RAZVOJ MALIH I SREDNJIH PODUZEĆA I PODUZETNIŠTVA U REPUBLICI SRBIJI I REPUBLICI HRVATSKOJ

Micro, small and medium-sized enterprises (SMEs) are an important generator of new jobs and additional value of every national economy. The European Union constantly points to the key role that SMEs play in ensuring competitiveness in the market, and uses various policies to create a more favorable business environment, as set out by the Lisbon strategy. Creating adequate conditions to encourage innovation and other factors that may improve the business of SMEs is very important in a dynamic market, but also because of increasingly sophisticated demands coming from clients. Various world studies show the following problems: inadequate level of activity in launching new business ventures, a small percentage of newly established enterprises, administrative barriers to the implementation of entrepreneurial activities, underdevelopment of financial markets and lack of entrepreneurship education which provides knowledge and skills in business. The aim of this paper is to review the current situation of small and medium-sized enterprises in the Republic of Serbia and in the Republic of Croatia through several aspects: dynamism, innovation, importance of the sector for the economy and regional development, access to finance, access to educational programs and professional services, as well as the possibilities of financing development through the European structural and investment (ESI) funds.Mikro, mala i srednja poduzeća (MSP) važan su generator stvaranja novih radnih mjesta i kreiranja dodatne vrijednosti svake nacionalne privrede. Europska unija kontinuirano ukazuje na ključnu ulogu koju mala i srednja poduzeća imaju u osiguravanju konkurentnosti na tržištu te različitim politikama usmjerenim na ovaj sektor kreira za njih povoljnije poslovno okruženje, kako se i navodi u Lisabonskoj strategiji. Kreiranje adekvatnih uvjeta za poticanje inovativnosti i drugih činitelja koje mogu utjecati na bolje poslovanje MSP-a vrlo je važno na dinamičnom tržištu, ali i zbog sve sofisticiranijih zahtjeva klijenata. Razna svjetska istraživanja u svojim izvještajima kao prepreku prikazuju nedovoljan nivo aktivnosti u pokretanju novih poslovnih pothvata, mali postotak novootvorenih poduzeća, administrativne prepreke za provođenje poduzetničkih aktivnosti, nedovoljnu razvijenost financijskog tržišta te nedostatak edukacije usmjerene na razvoj poduzetničkih znanja i vještina. Cilj je ovoga rada prikazati pregled trenutnog stanja sektora malih i srednjih poduzeća u Republici Srbiji, kao i u Republici Hrvatskoj preko nekoliko aspekata: dinamičnost, inovativnost, značaj sektora za privredu i regionalni razvoj, pristup izvorima financiranja, dostupnost obrazovnih programa i profesionalnih usluga, kao i mogućnosti financiranja razvoja Europskim strukturnim i investicijskim (ESI) fondovima

Integrisani biofarmaceutski pristup u razvoju i karakterizaciji lekova: opšti koncept i primena

The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients’ needs and expectations.Značaj biofarmaceutskih razmatranja u razvoju i karakterizaciji lekova s ciljem uspostavljanja korelacije i mogućnosti predviđanja odnosa između in vitropodataka, odnosno karakteristika kvaliteta leka i njegovog in vivoponašanja/kliničkog učinka, prepoznata je kako od strane farmaceutske industrije, tako i od strane odgovarajućih regulatornih tela. U radu je dat pregled savremenih biofarmaceutskih alata,uključujući prediktivno ispitivanje brzine rastvaranja lekovite supstance iz farmaceutskog oblika leka, Biofarmaceutski sistem klasifikacije, fiziološki zasnovano farmakokinetičko i biofarmaceutsko modelovanje i simulacije, in vitro-in vivokorelaciju i mogućnost izostavljanja in vivostudija bioekvivalencije (engl. biowaiver) iz aspekta opštih principa i mogućnosti primene u razvoju i karakterizaciji lekova.Predstavljena je i nedavno osmišljena inovativna strategija za razvoj leka usmerena ka pacijentu, uz primenu integrisanog sistemskog pristupa zasnovanog na osnovnim biofarmaceutskim konceptima, uvidu u kliničku situaciju i definisanim terapijskim ciljevima označena kao Plan aktivnosti za procenu biofarmaceutskog rizika (engl. Biopharmaceutics Risk Assessment Roadmap, BioRAM). Očekuje se da će daljem razvoju u ovoj oblasti najviše doprineti združene aktivnosti i razmena znanja i iskustava između farmaceutskih kompanija i regulatornih agencija sa zajedničkim ciljem da se ubrza razvoj efikasnih i bezbednihlekova dizajniranih u skladu sa potrebama i očekivanjima pacijenata

Malignant properties of cancer stem cells

Maligni tumori su jedna od najučešćih bolesti modernoga doba. U Hrvatskoj svaka četvrta osoba oboli od nekoga oblika maligne bolesti. U liječenju malignih tumora koristimo najčešće kirušku terapiju, kemoterapiju (citostatike), hormonsku terapiju, imunoterapiju i radioterapiju. Usprkos svim tim metodama i visoko razvijenim protokolima liječenja recidivi tumora su česti. Povratak tumora nakon određene terapije najvjerojatnije potječe od zaostalih tumorskih stanica koje nisu uklonjene liječenjem. Jedna od ključnih karakteristika tumora je velika raznolikost tumorskih stanica za koju se vjeruje da je nastala mutacijama i klonskom ekspanzijom pojedinih tumorskih stanica. Rezistencija tumora na ne-kirurške oblike liječenja se upravo pripisuje pojedinim podpopulacijama tumorskih stanica. Terapijska intervencija može djelovati kao selekcijski čimbenik čiji je rezultat ekspanzija rezistentnih klonova. Povrh toga, povratak bolesti nakon terapije može se objasniti i postojanjem posebne podpopulacije tumorskih stanica koje se nazivaju tumorske matične stanice (eng. cancer stem cells ili CSC). Tumorske matične prepoznate su u onkologiji kao važna ciljna. U radu će biti prikazane osnovne karakteristike tumorskih i ne-tumorskih matičnih stanica. Prikazat ću i kratki razvoj modela tumorskih matičnih stanica te pojasniti njihove osnovne karakteristke i ulogu u razumjevanju povrata bolesti i rezistencije na kemoterapeutike. Kratko ću prikazati osnovne markere ovih stanica te potencijalne mete za djelovanje kemoterapeutika. Također ću raspraviti i o važnosti nastavka istraţivanja tumorskih matičnih stanica u svrhu prevladavanja izazova na putu ka uspješnom liječenju onkoloških bolesnika.Cancer is one of the most common diseases of the modern era. In Croatia every fourth person is diagnosed with some form of cancer. In treating cancer most common therapeutic approaches are surgical therapy, chemotherapy, hormonal therapy, immunotherapy and radiotherapy. Even though we have all these methods and highly developed protocols for cancer treatment, relapse often occurs. Relapse after certain therapy approach is more likely to be caused by some cancer cells which have not all been eradicated by treatment. Almost all tumors are composed of a heterogeneus cell population, making them difficult to treat. A small cell subpopulation called cancer stem cells (CSCs) with a low proliferation rate and high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Cancer stem cells have been recognized as a major target cell population in oncology in recent years, and considerable effort has been made to identify novel CSC markers and target expression profiles as well as to measure the response of these cells to various targeted drugs as curative cancer therapy is effective only when a cancer stem cell subpopulation is completley eradicated. This thesis will discuss main characteristics of normal and cancer stem cells and the role of CSC in tumor relapse and resistance to standard chemotherapy protocols. I will also write about the evolution of the CSC model, potential new therapy targets and the importance of continuing the research on CSCs in order to overcome the challenges to sucessfully treating oncological patients

Highlight on the benefits of PBPK modeling: A link between drug properties and its in vivo performance

Physiologically based pharmacokinetic (PBPK) modeling or more recently also known as physiologically based biopharmaceutics modeling (PBBM) is a computer-aided (in silico) biopharmaceutical tool, designed to mechanistically describe bioperformance of a drug and predict its absorption and systemic availability. PBPK/PBBM was quickly adopted by pharmaceutical companies and medical regulatory agencies, its scope has expanded over the years, and nowadays PBPK/PBBM represents an essential tool in various phases of drug and formulation development (1). A major advantage of PBPK modeling over traditional in vitro and preclinical animal studies is the ability to link the physicochemical properties of a drug to its dissolution, absorption and disposition in a target patient or population, taking into account specific physiological conditions. This is accomplished through linked differential equations that describe simulta-neous or sequential dynamic processes that a drug undergoes in the body following dif-ferent routes of administration. PBPK predictions can refer to various physiological or disea-se states, so this unique approach can support personalized pharmacotherapy and drug/do-se/dosing regimen selection in different patient populations or individual patients (2). Although PBPK modeling can rely solely on the in silico generated data regarding drug’s properties (i.e., predicted based on the chemical structure of a drug), the prediction accuracy can be significantly improved with experimentally obtained input values. Therefore, any improvement in experimental drug characterization methods will inevitably lead to more reliable PBPK predictions. To illustrate the concept and implementation of PBPK modeling, this presentation will provide basic information on the structure of a PBPK model, and emphasis will be placed on case studies describing the interplay between drug-specific and physiologically relevant parameters that determine drug performance in vivo. Selected examples will be used to demonstrate how PBPK predictions can be used in conjunction with in vitro data on drug properties to answer clinically relevant questions, such as selecting appropriate drug therapy in bariatric patients, and assessing the impact of changes in gastric pH resulting from impaired gastric secretion or co-administration of proton pump inhibitors on drug dissolution, potential gastrointestinal precipitation and concomitant oral absorption.10th IAPC Meeting, Book of Abstract

Malignant properties of cancer stem cells

Maligni tumori su jedna od najučešćih bolesti modernoga doba. U Hrvatskoj svaka četvrta osoba oboli od nekoga oblika maligne bolesti. U liječenju malignih tumora koristimo najčešće kirušku terapiju, kemoterapiju (citostatike), hormonsku terapiju, imunoterapiju i radioterapiju. Usprkos svim tim metodama i visoko razvijenim protokolima liječenja recidivi tumora su česti. Povratak tumora nakon određene terapije najvjerojatnije potječe od zaostalih tumorskih stanica koje nisu uklonjene liječenjem. Jedna od ključnih karakteristika tumora je velika raznolikost tumorskih stanica za koju se vjeruje da je nastala mutacijama i klonskom ekspanzijom pojedinih tumorskih stanica. Rezistencija tumora na ne-kirurške oblike liječenja se upravo pripisuje pojedinim podpopulacijama tumorskih stanica. Terapijska intervencija može djelovati kao selekcijski čimbenik čiji je rezultat ekspanzija rezistentnih klonova. Povrh toga, povratak bolesti nakon terapije može se objasniti i postojanjem posebne podpopulacije tumorskih stanica koje se nazivaju tumorske matične stanice (eng. cancer stem cells ili CSC). Tumorske matične prepoznate su u onkologiji kao važna ciljna. U radu će biti prikazane osnovne karakteristike tumorskih i ne-tumorskih matičnih stanica. Prikazat ću i kratki razvoj modela tumorskih matičnih stanica te pojasniti njihove osnovne karakteristke i ulogu u razumjevanju povrata bolesti i rezistencije na kemoterapeutike. Kratko ću prikazati osnovne markere ovih stanica te potencijalne mete za djelovanje kemoterapeutika. Također ću raspraviti i o važnosti nastavka istraţivanja tumorskih matičnih stanica u svrhu prevladavanja izazova na putu ka uspješnom liječenju onkoloških bolesnika.Cancer is one of the most common diseases of the modern era. In Croatia every fourth person is diagnosed with some form of cancer. In treating cancer most common therapeutic approaches are surgical therapy, chemotherapy, hormonal therapy, immunotherapy and radiotherapy. Even though we have all these methods and highly developed protocols for cancer treatment, relapse often occurs. Relapse after certain therapy approach is more likely to be caused by some cancer cells which have not all been eradicated by treatment. Almost all tumors are composed of a heterogeneus cell population, making them difficult to treat. A small cell subpopulation called cancer stem cells (CSCs) with a low proliferation rate and high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Cancer stem cells have been recognized as a major target cell population in oncology in recent years, and considerable effort has been made to identify novel CSC markers and target expression profiles as well as to measure the response of these cells to various targeted drugs as curative cancer therapy is effective only when a cancer stem cell subpopulation is completley eradicated. This thesis will discuss main characteristics of normal and cancer stem cells and the role of CSC in tumor relapse and resistance to standard chemotherapy protocols. I will also write about the evolution of the CSC model, potential new therapy targets and the importance of continuing the research on CSCs in order to overcome the challenges to sucessfully treating oncological patients

Modelling the Relationship Between Entrepreneurial Orientation and BusinessSuccess

Glavni rezultati istraživanja predstavljaju doprinos naučnoj literaturi koja izučava odnos između preduzetničke orijentacije i učinka preduzeća. Najpre je dokazano postojanje direktne i pozitivne relacije između preduzetničke orijentacije kao latentnog konstrukta i ukupnog učinka preduzeća, u sklopu opšte hipoteze. Jedan segment literature ističe da je tako postavljena direktna relacija preterano jednostavna i redukcionistička i da postoji potreba da se uvedu posredne varijable u funkciji medijatora ili moderatora, koje će detaljnije i potpunije objasniti kako se promene u preduzetničkoj orijentaciji odražavaju na učinak preduzeća. Alternativnim hipotezama u ovom radu definisane su indirektne relacije između dimenzija preduzetničke orijentacije (partnerske mreže, tokovi znanja, nekonvencionalnost i politike preduzeća) i ukupnog učinka u kojima posredničku ulogu imaju učinak funkcije istraživanje i razvoj, učinak funkcije proizvodnja i učinak funkcije marketing i prodaja. Time je smanjen identifikovani naučni jaz u delu literature koji se bavi ulogom koju interni organizacioni faktori imaju u odnosu između preduzetničke orijentacije i učinka preduzeća.The main results of the research contribute to the scientific sources that study the relationship between entrepreneurial orientation and company performance. The research results confirm the existence of a direct and positive relationship between entrepreneurial orientation as a latent construct and the overall performance of the company, within the general hypothesis. One stream of the sources points out that the direct relationship established in this way is oversimplified and that there is a need to introduce indirect variables like mediators or moderators, which will explain in more detail how changes in the entrepreneurial orientation affect company performance. The alternative hypotheses in this paper define indirect relations between the dimensions of entrepreneurial orientation (partnership networks, knowledge flows, unconventionality, and company policies) and the overall company performance in which performances of research and development, production, and marketing and sales functions have the role of mediator. This reduces the identified scientific gap in the part of the sources that deal with the role that internal organizational factors play in the relationship between entrepreneurial orientation and company performance

Primena fiziološki zasnovanog modelovanja u razvoju inovativnih lekova: digitalni prozor u putovanje leka kroz organizam

The application of computer-based (in silico) modeling&simulation tools has become a global trend in different areas of science, including pharmaceutical sciences. These methods have been increasingly used in different phases of formulation development, starting with defining a sound formulation strategy, through the selection of drug dose and optimal formulation for clinical studies, to the prediction of drug absorption/disposition in different populations, identification of potential drug-drug interactions, prediction of bioequivalence study outcomes and justification of biowaivers (1). In silico tools for the prediction of drug bioperformance incorporate the so called physiologically-based models i.e., systems of data on physiological conditions and processes a drug undergoes in the organism, with an adequate mathematical background to describe these processes. As such, these models allow prediction of the expected therapeutic outcomes following drug administration, and offer a distinctive opportunity to test hypotheses and identify the underlying mechanisms responsible for the phenomena a drug undergoes in vivo. In other words, they act as a digital window to “drug’s journey through the body”. Physiologically-based models have been upgraded continuously, and relatively simple models evolved into the model-based drug development platforms, initiating a transformational change in drug formulation research&development. Opposed to the traditional “trial&error” methods, the outcomes of in silico modeling are based on the knowledge of in vivo processes, and planning of the optimal formulation strategy depending on drug biopharmaceutical properties and physiological characteristics of the target population. The selected examples will demonstrate the basic principles of in silico modeling in the development of pharmaceutical formulations.Primena računarski podržanih (in silico) metoda modelovanja i simulacija postala je globalni trend u različitim oblastima nauke, uključujući i farmaceutske nauke. Poslednjih godina ove metode nalaze sve širu primenu u različitim fazama razvoja leka, od definisanja strategije za razvoj formulacije, preko izbora odgovarajuće doze leka i optimalne formulacije za kliničke studije, do predviđanja apsorpcije i dispozicije leka u različitim populacijama pacijenta, identifikacije potencijalnih lek-lek interakcija, predviđanja ishoda studija biološke ekvivalencije i argumentovanja biowaiver-a (1). Programi za in silico simulaciju/predviđanje “ponašanja leka u organizmu” predstavljaju tzv. fiziološki-zasnovane modele, bazirane na saznanjima o fiziološkim uslovima i procesima kojima lek podleže u organizmu, kao i primeni odgovarajućih matematičkih relacija kojima je ove procese moguće opisati. Stoga predstavljaju korisno sredstvo, ne samo za predviđanje očekivanih terapijskih ishoda koji prate primenu leka, već i za testiranje hipoteza, odnosno, identifikaciju mehanizama koji su odgovorni za fenomene kojima lek podleže in vivo. Drugim rečima, predstavljaju digitalni prozor u “putovanje leka kroz organizam”. Fiziološki-zasnovani modeli se kontinuirano unapređuju, te su relativno jednostavni modeli evolirali u tzv. model-zasnovane platforme za razvoj lekova, što je na neki način pokrenulo revoluciju u oblasti istraživanja i razvoja lekova. Za razliku od tradicionalnih metoda „pokušaja i greške“, ishodi in silico modelovanja su zasnovani na poznavanju procesa koji se dešavaju in vivo i planiranju optimalne strategije za razvoj formulacije, u zavisnosti od biofarmaceutskih svojstava lekovite supstance i fizioloških karakteristika ciljane populacije pacijenata. U ovom izlaganju će, na odabranim primerima, biti prikazani osnovni principi in silico modelovanja u razvoju formulacija farmaceutskih preparata.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products

Modelling the Relationship Between Entrepreneurial Orientation and BusinessSuccess

Glavni rezultati istraživanja predstavljaju doprinos naučnoj literaturi koja izučava odnos između preduzetničke orijentacije i učinka preduzeća. Najpre je dokazano postojanje direktne i pozitivne relacije između preduzetničke orijentacije kao latentnog konstrukta i ukupnog učinka preduzeća, u sklopu opšte hipoteze. Jedan segment literature ističe da je tako postavljena direktna relacija preterano jednostavna i redukcionistička i da postoji potreba da se uvedu posredne varijable u funkciji medijatora ili moderatora, koje će detaljnije i potpunije objasniti kako se promene u preduzetničkoj orijentaciji odražavaju na učinak preduzeća. Alternativnim hipotezama u ovom radu definisane su indirektne relacije između dimenzija preduzetničke orijentacije (partnerske mreže, tokovi znanja, nekonvencionalnost i politike preduzeća) i ukupnog učinka u kojima posredničku ulogu imaju učinak funkcije istraživanje i razvoj, učinak funkcije proizvodnja i učinak funkcije marketing i prodaja. Time je smanjen identifikovani naučni jaz u delu literature koji se bavi ulogom koju interni organizacioni faktori imaju u odnosu između preduzetničke orijentacije i učinka preduzeća.The main results of the research contribute to the scientific sources that study the relationship between entrepreneurial orientation and company performance. The research results confirm the existence of a direct and positive relationship between entrepreneurial orientation as a latent construct and the overall performance of the company, within the general hypothesis. One stream of the sources points out that the direct relationship established in this way is oversimplified and that there is a need to introduce indirect variables like mediators or moderators, which will explain in more detail how changes in the entrepreneurial orientation affect company performance. The alternative hypotheses in this paper define indirect relations between the dimensions of entrepreneurial orientation (partnership networks, knowledge flows, unconventionality, and company policies) and the overall company performance in which performances of research and development, production, and marketing and sales functions have the role of mediator. This reduces the identified scientific gap in the part of the sources that deal with the role that internal organizational factors play in the relationship between entrepreneurial orientation and company performance