Моноклонални антитела како анти-канцер терапија

Моноклоналните антитела можат да се користат како слободни – неконјугирани, или конјугирани со различни лекови, токсини или радиоизотопи со цел за подобрување на специфичноста и фармаколошкиот одговор и намалување на несаканите ефекти. До денес од страна на FDA (Агенцијата за храна и лекови) се регистрирани единаесет моноклонални антитела кои се користат како анти-канцер терапија

Technetium Nitrido-Peroxo Complexes: An Unexplored Class of Coordination Compounds

The purpose of this work was to further expand the chemistry of mixed technetium nitrido-peroxo complexes, a still poorly explored class of compounds containing the Tc(VII) moiety, [99gTc][Tc(N)(O2)2]. A number of novel complexes of the formula [99gTc][Tc(N)(O2)2(L)] with bidentate ligands (L) (where L = deprotonated alanine, glycine, proline) were prepared by reacting a solution of nitrido-technetic(VI) acid with L in the presence of a source of H2O2. Alternatively, the complex [99gTc][Tc(N)(O2)2X]− (X = Cl, Br) was used as a precursor for substitution reactions where the halogenide ion was replaced by the bidentate ligand. The new complexes were characterized by elemental analysis and mass spectroscopy. The preparation of the analogous [99mTc][Tc(N)(O2)2] moiety, radiolabeled with the metastable isomer Tc-99m, was also studied at a no-carrier-added level, using S-methyl-N-methyl-dithiocarbazate as the donor of the nitrido nitrogen atoms

Clinical aspects of different pharmaceutical formulations of propranolol in the treatment of infantile hemangioma

Infantile hemangiomas are oneof the most common benign vascular tumors in infants and children. Because hemangiomas can resolve spontaneously, they usually do not require specific treatment unless the proliferation interferes with normal function or causes interference with the function of essential vital organs. There are severaltypes of therapy, but in recent decades the use of propranolol has become more common due to its excellent effectiveness. The purpose of this paper is to analyze different pharmaceutical formulations of propranolol in the treatment of infantile hemangioma, including technological differences of the oral and topical pharmaceutical dosage forms of propranolol. The European Medicines Agency (EMA) has approved the commercially available oral propranolol therapy in the countries of the European Union, but thisis not yet happened in our country. Recommendations to follow and use the protocols for the oral application of propranolol in the treatment of this disease are difficult due to the fact that this drug formulation is not registered in our country and patients are forced to obtain it from countries where it is registered. The use of syrup as an oral form of therapy has been clinically proven and has a high percentage of efficiency in infantile hemangioma, but side effectssuch as sleep disturbance, bronchospasm, hypoglycemia, hypotension. The goal of this publication is to propose the most appropriate topical formulation of propranolol for external use in infantile hemangioma through a review of relevant published data on the use of various pharmaceutical formulations of propranolol in clinical studies and documents from the European Medicines Agency,In this paper, we used compilation and comparison methods, as most useful for a high-quality critical evaluation of the literature regarding problematic topics, in our case the pharmaceutical formulation of propranolol, the effect of clinical treatment and the required legislation, and which have the potential to promote clearer, shared understandings and accelerate advances in the research. Our results were focused on obtained and published data related to pharmaceutical-technological aspects of production of topical formulations and the effect of clinical application, especially when it is necessary to define exactly the amount of the released active compoundfrom the topical form (cream, ointment or gel) and its absorption through the skin.Topical form of propranolol avoids the side effects of oral administrated propranolol, can help maintain a high level of active ingredient in a local or focal region, and has an easy way of administration.The obtained research data showed that the topical application and penetration of propranolol through the skin is good and has a lower and controlled systemic absorption. To achieve this, the choice of the formulation andthe excipients used are particularly important. Lipophilic formulations have limited release and penetration of propranolol. The best results are achieved by using a hydrophilic cream.After the research done, we can conclude that the production of topical formulations containing specific active components with a strong systemic effect, such as propranolol, can be carried out in galenic laboratories or hospital pharmacies. For this, already existing validated equipment and excipients that are readily available can be used. We believe that the use of topical pharmaceutical forms for local application, even in children such as the case of propranolol in infantile hemangioma, is justified, especially to the fact that so far no side effects have been registered even after long-term therap

Connection of the ABO blood group system from the whole blood groups with the diabetes mellitus typ 2 for the period 2005-2009

Introduction:The real dimension of the connection between any blood group from the ABO system of blood groups and diabetes mellitus typ 2 in the eastern part of Republic of Macedonia in not well known. Aim:The aim of our study was to establish the connection of the blood group from the ABO system of blood groups with diabetes mellitus typ 2. Material and methods:The total number of registered patients with diabetes mellitus typ 2 in the Center of diabetes in Clinical hospital in Stip for the period 2005-2009 is 5,342. They were followed belong to ABO system of blood group by the determination of the ABO blood group and after receiving the written permission.The control group contained 12,500 healthy blood donors donated blood during the same period. The examination of the patients was realized in the RE of Transfusion in Stip using micro-agglutinated cards (Dia Med-ID Mikro Typing Systems). Results:The results using Chi-square test showed no connection between ABO blood groups and diabetes mellitus typ 2. Blood group "A" and "O" were negatively associated with diabetes mellitus typ 2 (P < 0,005) because the biggest part of that blood group were no diabetic patients. There is no significant association between blood group "B" and "AB" with diabetes mellitus typ 2, although most of patients with diabetes mellitus typ 2 were with blood group "B". Discussion and conclusion:After completed the study, obtained results confirmed that there is a negative correlation of blood group "A" and "O" from the ABO system od blood groups with diabetes mellitus type 2

Приоди за радиобележување со Астатин-211

Астатин-211 (211At) е радиоактивен изотоп кој емитира алфа честици. Во последниве години постои голем интерес за негова употреба во таргетирана алфа терапија кај пациенти со различен малигнитет. Тој е најреткиот и нај нестабилниот елемент во природата кој се добива во циклотрон. Астатинот припаѓа на групата на халогени елементи, но покажува и карактеристики на метал, што го прави елемент со дуална природа и со различни карактеристики при споредба со халогените. Во широката палета на биомолекули кои се користат како таргет за радиобележување, опишани се поголем број, меѓу кои најмалите нанободи, пептиди, фрагменти од антитела, па се до најголемите моноклонални антитела. Предизвикот при радиобележувањето со астатин-211 е неговото релативно кратко време на полураспаѓање од 7,2 часа. Механизмот на радиобележување на моноклонални антитела, познат како астатинација, вклучува нуклеофилна супституција со халогени елементи или електрофилно раскинување на врската со калај и замена со астатин (дестанилација). Овие два механизми може да се изведат преку постапка што вклучува обележување во еден чекор, односно вклучува пред-третман на конјугација на моноклоналното антитело и потоа директно обележување со радиоактивен астатин-211. Исто така, антителото може да се обележи и со постапка во два чекора, каде што се користи простетична група која примарно стапува во реакција со радиоактивниот астатин-211, а потоа се обележува антителото. И двата начина даваат задоволителни резултати за принос по радиобележување и радиохемиска чистота, но се разликуваат во времето потребно за нивна изведба. Последните истражувања се насочени на користење на кластери од бор како простетична група, за да се надмине ослободувањето на радиоактивен слободен астатин-211

Research on the influence of different types of anion-exchange cartridges on the quality of [18f]NaF radiopharmaceutical as part of production process development

[18F]Sodium Fluoride radiopharmaceutical is a sterile solution for intravenous administration, intended for skeletal visualization by positron emission tomography (PET). [18F]Sodium Fluoride for bone imaging was introduced in early 1960's, but with the increased availability of PET scanners in the last two decades, this radiopharmaceutical has growing use in clinical practice for the detection of bone metastases. The production process of [18F]NaF includes production of the radioisotope [18F]Fand purification and formulation of the [18F]NaF radiopharmaceutical. The radioisotope [18F]Fis produced by a cyclotron via the 18O(p,n)18F nuclear reaction, followed by recovery of [18F]Ffrom [18O] proton-irradiated water by adsorption and desorption from anionexchange resins. The fluoride anions are trapped on the anion-exchange SPE (solid-phase extraction) cartridge, and all other cationic and water-soluble radionuclide impurities present in irradiated enriched water are collected in the waste vial. Next step is desorption of the fluoride anions from the cartridge by elution with saline solution (0.9% NaCl). This study aimed to define the most appropriate type of anion-exchange SPE cartridge which could be used for routine production [18F]Sodium fluoride radiopharmaceutical which meets the quality requirements defined in European pharmacopeia monograph. For that purpose, as part of development of in-house production method, manual productions with four different types of anion-exchange cartridges were performed. The influence of sorbent substrate and counter-ion of the cartridge on the final yield and the quality of the produced radiopharmaceutical was investigated. The study also aimed to define the minimum volume of physiological solution required for the pH parameter to be within limits. The results have shown that the quality parameters: appearance, chemical purity, radiochemical purity and radionuclide purity were in defined acceptance criteria and did not differ when using different anion-exchange cartridges. The pH analyses have demonstrated that the type of cartridge and counter-ion influence the final pH of [18F]NaF solution. This study confirmed that the three types of anion-exchange resins (QMA-Cl-, QMA-CO32- and PS-OH-) could be used for production. In the experiments where QMA-Cl- was used, the required pH level was obtained even without dilution. The other cartridges could be used in the [18F]NaF production process, but further dilution is necessary in order to obtain the pH value in acceptance criteria. On the basis of this study, the QMA-Cl is chosen as a cartridge to be used in the further development of the in-house method for [18F]NaF radiopharmaceutical production

Analytical approaches for assessing immunoconjugates integrity and characterization prior to radiolabeling

Immunoconjugates, which have highly specific targeting towards certain antigens, are molecules that are built from three parts: an antibody, a therapeutic payload, and a linker between them. Based on the mechanism of the therapeutic agent, they are divided into defined groups: antibody-drug conjugates (therapeutic payload), radioimmunoconjugates (radioisotope), or immunotoxins (catalytic, protein toxins). The major interest of this research is focused on immunoconjugates ready to be radiolabeled, and the analytical techniques used for assessing their integrity and characterization. Testing of the immunoconjugates generally can be as quality control testing in qualified good manufacturing practices laboratories or characterization using research and development methods. The used techniques, electrophoresis (reducing conditions), Infrared spectroscopy and Raman spectroscopy, give information about the integrity, primary structure, and the number of chelators attached to the mAb with MALDI – TOF analysis. This can be as primary analysis for integrity and characterization of immunoconjugates prior radiolabeling. The success of a radiolabeling process, as well as the distribution of immunoconjugate after labeling to tumor cells, depends primarily on antibody characteristics, the appropriate chelator, and the method of their conjugation. The choice of methods used for quality control of the formed immunoconjugates is crucial to correctly assess and perform categorization prior to radiolabeling process

Trastuzumab radioimmunoconjugates - promising strategy for selective anticancer therapy

Monoclonal antibody Trastuzumab is the first humanized approved antibody for tratment of HER-2 positive breast cancer. Led by its promising indication, we made further improvemetns to prepare freeze-dried immunogates with bifunctional chelators, ready to use kit formulation for radiolabeling. Formulation of freeze dried immunoconjugates of trastuzumab was prepared after purification of commercially available drug, already used for treatment, using bifunctional chelating agent (BFCA) with acyclic (1B4M-DTPA) and macrocyclic (DOTA) structure. A several chemical techniques have been used to determine the stability and retained immunoreactivity of the antibody in the formulated immunoconjugates and after their labelling with radioactive and non-radioactive isotopes. The appearance of two bands of fragments in SDS-PAGE gels in lyophilized and labeled conjugates have shown retained secondary structure. The presence of characteristic amide bands in IR spectra and Raman spectra have indicated that all samples have retained native secondary structure. An average of 4.3-5.3 groups linked to the antibody determined by MALDI analysis helped in the decision of molar ratio Ab: BFCA and successful labeling. Stability of freeze dried immunoconjugates (in molar ratio 1:20) were characterized by HPLC-UV and yield of labelling with 177Lu and 90Y by ITLC-SG. According to all obtained results and previous experiens related to the freeze dried formulation of antibody conjugates, we have hope that this approach can give a distinctive contribution in the fields of radioimmunotherapy using beta emitters and alpha as well