OFFICIAL MEDICATIONS FOR ANTI-TUMOR GENE THERAPY

This is a review of modern literature data of official medications for anti-tumor gene therapy as well as of medications that finished clinical trials.The article discusses the concept of gene therapy, the statistical analysis results of initiated clinical trials of gene products, the most actively developing directions of anticancer gene therapy, and the characteristics of anti-tumor gene medications.Various delivery systems for gene material are being examined, including viruses that are defective in  replication (Gendicine™ and Advexin) and oncolytic (tumor specific conditionally replicating) viruses (Oncorine™, ONYX-015, Imlygic®).By now three preparations for intra-tumor injection have been introduced into oncology clinical practice: two of them – Gendicine™ and Oncorine™ have been registered in China, and one of them – Imlygic® has been registered in the USA. Gendicine™ and Oncorine™ are based on the wild type p53 gene and are designed for treatment of patients with head and neck malignancies. Replicating adenovirus is the delivery system in Gendicine™, whereas oncolytic adenovirus is the vector for gene material in Oncorine™. Imlygic® is based on the  recombinant replicating HSV1 virus with an introduced GM–CSF gene and is designed for treatment of  melanoma patients. These medications are well tolerated and do not cause any serious adverse events. Gendicine™ and Oncorine™ are not effective in monotherapy but demonstrate pronounced synergism with chemoand radiation therapy. Imlygic® has just started the post marketing trials

Antimicrobial resistance in clinical <I>Escherichia coli</I> isolates obtained from animals

The article presents data on the phenotypic and genotypic characteristics of antimicriobial resistance in Escherichia coli clinical isolates recovered from bovine microbiota (secretions from mammary glands, cervical swabs). 127 Escherichia coli isolates were studied, i.e. 44 from mammary glands secretions and 83 from cervical swabs. Disk diffusion method was used to study antimicrobial resistance of the cultures; minimum inhibitory concentrations of antimicrobials were determined in a serial dilution method; resistance genes were detected by polymerase chain reaction. The carried out research demonstrates a wide distribution of the isolates belonging to the phenotype resistant to ansamycins (rifampicin), semi-synthetic penicillins (ampicillin and amoxicillin), tetracyclines (doxycycline). The isolates showed a lower level of resistance to macrolides (azithromycin), amphenicols (levomycetin) and aminoglycosides (tobramycin). It was found that Escherichia coli clinical isolates are sensitive to third-generation cephalosporins and fluoroquinolone antimicrobials. However, since 28.46% of cultures demonstrate intermediate resistance to third-generation cephalosporins and 49.02% of Escherichia coli DNA samples isolated from mammal gland secretions had blaDHA gene associated with resistance to this group of antimicrobials, these antimicrobials could be hardly recommended as antibiotics of choice. Absence of VIM carbapenemase-encoding gene in the DNA of the recovered isolates and a low level of phenotypic resistance (10.22% of isolates from cervical swabs) can be one of the reasons for recommending first-line carbapenems as antibiotics of choice to treat animal diseases associated with Escherichia coli, along with fluoroquinolones as reserve antimicrobials. It was found that the recovered Escherichia coli isolates are more sensitive to combination antibiotics than to mono-antibiotics

Development of an experimental plant and a numerical model of an axial magnetic rotor suspension

This article presents the results of the work on the creation of an experimental plant, its testing, as well as the development of a computational model of a rotor magnetic suspension with the use of axial electromagnets. The main purpose of producing the plant was to test the results of the developed numerical finite element model. An automatic control system was developed for the experimental installation. The electrical circuit was assembled on the basis of a ESP32 microcontroller with a clock frequency of 240 MHz and a PWM with a capacity of 10 bits. A PID-regulator program was developed. The coefficients kP, kD, kI used in the code of the electronic control system program (PID-controller) were selected. An experimental study of the bearing capacity of the axial active magnetic bearing under the influence of an external axial force was conducted. The required power of the axial active magnetic bearing was determined. The maximum load-bearing capacity of the installation for the selected coefficients of the PID-controller was determined. An axisymmetric finite-element model of the axial active magnetic bearing was created in the open-source program FEMM 4.2. The load-bearing capacity of the installation for a given current intensity value was calculated. The results of the numerical modelling were compared with the experimental data obtained. The basic principles of creation and operation of the experimental plant and its numerical model are outlined

Antiarrhythmic therapy effects on quality of life among patients with extrasystoles

To investigate antiarrhythmic therapy effectiveness, safety and impact on quality of life (QoL) among patients with symptomatic extrasystolia, a study was performed in 152 individuals, with 140 completing the study. Mean age of the patients was 57 years; 102 patients sufferedfrom chronic coronary heart disease (CHD), 33 - from Grade IIessential arterial hypertension (AH) without CHD. Therapy included propafenone (Propanorm, PRO/ MED.CS Praha a.s.) in the dose of 300-450 mg/d, amiodarone (Cordaron, SANOFIWINTHROPINDUSTRIE), in the initial dose of 600 mg/d, gradually reduced to 200 mg/d, and metoprolol (Egilok, EGIS PHARMACEUTICAL Ltd.) in the dose of 50-100 mg/d. The treatment started in the hospital, followed by out-patient therapy. The follow-up period varied from 12 to 24 months, with mean duration of 18 months. If clinical course improved, antiarrhythmic therapy (AAT) could be stopped, starting again in case of recurrent extrasys-tolia. AAT effectiveness was assessed by Holter ECG monitoring, QoL - by special questionnaires. Assessment took place at baseline, as well as 10-21 days and 12 months after the therapy start. In general, AAT was well tolerated. AAT discontinuation due to adverse effects took place in 11,4 %, 9,5%, and 6,1 % of those receiving amiodarone, propafenone, and metoprolol, respectively. AAT with propafenone, amiodarone and metoprolol was associated with reduction in the extrasystolia number by ≥70 %, 62 %, and 38,2 %, respectively. It was also associated with QoL improvement and reduced anxiety and depression. These changes were maximal and reaching statistical significance in those receiving propafenone and amiodarone, comparing to the metoprolol group. QoL improvement correlated with reduction in extrasystolia number. Therefore, AAT with propafenone, amiodarone, and to a lesser extent, metoprolol, improved QoL in patients with subjective arrhythmia symptoms. The magnitude of this effect depended on antiarrhythmic effectiveness of the medications used. Long-term AAT, in particular, with propafenone and amiodarone, was safe, including patients with chronic CHD

Anti-Tumour Drugs: Planning Preclinical Efficacy and Safety Studies

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research

Противоопухолевые лекарственные препараты: планирование доклинических исследований по оценке эффективности и безопасности

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.Расшифровка структуры ДНК и разработка новых молекулярных методов ее анализа, идентификация специфических геномных изменений, ответственных за неопластическую трансформацию, стали поворотными моментами в разработке инновационных лекарственных средств — таргетных противоопухолевых агентов, направленных на молекулярные и генетические мишени опухолевого роста. Переход от эмпирического скрининга агентов, механизм действия которых основан на ингибировании пролиферации опухолевых клеток, к молекулярно-нацеленным методам анализа привел к возникновению ряда важных методологических вопросов, связанных с доклинической разработкой инновационных лекарственных средств. Цель работы — анализ общих принципов и особенностей доклинических исследований эффективности и безопасности современных противоопухолевых препаратов различных классов для усовершенствования существующих национальных методических рекомендаций. В работе рассмотрены вопросы доклинических исследований различных классов противоопухолевых лекарственных средств (синтетических химиотерапевтических препаратов, гормонов и антагонистов гормонов, препаратов алкилирующего действия, антиметаболитов, препаратов микробного и растительного происхождения, а также моноклональных антител). Приведены общие принципы изучения их фармакологической активности в системах in vitro, ex vivo и in vivo, определения фармакокинетических параметров, описаны используемые методы и модели исследований. Указаны особенности определения генотоксичности, канцерогенности, репродуктивной токсичности, мутагенности, острой и хронической токсичности препаратов разных групп, перечислены критерии выбора доз для токсикокинетических исследований. Необходимость гармонизации национальных требований к проведению доклинических исследований с европейскими нормами влечет за собой унификацию терминологии и дальнейшую разработку общих алгоритмов выбора доз и определения необходимых объемов исследования. Использование биомаркеров в доклинических исследованиях позволит исключить дальнейшие исследования неэффективных соединений