The post-communist transition at 30

In the 30 years since the fall of communism, the countries of the former Soviet bloc and Yugoslavia have undergone tremendous change. Income per capita at purchasing power parity more than tripled in Albania, Bosnia and Herzegovina, Estonia, Latvia, Lithuania, Poland, and Slovakia. All seven economies outpaced such celebrated growth engines as Singapore and Korea at the same stage of their development. But in Tajikistan and Ukraine average income fell relative to 1989. In Moldova and the Kyrgyz Republic income growth was modest, below 20 percent cumulatively. We test three theories on this divergence in income growth. We find that Orthodox countries and countries with less democratic accountability grow less

Survival of firms during economic crisis

We estimate the survival time of nearly 7,000 firms in a dozen of high-income and middle-income countries in a scenario of extreme economic distress, using the World Bank's Enterprises Surveys. Under the assumption that firms have no incoming revenues and cover only fixed costs, the median survival time across industries ranges within 8 to 19 weeks, while on average firms have liquidity to survive between 12 and 38 weeks. Schumpeter's (1934) theory of creative destruction is not corroborated in the data, as potential exit is not predicated on the size of firms, their age or their productivity

Дизајн на физибилити студија за воспоставување на производство на zirconium-89 радиоизотоп и имплементација на 89Zr-радиофармацевтици во клиничката пракса во Република Северна Македонија

In the last decade, the application of radiopharmaceuticals based on zirconium-89 (89Zr) radiometal has increased in both preclinical and clinical studies. The most frequently used 89Zr-radiopharmaceutical is 89Zr-trastuzumab used in the management of patients with breast cancer. Breast cancer is the most common cancer among women in North Macedonia and the most common cause of death from malignant neoplasms in this population; therefore, the introduction of new nuclear medicine procedures in these patients might improve the management of this disease. However,the introduction of radioisotope and radiopharmaceutical production requires significant investments, both manpower and financial. The purpose of this work is to present the design conceptualization of a feasibility study for the establishment of production of zirconium-89 radioisotope and implementation of 89Zr-radiopharmaceuticals in clinical practice in the Republic of North Macedonia and to present the initial results from the first phases of the study. This feasibility study is designed to include preliminary analysis, market research, technical feasibility analysis, economic analysis, review and analysis of all data and feasibility conclusion. The evaluation of the data from the analyses conducted in all study phases is needed to identify the favourable and unfavourable factors and circumstances in order to make a final assessment of the feasibility of establishing the zirconium-89 radioisotope and 89Zr-radiopharmaceuticals production and implementation of 89Zr-trastuzumab use in nuclear medicine practice.Во последната деценија, радиофармацевтските препарати што содржат zirconium-89 (89Zr) радиоизотоп имаат зголемена примена како во претклиничките, така и во клиничките студии. Најчесто користен 89Zr-радиофармацевтик е 89Zr-trastuzumab кој се применува во насока на планирање на терапија на пациенти со рак на дојка. Ракот на дојката е најчестиот карцином кај жените во Северна Македонија и најчеста причина за смрт од малигни неоплазми кај оваа популација, затоа воведувањето нови дијагностички процедури во нуклеарната медицина може да придонесе за подобро планирање на терапијата кај овие пациенти. Сепак, воспоставувањето на производство на радиоизотопи и радиофармацевтици бара значителни инвестиции, финансиски и кадровски. Целта на овој труд е да го претстави дизајнот на физибилити студијата за воспоставување на производство на zirconium-89 радиоизотоп и имплементација на 89Zr-радиофармацевтици во клиничката пракса во Република Северна Македонија, како и да ги претстави резултатите од почетните фази на студијата. Оваа физибилити студија е дизајнирана така што вклучува прелиминарна анализа, истражување на пазарот, анализа на техничка изводливост, економска анализа, преглед и анализа на сите податоци и заклучок за физибилност. Евалуацијата на податоците од анализите во рамки на сите фази на студијата е потребна за да се идентификуваат поволните и неповолните фактори и околности за да се донесе конечна проценка на физибилноста за воспоставување на производство на zirconium-89 радиоизотоп и 89Zr-радиофармацевтици и воведување на 89Zr-trastuzumab во нуклеарно-медицинската пракса

Aseptic process validation of [18F]Sodium Fluoride radiopharmaceutical in-house production

Sodium fluoride ([18F]NaF) is a PET radiopharmaceutical for vizualization of the skeletal system and microcalcification. In the originally designed in-house method, [18F]NaF is recovered in aqueous solution after cyclotron irradiation, sterilized by passage through a 0.22 μm sterile filter and dispensed under aseptic conditions. To ensure the microbiological safety of drugs produced under aseptic conditions, validation of aseptic procedures is always recommended. This is essential for radiopharmaceuticals because most of them are released for administration before any sterility test can be completed due to their radioactive nature. This study reports the validation of the aseptic process applied to the internal production of [18F]NaF carried out in two phases: testing the number of viable microorganisms in radiopharmaceutical product prior to sterilization and process simulation studies (media fill tests). We found that all samples were sterile and the endotoxin concentration was well below the maximum acceptable level reported in the Ph Eur. monograph on [18F]NaF. The results confirmed that the entire production process of [18F]NaF can be carried out under strictly aseptic conditions following the validated procedures preserving the sterility of the final product

Comparison of the impact of two versions of reagent and ancillary sets on the [18F]FDG radiochemical yield

Aim: The purpose of this study is to compare the impact of the optimised versus standard version of the reagent set and ancillary kit on the [18F]FDG radiochemical yield. Materials and Methods: [18F]Fradioisotope is produced in a cyclotron (GE PETtrace 16.5 MeV) by irradiating enriched 18O water with protons. [ 18F]FDG radiosynthesis (a nucleophilic 18F-fluorination followed by base-catalyzed hydrolysis) is conducted using an automated synthesizer IBA Synthera V2 module and a single-use disposable system – Integrated Fluid Processor (IFP) as well as reagents and ancillary set. There are two commercially available versions of these sets. In the new version of the reagents set, the molar ratio acetonitrile-water in the cryptand solution is 4:1 instead of 1:1. As the separation cartridge in the new version of the ancillary kit is used QMA Carbonate Plus Light, instead of QMA Plus Light. A modification is also made in the purification cartridges, Oasis HLB in place of the C18 cartridge. In this study, 100 [18F]FDG batches in total are analyzed. 50 batches were synthesized using the standard version of the reagent and ancillary kits, while the other 50 batches were with the optimised version. The mean radiochemical yield (RCY), decay-corrected, and relevant standard deviation (SD) are calculated for both types of analyzed batches. Results: [18F]FDG batches produced using the optimised version of reagents and ancillary kit has higher RCY (65.01% ± 4.52%) compared to the batches produced using the standard version (57.83% ± 3.61%). Conclusion: This study confirms that the optimisation of the reagent and ancillary sets contributes to a higher radiochemical yield of the produced [ 18F]FDG

Design of feasibility study for the establishment of production of zirconium-89 radioisotope and implementation of 89Zr-radiopharmaceuticals in clinical practice in the Republic of North Macedonia

The radiopharmaceuticals based on zirconium-89 (89Zr) radiometal, in the last decade, have increased application in both preclinical and clinical studies. The most frequently used 89Zr-radiopharmaceutical is 89Zr-trastuzumab used in the management of patients with breast cancer. Breast cancer is the most common cancer among women in North Macedonia and the most common cause of death from malignant neoplasms in this population, therefore the introduction of new nuclear medicine procedures in these patients might improve the management of this disease. However, the introduction of radioisotope and radiopharmaceutical production requires significant investments, both manpower and financial. In order to assess the feasibility of establishing the production of zirconium-89 radioisotope and 89Zr-radiopharmaceuticals at the University Institute of Positron Emission Tomography (UI PET), a feasibility study is designed. The purpose of this work is to present the design conceptualization of a feasibility study for the establishment of production of zirconium-89 radioisotope and implementation of 89Zr-radiopharmaceuticals in clinical practice in the Republic of North Macedonia and to present the initial results from the first phases of the study. This feasibility study is designed to include preliminary analysis, market research, technical feasibility analysis, economic analysis, review and analysis of all data and feasibility conclusion. The evaluation of the data from the analyses conducted in all study phases is needed to identify the favourable and unfavourable factors and circumstances in order to make a final assessment of the feasibility of establishing the zirconium-89 radioisotope and 89Zr-radiopharmaceuticals production and implementation of 89Zr-trastuzumab use in nuclear medicine practice. Keywords: feasibility study, zirconium-89 radioisotope, 89Zr-radiopharmaceuticals, production, 89Zr-trastuzuma

Production of [11C] Choline in The University Institute for PET – new perspective in diagnostics of prostate malignancy in R. of Macedonia

[11C] Choline injection is radiopharmaceutical for oncological PET imaging of tumors which overexpress choline kinase. The most important clinical application of this PET radiopharmaceutical is in prostate cancer that can be visualized precisely, having differentiated localization located in comparison with benign tissue. The uptake of specific radiopharmaceutical remains constant thereafter, allowing better visualization of this kind of tumor. [11C]Choline PET/CT could represent an important imaging modality also in the detection of distant relapses in prostate cancer patients with biochemical recurrence

Quality control of PET radiopharmaceuticals, with reference to its specifics vs quality control of conventional pharmaceuticals

Radiopharmaceutical preparations or radiopharmaceuticals are medicinal products which, when ready for use, contain one or more radionuclides (radioactive isotopes) included for a medicinal purpose. As well as pharmaceuticals, they undergo strict quality control (QC) tests and procedures before release for use in patients. PET radiopharmaceuticals are usually formulated as sterile, apyrogenic injections, so they have to fulfill requirements for quality, efficacy and safety of conventional parenteral preparations. The specifics of QC of the radiopharmaceuticals arise from the very nature and the short half-life of the radioisotopes. The presence of radioisotope require introducing tests for radionuclidic and radiochemical identity and purity which are unique for radiopharmaceuticals. The presence of undesirable, extraneous radionuclides increases the undue radiation dose to the patient and may also degrade the scintigraphic images. Radionuclidic purity (RNP) is defined as the fraction of the total radioactivity in the form of the desired radionuclide present in a radiopharmaceutical, usually expressed as a percentage. RNP is determined by measuring the half-lives and emitted gamma radiation (gamma spectroscopy method). Radiochemical purity (RCP) is the fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical. For most radiopharmaceuticals, radiochemical purity above 95 % is desirable, since the impurities will almost certainly have a different biodistribution which can distort the image and interfere with the interpretation of the scan. Determination of the radiochemical purity can be carried out by a variety of chromatographic methods like TLC, HPLC. Unlike conventional pharmaceuticals, radiopharmaceuticals cannot be manufactured, then tested and left in quarantine until the results of all tests are available, as most (if not all) of the radioactivity will decay to a level when this radiopharmaceutical will become useless. The radiopharmaceuticals have to be manufactured, tested for quality and then administered to the patient within a short period of time. Since the execution of some of the tests takes more time, it is not mandatory these tests to be completed before release for use. These tests are strictly defined in the individual pharmacopeia monographs. In addition, due to the presence of source of radiation, all aspects of radiation protection should be retained while doing the tests for quality control of radiopharmaceuticals. Key words: radiopharmaceuticals, QC control, radioisotope, radionuclide impurity, radiochemical impurity, radiation protection

Optimization of production of [11C]CH3I with Methylator II for synthesis and development of [11C]radiopharmaceuticals

Aim: University Institute of Positron Emission Tomography Skopje is equipped with the Methylator II (Comecer Spa. Former Veenstra In- struments BV.), a module designed for the production of high spe- cific activity MethylIodide ([11C]CH3I) and/or Methyl Triflate ([11C]CH3OSO2CF3) and CarbonSynthon I (Comecer Spa.) for produc- tion of simple 11C radiopharmaceuticals. The synthesis process starts with the production of [11C]CO2 in the cyclotron (GE PETtrace 16.5MeV) via the 14N(p,α)11C nuclear reaction. The produced [11C]CO2 is delivered into the Methylator, where it first was trapped and sub- sequently reduced to [11C]CH4 and converted thereafter into [11C]CH3I and/or [11C]CH3OSO2CF3. The trapped [11C]CO2 in the Methanizer was reduced into a [11C]CH4 with hydrogen on a nickel catalyst (Shinwasorb) at a rather moderate temperature 350 0C. The next step was the purification of the [11C]CH4 over a Carboxen 1000 column, with the knowledge that the H2 will flow about 7 times fas- ter than [11C]CH4 through carbon packing causing the separation of H2 and CH4. This is one of the most important steps in the produc- tion process which affects directly the equilibrium reaction which forms the [11C]CH3I and HI, which is formed in the iodine oven by the reaction of H2 and I2 as well Methods: Optimization experiments where performed maximizing the yield of [11C]CH3I. By changing the time for switching the valve V04 (see diagram) the effectiveness of the purification was influ- enced. In ‘Active’ state the formed [11C]CH4 and excess of H2 was di- rected toward waste, but in ‘Inactive’ state in direction of the Iodine Oven. If the time was too short the reduced [11C]CH4 would not be separated thorougly enough from the H2, but when the time was too long the produced [11C]CH4 would be lost into waste. The first syntheses were performed with V04 active for 25 sec upon release of the [11C]CH4, after which it was deactivated. Different timings for switching the valve were tested and the different yields were obtained. Results Our result presented in the Table showed that yield of [11C] CH3I and [11C] Choline is purification time depended. By increasing the time of purification (from 20 to 37 seconds) obtained trapped [11C] CO2, is more than four time higher and harvested [11C] CH3I as well. After 37 seconds we obtained 41% of [11C] CH3I that is directly reflected to the yield of [11C] Choline (34.6), fitting with our protocol for synthesis of [11C] Choline. Conclusion: The module and software give us a big opportunity and flexibility for testing and optimization of the production achieving a better yield, and also the development of new 11C radiopharmaceuticals

2-[18F]fluoro-2-deoxy-D-glucose production: correlation between yield and eob activity

2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) production is a routine synthesis process, involving fully automated synthesizer with single-use disposable system - integrated fluidic processor (IFP cassette) and overall synthesis time of 30 minutes. The synthesis of [18F]FDG is a six-step process consisting of two chemical reactions, a nucleophilic 18F- fluorination followed by a base-catalyzed hydrolysis. 18F- is produced by irradiating enriched [18O]-water with protons with GE PETtrace 16.5 MeV cyclotron, at University Institute of Positron Emission Tomography, Skopje. The amount of starting radioactivity depends on the desired radioactivity of final product, so because of that, our objective was to determine whether amount of starting radioactivity affects the radiolabeling efficiency and the capacity of starting materials or the production yield. Forty batches of [18F]FDG were produced with same IFP cassette and the same reagent kit (different batch production but same producer). The mean decay corrected production yield for [18F]FDG produced by starting radioactivity of 18F- from 20-35 GBq, 55-75 GBq and 150-170 GBq were 71,44% ± 5,5%, 70,13% ± 5,5% and 67,11% ± 2.3%, respectively. The results confirm that the starting radioactivity of radioisotope does not affect the production yield and there is no significant difference between the results in these three groups of results, p>0.05 (0.069). [18F]FDG was successfully synthesized with a production yield above 60% in all batches, as result of the high-quality and the large capacity of starting materials for radioactivity to give efficient radiochemical synthesis