
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Laboratory is a part of the Department of Pharmacy in the Faculty of Medical Sciences, at the Goce Delcev University in Stip. Main activities are focused on improving knowledge for radiopharmacy of bachelor students, master students and... more
Laboratory is a part of the Department of Pharmacy in the Faculty of Medical Sciences, at the Goce Delcev University in Stip. Main activities are focused on improving knowledge for radiopharmacy of bachelor students, master students and doing PhD thesis. Also, we are trying to provide services for external associates as a testing laboratory. As a developing country, we are facing with the begging’s of the process of accreditation. The accreditation process is a lengthy and time consuming method. There isn’t specific time frame for preparation for accreditation. We incorporate an overall system for technical and quality management, which results in benefits observed in daily laboratory practices. With ISO 17025 standard incorporation we achieve traceability of the whole documentation, daily good working plan, including preventive and corrective actions and we are doing training and education of laboratory stuff for better work conditions and best protection. Benefits of getting MKC E...
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И покрај својот голем напредок, современата фармакотерапија се уште се соочува со многу предизвици, како што е појавата на несаканите реакции кон лекови, кои не одговораат на стандардната терапија, а понекогаш се многу сериозни па дури и... more
И покрај својот голем напредок, современата фармакотерапија се уште се соочува со многу предизвици, како што е појавата на несаканите реакции кон лекови, кои не одговораат на стандардната терапија, а понекогаш се многу сериозни па дури и смртоносни. Истакнатите варијабилности и разликите кои може да се набљудуваат во индивидуалните одговори кон фармакотерапијата, делумно зависат од добро познати општи фактори (возраст, пол, тежина, црнодробна и бубрежна функција, други лекови кои се аплицираат истовремено, и др), но и од други специфични фактори, како наследните варијации кај ензимите за метаболизирање на лекови, транспортерите (носачи) на лекови, рецепторите и молекулите на сигнал-трансдукциските каскади. Комбинацијата од сите претходно наведени карактеристики има големо влијание врз формирањето на индивидуалниот одговор на пациентот кон лекот.Генетскиот полиморфизам е важна причина за променет одговор кон лек аплициран кај определена индивидуа.Предизвик во фармакотерапијата ќе бид...
Со брзиот економски развој и индустријализација, широк спектар на генотоксични хемикалии се продуцираат и дистрибуираат во животната средина. Токсичните хемикалии влијаат врз индивидуалното здравје кога интерферираат со нормалните... more
Со брзиот економски развој и индустријализација, широк спектар на генотоксични хемикалии се продуцираат и дистрибуираат во животната средина. Токсичните хемикалии влијаат врз индивидуалното здравје кога интерферираат со нормалните физиолошки процеси во организмите. Тешките метали ја сочинуваат една од најголемите групи на загадувачи на животната средина кои се сериозна закана за општата состојба во биосферата. Иако есенцијалните метали имаат важна биолошка функција како кофактори на многу металопротеини и ензими, кога се акумулираат во клетките имаат цитотоксичен ефект. Фитотоксичноста на металите е поврзана со индуцирање оксидативен стрес поврзан со оксидација на протеините и мембранските липиди, како и специфичен одговор со DNA оштетување. Поради строго регулираната структура на генетскиот материјал, возможно е да се користат најразлични растителни и животински видови во тестовите за генотоксичност. Претставниците од класата виши растенија обезбедуваат корисен генетски систем за с...
Бидејќи мигрената претставува едно од најчестите заболувања кои водат до невролошки инвалидитет во светот и поради нејзината зачестеност од една страна и недостатокот на соодветна терапија од друга, се налага потребата од откривање на... more
Бидејќи мигрената претставува едно од најчестите заболувања кои водат до невролошки инвалидитет во светот и поради нејзината зачестеност од една страна и недостатокот на соодветна терапија од друга, се налага потребата од откривање на нови начини за превенција и третман на истата. Имено, како нова група лекови против мигрена во моментов се испитуваат лекови кои функционираат на принцип на блокирање на пептидот поврзан со калцитонин генот – CGRP или блокирање на неговиот рецептор. До денес се развиени две различни класи на лекови кои го блокираат CGRP: - мали молекули-CGRP рецепторни антагонисти (гепанти) и - моноклонални антитела, насочени кон CGRP пептидот или кон CGRP рецепторот. Ефектите на гепантите и моноклоналните антитела се комплементарни едни на други, но двете класи нудат различни терапевтски предности. Потребни се дополнителни студии за да се испитаат детално терапевтските ефекти, како и ефикасноста и безбедноста на овие нови групи на лекови особено при долготрајна употре...
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Рекомбинантните моноклонални антитела и пептиди во моментов се оценети како значајна и растечка класа на лекови со биолошко потекло. Имајќи ја предвид употребата на радиоимуноконјугати за терапија на не-Хочкинов лимфом (NHL), во рамките... more
Рекомбинантните моноклонални антитела и пептиди во моментов се оценети како значајна и растечка класа на лекови со биолошко потекло. Имајќи ја предвид употребата на радиоимуноконјугати за терапија на не-Хочкинов лимфом (NHL), во рамките на овој труд направено е испитување на ново подготвена лиофилизирана формулација, обележана со нерадиоактивни (Lu и Y) или радиоактивни изотопи (177Lu), на три различни конјугати на ритуксимаб со бифункционален хелатирачки агенс (BFCA), за проценка и потврдување на структурата. Беа користени три типа BFCA, p-Bn-SCN-DOTA, p-Bn-SCN-DTPA и 1B4M-DTPA. Од резултатите добиени со SDS-PAGE потврдено е дека чекорите на конјугација и процесот на лиофилизација, како и обележувањето на имуноконјугатите со Lu и Y е успешно, без да предизвика значајни промени во молекулите на имуноконјугатите и без формирање на споредни производи (фрагментирање на антителото и/или присуство на агрегати). Карактеризацијата на конјугатите и утврдувањето на просечниот број на молекул...
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The presented experience was in freeze-drying of monoclonal antibody – rituximab, conjugated with three types of bifunctional chelating agents, p-SCN-Bn-DOTA, p-SCN-Bn-DTPA, and 1B4M-DTPA, and evaluation of possible changes in... more
The presented experience was in freeze-drying of monoclonal antibody – rituximab, conjugated with three types of bifunctional chelating agents, p-SCN-Bn-DOTA, p-SCN-Bn-DTPA, and 1B4M-DTPA, and evaluation of possible changes in post-freeze-drying phase, using SDS-PAGE electrophoresis, FT-IR and Raman spectroscopy techniques
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Herbal products used in Traditional Chinese Medicine (TCM) shows special interest because they have been identified to possess multi-effect on cancer cells: cytotoxicity, immunomodulation, anti-angiogenesis and anti-metastatic effect
Терапијата со лекови и препишувањето лекови, се најчести активности и во улога на пациент и во улога на оние кои се грижат за пациентите. Неопходно се наметнува потребата да примената на лековите биде мониторирана со еднакво високи... more
Терапијата со лекови и препишувањето лекови, се најчести активности и во улога на пациент и во улога на оние кои се грижат за пациентите. Неопходно се наметнува потребата да примената на лековите биде мониторирана со еднакво високи стандарди како оние кои постојат во тек на развојот и евалуацијата на истите
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Dental caries is the most common bacterial infectious disease in human and has become the basic cause of oral discommode and tooth damage, seriously touching the quality of life of the patients. It is induced by specific class of... more
Dental caries is the most common bacterial infectious disease in human and has become the basic cause of oral discommode and tooth damage, seriously touching the quality of life of the patients. It is induced by specific class of acid-producing bac¬terias (e.g., Streptococcus mutans). S. mutans has been strongly concerned as the prominent pathogen of dental caries in human. Anti-caries DNA vaccination is a new immunization procedure against dental infectious disease, and has many preferences over traditional vaccines, such as easy proceeding and contribution, and induction of long-lasting cellular and humoral immune responses. Anti-caries DNA vaccine may act as a multi-epitope vaccine and elevate strong immune response targeting S. mutans associ¬ated antigens. Anti-caries DNA vaccine can induce S-IgA antibod¬ies against S. mutans, decrease adherence and biofilms disposition, reducing the frequency of dental caries as a result. As a disadvantage, this vac¬cine has low immunogenicity ...
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Практикумот по Хемија содржи 12 релевантни вежби од материјалот по предметот Хемија за Општа медицина за студентите при УГД Штип
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Последните научни достигнувања во дополнителното расветлување на механизмите на дејство на метформинот, првично развиен како бигванидински дериват и успешно докажан лек од прв избор за орална терапија на дијабетес тип 2, со што е... more
Последните научни достигнувања во дополнителното расветлување на механизмите на дејство на метформинот, првично развиен како бигванидински дериват и успешно докажан лек од прв избор за орална терапија на дијабетес тип 2, со што е постигнатао истиот да е најшироко застапен лек и со најголем обрт во прометот на препишани лекови, ја оправдуваат терапијата со овој лек и во третмани и на многу други болести и нарушувања
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Several properties of exosomes make them potential drug delivery systems, especially the fact that they can be regarded as natural liposomes. Their endogenous origin and potential of reduced side effects and targeted action make them more... more
Several properties of exosomes make them potential drug delivery systems, especially the fact that they can be regarded as natural liposomes. Their endogenous origin and potential of reduced side effects and targeted action make them more attractive to researchers worldwide. Since this new technology of implementation of exosomes as drug carriers is just emerging, several authors presented incorporation of anticancer agents into exosomes. Namely, for this purpose, curcumin has been used, thus reportedly resulting with curcumin-loaded exosomes that presented increased solubility, stability, and bioavailability, and its’ increased delivery to activated monocytes. Doxorubicin has also been incorporated into exosomes, resulting in its specific delivery to tumor tissues, and leading to inhibition of tumor growth in tumor-bearing nude mice model. In addition, paclitaxel has also been investigated for incorporation in exosomes using different techniques, reportedly showing increased cytoto...
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Drugs with biological origin or biopharmaceuticals are products where the active substance is composed of or derived from living organisms and often represent the crossing of the boundaries of medical science and different fields of... more
Drugs with biological origin or biopharmaceuticals are products where the active substance is composed of or derived from living organisms and often represent the crossing of the boundaries of medical science and different fields of research (Walsh, 2003). They can be composed of carbohydrates, nucleic acids, proteins, or complex combinations of these substances, or may be composed from live cells or tissues. Unlike chemically synthesized small molecules that have a well-defined structure and are thoroughly characterized, the pharmaceutical products with biological origin are complex in structure and therefore their full characterization is great achievement. Analytical methodology that is currently in use enables a comprehensive characterization and identification of biopharmaceuticals (determination of molecular weight and particle size, physico-chemical properties, identity, purity and homogeneity, biological activity, immunochemical properties, purity/impurities (if present), pr...
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The main aim and objective of the Action is to expand our knowledge on intestinal drug absorption to make drug development and clinical treatment more knowledge-driven by focussing on four key topics: specific patient populations,... more
The main aim and objective of the Action is to expand our knowledge on intestinal drug absorption to make drug development and clinical treatment more knowledge-driven by focussing on four key topics: specific patient populations, regional differences in absorption along the gastrointestinal tract, advanced formulations and the food-drug interface
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Monoclonal antibodies are new type of targeted anticancer therapy, which achieve specificity, selectivity and localization in tumor cells. There are many naked antibodies and immunoconjugates commercially approved for different types of... more
Monoclonal antibodies are new type of targeted anticancer therapy, which achieve specificity, selectivity and localization in tumor cells. There are many naked antibodies and immunoconjugates commercially approved for different types of cancer (Mehren et al., 2003). In order to improve specificity and selectivity of cytotoxic drugs and toxins, monoclonal antibodies are used for formulation of immunoconjugates. Many efforts are done to develop stable immunoconjugates of trastuzumab with various drugs, toxins and radioisotopes to improve the general conditions of the patients (Sharkey and Goldenberg, 2006). The aim of this paper is to focus on current achievements in the formulation of radioimmunoconjugates of HER2-targeting trastuzumab.
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Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody which is approved for therapy of HER2 positive breast cancer. Good clinical results and improvement of the patient’s general condition makes it interesting for further... more
Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody which is approved for therapy of HER2 positive breast cancer. Good clinical results and improvement of the patient’s general condition makes it interesting for further conjugation, in order to increase the therapeutic effect of trastuzumab. With the development of radiopharmacy many efforts are made for formulation of stable conjugates with various bifunctional chelators, further labelled with radioisotopes (α, β and γ emitters). According to the literature, successful conjugation of trastuzumab is achieved with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), TCMC (1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane), HYNIC (succinimidyl-6-hydrazino-nicotinamide) and DTPA derivate 1B4M-DTPA (2-(4-isothiocyanatobenzyl)-6-methyl-diethylene-triaminepentaacetic acid). Significant radiopharmaceuticals based on peptide and antibody for diagnostic and therapeutical pur...
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Increased understanding of subjective well-being (SWB), as well as factors that influence it, are essential to enhance well-being at the individual and national level. We have applied a hedonic and eudaimonic 9-item composed tool (SWB... more
Increased understanding of subjective well-being (SWB), as well as factors that influence it, are essential to enhance well-being at the individual and national level. We have applied a hedonic and eudaimonic 9-item composed tool (SWB score) to measure SWB across several Mediterranean (MED) and non-Mediterranean (non-MED) countries, and to explore the association between the SWB score and a range of sociodemographic, health and Mediterranean lifestyle factors. A specifically designed web-based questionnaire was distributed to adult participants (N = 2400) from Spain, Italy, Portugal, Bulgaria and Republic of North Macedonia. Results showed that the SWB score was significantly different across the examined countries with the MED participants displaying slightly higher average scores than the non-MED ones (6.3 ± 1.5 vs. 6.1 ± 1.6, p = 0.002). Several sociodemographic, health status and lifestyle factors displayed a significant but limited association with the 9-item SWB score, with a ...
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Various radiolabeled monoclonal antibodies have been developed for the treatment and diagnosis of malignancies. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab selectively binds with high affinity to the CD20 antigen... more
Various radiolabeled monoclonal antibodies have been developed for the treatment and diagnosis of malignancies. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab selectively binds with high affinity to the CD20 antigen (human B-lymphocyte restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and on >90% of B cell non-Hodgkin’s lymphomas. These properties make the CD20 receptor a suitable target for radioactive therapy. 177Lu has been considered as a promising radionuclide for developing therapeutic radiopharmaceuticals, esp. radiolabeled monoclonal antibodies, owing to its suitable decay characteristics, as well as the feasibility of large-scale production in adequate specific activity and radionuclidic purity. In order to obtain 177Lu anti-CD20 radioimmunoconjugates for using in therapeutic studies, different bifunctional chelating agents-antiCD20 (rituximab) (BFCA-rituximab) were labeled by “cold” 17...
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Fourier Transform Infrared (FT-IR) and Raman spectroscopy were used to study the molecular structure of the recombinant monoclonal antibody and anti-CD20-conjugates which are intended to be used as anti-cancer therapeutic agents. We... more
Fourier Transform Infrared (FT-IR) and Raman spectroscopy were used to study the molecular structure of the recombinant monoclonal antibody and anti-CD20-conjugates which are intended to be used as anti-cancer therapeutic agents. We characterized the secondary structure of a therapeutic immunoconjugate of rituximab, formulated with three different bifunctional chelating agents (p-SCN-BnDOTA, p-SCN-Bn-DTPA, and 1B4M-DTPA) and labeled with non-radioactive lutetium and yttrium. The secondary structure content of all three immunoconjugates was assessed to be similar to that of unlabeled antibody. In addition, no significant changes upon lyophilizing procedures were observed. The results demonstrate that amide bands could be used as analytical tool which provides a quick and reliable way for screening of protein pharmaceuticals during the development of lyophilized formulations.
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Antibody conjugates are therapeutics that function through mediating alterations in antigen or receptor func¬tion, modulat¬ing the immune system (for example, changing Fc function and T cell activation) or delivering of a specific drug... more
Antibody conjugates are therapeutics that function through mediating alterations in antigen or receptor func¬tion, modulat¬ing the immune system (for example, changing Fc function and T cell activation) or delivering of a specific drug conjugated to antibody that targets a specific antigen. Four main classes using antibodies are investigated to target cytotoxic agents to cancer cells.Futhermore, dealing with the challenges in the process of target selection and selection of conjugate elements including the design of antibody formulation and toxicity assessment, is also imperative in the process of design of this type of therapeutics.
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The beginning of the new century brought approval of two monoclonal antibodies for therapy of Non Hodgkin's Lymphoma (NHL), Bexxar® and Zevalin®, and opened the gateway to the research in targeted therapy of, mostly haematological... more
The beginning of the new century brought approval of two monoclonal antibodies for therapy of Non Hodgkin's Lymphoma (NHL), Bexxar® and Zevalin®, and opened the gateway to the research in targeted therapy of, mostly haematological malignanices. Since then, the research has been directed toward improvement in three principal, but interdependent factors: the antibody, the radionuclide, and the target tumor/host. Among the most researched anti-CD 20 monoclonal antibodies is rituximab, and among the radionuclides, Y-90, In-111, Cu-64, Sm-153, and Lu-177–labeled antibodies have been described or are under development. The aim of our research was to develop a new lyophilized kit, ready-to label with Lu-177, with a potential to be used in diagnostic and therapeutic purposes. In our experiments, we used rituximab, purified from a commercial preparation, Mabthera®, that was conjugated using p-SCN-Bn-DOTA, p-SCN-Bn-DTPA and 1B4M-DTPA as chelating agents. The lyophilized kit was prepared i...
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For a protein based drug including antibody based radiopharmaceuticals, a structural characterization is mandatory before any possible start of a clinical trial. Vibrational spectroscopic techniques, as Fourier transform infrared (FTIR)... more
For a protein based drug including antibody based radiopharmaceuticals, a structural characterization is mandatory before any possible start of a clinical trial. Vibrational spectroscopic techniques, as Fourier transform infrared (FTIR) spectroscopy and Raman spectroscopy are one of the biophysical methods for structural characterization of proteins because of their sensitivity to the composition and architecture of molecules. Here we used vibrational spectroscopy to characterize the physico-chemical stability and structural changes of three immunoconjugates of rituximab, intended for labeling with radioisotope of choice (177Lu, 90Y and/or 68Ga), relevant for the stability of therapeutic/diagnostic antibodies during preparation, storage and/or transport.
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The chimeric anti-CD-20 antibody, rituximab is among standard treatment regimes in treating B-cell Non-Hodgkin’s lymphoma. The possibility of conjugation and subsequent radiolabeling with beta (gamma) - emmiting radioisotopes can provide... more
The chimeric anti-CD-20 antibody, rituximab is among standard treatment regimes in treating B-cell Non-Hodgkin’s lymphoma. The possibility of conjugation and subsequent radiolabeling with beta (gamma) - emmiting radioisotopes can provide an added value to this therapeutical, thus increasing the possibility of targeted action to mature, malignant B-cells. Furthermore, designing a “ready to label”, freeze-dried immunoconjugate holds much advantages both in preserving the antibody stability and in the preparation and labeling with radioisotopes. Design of freeze-dried immunoconjugate kit was the main aim of this work, specifically in decision whether to add or not a cryoprotective and bulking agent, mannitol. For this purpose, rituximab, previously conjugated with three different bifunctional chelating agents, p-SCN-Bn-DOTA, p-SCN-Bn-DTPA and 1B4M-DTPA, adjusted to concentration of 1 mg/mL in 0.1M PBS (pH=8.0), with and without 10 mg/mL mannitol was freeze-dried, using Labconco Free Zo...
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Recombinant monoclonal antibodies and peptides are currently rated as a significant and growing class of drugs with biological origin. According to the usage of the radioimmunoconjugates in therapy of non-Hodgkin's Lymphoma (NHL), we... more
Recombinant monoclonal antibodies and peptides are currently rated as a significant and growing class of drugs with biological origin. According to the usage of the radioimmunoconjugates in therapy of non-Hodgkin's Lymphoma (NHL), we made investigations to newly prepared lyophilized formulations labeled with non-radioactive (Lu and Y) or radioactive isotopes (177Lu), of three different rituximab-bifunctional chelating agents (BFCA) conjugates, for assessment and evaluation of the structure. Three types of BFCA, p-Bn-SCN-DOTA, p-Bn-SCN-DTPA and 1B4M-DTPA were used. The results obtained by SDS-PAGE confirmed that conjugation and lyophilization steps and labeling of immunoconjugates with Lu and Y is successful, without significant changes in the molecules and forming of by-products (fragmentation of the antibody and/or presence of aggregates). Characterization of conjugates and determination of the average number of molecules of BFCA attached to each molecule of the antibody was ma...
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Understanding the behaviour and function of biomolecules at the molecular level is key to the discovery and development of new drugs, as well as diagnostic techniques. The characterization of therapeutic monoclonal antibodies (mAbs) poses... more
Understanding the behaviour and function of biomolecules at the molecular level is key to the discovery and development of new drugs, as well as diagnostic techniques. The characterization of therapeutic monoclonal antibodies (mAbs) poses many challenges compared to those of low-molecular mass drugs because of their inherent complexity due to their protein nature. Achievements in this field of science have changed the way that drugs are being designed and developed nowadays. Vibrational spectroscopy techniques, like Fourier Transform Infrared (FTIR) spectroscopy and Raman spectroscopy (RS) have helped to determine the secondary structure of complex protein molecules, as well as protein-ligand complexes. Other advantages of these techniques include the need of very low sample concentration and the ease of sample preparation. Therefore, they are gaining growing importance in the field of medicine and pharmacology. Our group has demonstrated the use of these tools to understand protein...
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Radioimmunotherapy (RIT) of Non-Hodgkin’s lymphoma (NHL) is said to be more advantageous compared to unlabeled therapeutic antibodies. To this date, radiolabelled murine anti-CD20 mAbs, Zevalin® and Bexxar® have been approved for imaging... more
Radioimmunotherapy (RIT) of Non-Hodgkin’s lymphoma (NHL) is said to be more advantageous compared to unlabeled therapeutic antibodies. To this date, radiolabelled murine anti-CD20 mAbs, Zevalin® and Bexxar® have been approved for imaging and therapy. A preparation containing rituximab, chimeric mAb immunoconjugate suitable for Lu-177 labeling, could provide better imaging and therapeutic profile at the same time. This study was conducted to evaluate prepared lyophilized formulations of three rituximab immunoconjugates, intended for immediate Lu-177 labeling, for imaging and therapy. The results showed preserved antibody structure and suitability for successful radiolabeling with over 95% radiochemical purity, encouraging further evaluation experiments.
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Рекомбинантните моноклонални антитела и пептиди во моментов се оценети како значајна и растечка класа на лекови со биолошко потекло. Имајќи ја предвид употребата на радиоимуноконјугати за терапија на не-Хочкинов лимфом (NHL), во рамките... more
Рекомбинантните моноклонални антитела и пептиди во моментов се оценети како значајна и растечка класа на лекови со биолошко потекло. Имајќи ја предвид употребата на радиоимуноконјугати за терапија на не-Хочкинов лимфом (NHL), во рамките на овој труд направено е испитување на ново подготвена лиофилизирана формулација, обележана со нерадиоактивни (Lu и Y) или радиоактивни изотопи (177Lu), на три различни конјугати на ритуксимаб со бифункционален хелатирачки агенс (BFCA), за проценка и потврдување на структурата. Беа користени три типа BFCA, p-Bn-SCN-DOTA, p-Bn-SCN-DTPA и 1B4M-DTPA. Од резултатите добиени со SDS-PAGE потврдено е дека чекорите на конјугација и процесот на лиофилизација, како и обележувањето на имуноконјугатите со Lu и Y е успешно, без да предизвика значајни промени во молекулите на имуноконјугатите и без формирање на споредни производи (фрагментирање на антителото и/или присуство на агрегати). Карактеризацијата на конјугатите и утврдувањето на просечниот број на молекул...
Silver nanoparticles (AgNPs) have been intensively investigated due to great potential applications, for instance, in technology, physical, biomedical and pharmaceutical sciences. These nanoparticles can be synthesized by chemical,... more
Silver nanoparticles (AgNPs) have been intensively investigated due to great potential applications, for instance, in technology, physical, biomedical and pharmaceutical sciences. These nanoparticles can be synthesized by chemical, physical and biological methods. In general, physico-chemical methods can be toxic, expensive, produce NPs with low yield and limitations for medical/pharmaceutical use (contamination from precursors, solvents, etc.). Thus, the biosynthesis of NPs using plant extracts has become very important topic for research in recent years (Adil et al., 2015; Agressott et al., 2020). Plant extracts contain variety of natural compounds with different molecular structures that exhibit reduction to metal ions to elemental metal nanoparticles. Hence, preparing metal nanoparticles with plant extracts match the concept of green chemistry for their production and also increased biocompatibility as great advantage in their application. The increasing use of nanomaterials in ...
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Laboratory of Radiopharmacy is a part the Faculty of Medical Sciences, Department of Pharmacy in the Goce Delcev University in Stip and was granted by the Government of Republic of Macedonia as a part of the project for improvement of the... more
Laboratory of Radiopharmacy is a part the Faculty of Medical Sciences, Department of Pharmacy in the Goce Delcev University in Stip and was granted by the Government of Republic of Macedonia as a part of the project for improvement of the laboratories in the country. The main field in which the Laboratory of Radiopharmacy has focused after the establishment in 2011 is to introduce a new molecules as a potential radiopharmaceuticals, labeling with radioactive and not radioactive isotopes, defining their structure and especially chemical and radiochemical identification of potential impurities. In the same time carefully implementing radiation safety program for controlling laboratory environment. The Laboratory is deeply involved in the educational program in all cycles of academic degrees following a few international and local research projects. The laboratory staff is educated and trained in the national and international programs in the field of Radiopharmacy and Radiochemistry, ...
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The aim of this work was to perform conjugation of mAb rituximab, with three different BFCAs, p-SCN-Bn-DOTA, p-SCN-Bn-DTPA and 1B4M-DTPA in a form of ready-to-label kit formulations.
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Background: Positron emission tomography (PET) has a growing use in medical decision making and management of patients. To further apply the unique properties of PET, more clinically validated PET-radiopharmaceuticals are required and... more
Background: Positron emission tomography (PET) has a growing use in medical decision making and management of patients. To further apply the unique properties of PET, more clinically validated PET-radiopharmaceuticals are required and subsequently new and better radiochemical preparation methods are under development. With respect to radiochemistry development, most efforts have been made with the use of 11C and 18F as radionuclides. Also,labeling methods development stimulates the use of different radiometals as 68Ga, 89Zr and 64Cu for clinical use. These radionuclides have their specific characteristics with respect to half-life, positron energy (resolution), positron abundance and availability. Depending on the biological target of interest and the properties of the PET-radiopharmaceutical the proper radionuclide should be selected. For the treatment and diagnosis of malignancies, various radiolabeled monoclonal antibodies have also been developed. Rituximab selectively binds wit...
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Substance P (SP) has been known to trigger biological responses by linking to NK 1 receptors. The presence of functional NK1 receptors has already been documented in malignant brain tumors of glial origin, medullary thyroid cancer,... more
Substance P (SP) has been known to trigger biological responses by linking to NK 1 receptors. The presence of functional NK1 receptors has already been documented in malignant brain tumors of glial origin, medullary thyroid cancer, non-small cell lung cancer and pancreatic carcinoma 99mTc and 188Re radiolabeled SP was tested for cell surface binding after incubation with NK1 receptor expressing U-87 MG cells, and negative control cell line L-929 and preliminary whole-body biodistribution studies were carried out with 99mTc labeled SP using a hybrid SPECT/CT YAP(S)PET small-animal tomography scanner. Our results using 99mTc and 188Re radiolabeled SP, demonstrated the affinity of these radioconjugates for NK1 receptor expressing cells, showing pronounced cell surface binding after incubation with U-87 MG cells, compared to the negative control cell line L-929. Further preliminary whole-body biodistribution studies with 99mTc labeled SP using a hybrid SPECT/CT YAP(S)PET small animal to...
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The Mediterranean diet (MD) has been sponsored worldwide as a healthy and sustainable diet. Our aim was to update and compare MD adherence and food choices across several Southern European countries: Spain (SP), Portugal (PT), Italy (IT),... more
The Mediterranean diet (MD) has been sponsored worldwide as a healthy and sustainable diet. Our aim was to update and compare MD adherence and food choices across several Southern European countries: Spain (SP), Portugal (PT), Italy (IT), Greece (GR), and Cyprus (CY) (MED, Mediterranean), and Bulgaria (BG) and the Republic of North Macedonia (NMK) (non-MED, non-Mediterranean). Participants (N = 3145, ≥18 y) completed a survey (MeDiWeB) with sociodemographic, anthropometric, and food questions (14-item Mediterranean Diet Adherence Screener, 14-MEDAS). The MED and non-MED populations showed moderate (7.08 ± 1.96) and weak (5.58 ± 1.82) MD adherence, respectively, with significant yet small differences across countries (SP > PT > GR > IT > CY > BG > NMK, p-value < 0.001). The MED participants scored higher than the non-MED ones for most of the Mediterranean-typical foods, with the greatest differences found for olive oil (OO) and white meat preference. In most coun...
Preparations containing antibodies are more easily formulated in solution, but their stability is often impaired, concerning the fact that aqueous solutions are prone to numerous physical and chemical changes, Freeze-drying is often used... more
Preparations containing antibodies are more easily formulated in solution, but their stability is often impaired, concerning the fact that aqueous solutions are prone to numerous physical and chemical changes, Freeze-drying is often used process in biopharmaceutical production, because the chemical and physical degradation rate can be significantly reduced in dry state. Our experience was in designing a freeze-drying process in order to formulate freeze-dried kit, containing conjugated Anti-CD-20 antibody, ready-to label with radioactive isotopes. Using freeze-dryer able to controll process parameters, (Labconco Free Zone Stoppering Tray Dryer, USA), two types of freeze-drying protocols were applied, a protocol with direct freezing to the initial temperature of -40 °C and a protocol with gradual freezing from 5 °C to -40 °C, at a rate of 0,40 °C/min. Appearance after reconstitution of the finished product and presence of aggregates were evaluated, as well as the IR and Raman spectra...
During the intensive research in past decades, the scientific community and regulatory agencies also, focused their interest on measuring contaminant levels in tissues and environmental samples and on understanding the mechanisms of... more
During the intensive research in past decades, the scientific community and regulatory agencies also, focused their interest on measuring contaminant levels in tissues and environmental samples and on understanding the mechanisms of toxicity of different and pervasive contaminants. Among them, metals were always in focus because of possible detrimental and long lasting effects on living organisms. The current study was designed to assess the effects of long term, high metal exposition (cadmium, lead, copper, nickel and zinc) on DNA damage.
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Investigations for NHL treatment are oriented towards radiolabelled therapeutics. This research focuses on formulation and characterization of a new, ready to label immunoconjugate, 1B4M-DTPA-rituximab, which is suitable for labeling with... more
Investigations for NHL treatment are oriented towards radiolabelled therapeutics. This research focuses on formulation and characterization of a new, ready to label immunoconjugate, 1B4M-DTPA-rituximab, which is suitable for labeling with Lu-177. The conjugation was performed using 20-fold molar excess of the bifunctional chelating agent, 1B4M-DTPA and subsequent lyophilization. The characterization of the (radio)immunoconjugate was performed using SE-HPLC, SDS-PAGE and MALDI-TOF-MS. The results show that the conjugation reaction yields immunoconjugates with average of 8.3 chelating groups per one rituximab molecule and the subsequent lyophilization did not affect the integrity, the structure, or radionuclide-binding properties. The radiolabelling with 555 GBq/mg Lu-177 resulted in over 95% radiochemical purity, which makes this agent a good candidate for further investigation of biological and pharmacological potency in NHL therapy.
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The present work outlines the biosynthesis of silver nanoparticles (AgNPs) using black pepper fruit extract (piperine) as bioreductive and capping agent, followed by their conjugation with piperine and characterization thereof. Several... more
The present work outlines the biosynthesis of silver nanoparticles (AgNPs) using black pepper fruit extract (piperine) as bioreductive and capping agent, followed by their conjugation with piperine and characterization thereof. Several approaches for elucidation of the properites of both non-conjugated and piperine-conjugated AgNPs were implemented. The formation of silver nanoparticles was monitored at 420 nm, corresponding to the surface plasmon resonance band of the obtained AgNPs. SEM and AFM analyses demonstrated the spherical shape of the NPs, while the DLS analysis revealed the negative charge of the NPs with mean diameter of 116.6 ± 8.9 nm and 142.1 ± 10.7 nm for AgNPs and piperine-conjugated AgNPs, respectively. Characteristic Raman bands at 237 cm−1 for AgNPs and at 249 cm−1 for piperine-AgNPs, indicate Ag+ reduction to nanoscaled Ag, in addition to emergence of new bands as a result of the formation of bonds with oxygen atoms from the extracted organic molecules. The bands in the Amide I region characteristic for β-sheets in the structure, followed by bands from the α-helices were also assigned. The work represents the first conjugation of the AgNPs with bioactive piperine, that further might be evaluated as promising new delivery system in the pharmaceutical and biomedical industry.