Metabolic, Apoptotic and Fibro-Inflammatory Profiles of the Heart Exposed to Environmental Electromagnetic Fields.

Environmental stress can disturb the integrative functioning of the cardiovascular system and trigger a number of adaptive and/or maladaptive cell responses. Concomitant with the expanding use of mobile communication systems, public exposure to electromagnetic fields (EMFs) raises the question of the impact of 900 MHz EMFs on cardiovascular health. Therefore, in this study, we experimentally investigated whether 915 MHz EMF exposure influenced cardiac metabolic, antioxidant, apoptotic, and fibro-inflammatory profiles in a mouse model. Healthy mice were sham-exposed or exposed to EMF for 14 days. Western blot analysis using whole cardiac tissue lysates demonstrated that there was no significant change in the expression of oxidative phosphorylation (OXPHOS) complexes between the control and EMF-exposed mice. In addition, the myocardial expression of fibro-inflammatory cytokines, antioxidant enzymes, and apoptosis-related markers remained unchanged in the EMF-challenged hearts. Finally, the structural integrity of the cardiac tissues was preserved among the groups. These findings suggest that the apoptotic, antioxidant, metabolic, and fibro-inflammatory profiles of the heart remained stable under conditions of EMF exposure in the analyzed mice.

Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial.

OBJECTIVE: To assess non-inferiority of s.c. to i.v. CT-P13 in RA. METHODS: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6). RESULTS: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. CONCLUSION: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.

THE ROLE OF ADVERSE CHILDREN'S EXPERIENCE IN THE DEVELOPMENT OF PSYCHOLOGICAL DISORDERS AMONG PARTICIPANTS IN ANTI-TERRORISM OPERATION.

OBJECTIVE: The aim: The sense of our research was to examine the reason for the consequential links between negative childhood experiences and the mental state of participants of anti-terrorist operations. PATIENTS AND METHODS: Materials and methods: A standard "Adverse Childhood Experiences (ACEs)" questionnaire was used to obtain primary data. Conflict tactics scales were used to determine emotional, physical, and domestic violence in respondents. RESULTS: Results: The study evaluated 7 categories of ACEs: physical indifference (lack of care and protection); emotional neglect (lack of love); physical violence (pushing, grabbing or slapping); emotional violence (scolded, insulted or suppressed); sexual violence; domestic violence and a family history of mental disorders, diseases or alcohol abuse. All respondents were divided into two groups: those who had psychological disorders and those who were healthy. CONCLUSION: Conclusions: The data obtained in the study indicate that the chances of having psychological disorders increase in those fighters who complained of emotional violence - the feeling of humiliation; physical violence - those who were beaten in childhood; domestic violence was manifested in the fact that the mother was beaten; disadvantaged families where a family member has used drugs or abused alcohol; the presence of depression in parents.

RELATIONSHIP BETWEEN CERVICAL CANCER AND THE LEVEL OF PREVENTIVE ONCOLOGICAL EXAMINATIONS.

OBJECTIVE: The aim: Of this study is to determine the relationship between the development of cervical cancer and the level ofconducting of preventive oncological examinations. To identify risk factors of cervical cancer, we considered seven prognostic variables, that are associated with the development of cervical cancer. PATIENTS AND METHODS: Matherials and methods: We conducted a survey of 120 women, among them 40 (33.3%) women had a confirmed diagnosis of cervical cancer, and 80 (66.7%) women were healthy. RESULTS: Results: We find, that factors that increase risk of cervical canser is age after 40 years increases the chances of cervical cancer by 14 times; untimely medical examinations increase by 5,4 times; the number of sexual partners, more than 4 - in 6 times. CONCLUSION: Conclusions: A comprehensive medical and social study has established a reliable relationship between the development of cervical cancer and the level of preventive cancer examinations.

Organization and legislative regulation of rehabilitation assistance to participants of joint force operations.

OBJECTIVE: The aim of our study was to investigate the mechanisms of rehabilitation, primarily medical, of participants in the armed conflict in the eastern regions of Ukraine (anti-terrorist operation/Joint Forces operation). PATIENTS AND METHODS: Materials and methods: Standard statistical methods were used to accomplish these tasks - bibliosemantic and content analysis methods. So, as can be seen from the conducted research, in Ukraine there is a legal regulation of the process of providing rehabilitation assistance (social, psychological, medical) for the participants of armed conflict in the eastern regions of Ukraine (ATO / JFO). RESULTS: Review: It should be noted separately that the organizational mechanisms for the provision of rehabilitation are constantly improving: introduction of the International Classification of Functioning, Restrictions of Life and Health and the International Classification of Functioning, Restrictions of Life and Health of Children and Adolescents in Ukraine introduced the qualification characteristics of rehabilitation specialists and rehabilitation specialists , physical therapist, ergotherapist, physical therapist assistant, ergotherapist assistant. CONCLUSION: Conclusions: It was also determined that despite the constant improvement of the organizational and regulatory frameworks for the provision of rehabilitation, there is a problem of the lack of unified protocols for the provision of medical rehabilitation - there is only a protocol of measures for post-traumatic stress disorder. Available and applicable the "road map" of providing of medical assistance, reparative treatment and rehabilitation measures in health care facilities for ATO participants.

Epidemiology of diseases of the circulatory system among the population of Poltava region.

OBJECTIVE: Introduction: In Ukraine more than half of deaths have been caused by cardio-vascular diseases (CVD). Among the able-bodied population, the share of CVD in the structure of causes of mortality is 29,9%. In the structure of causes of mortality among the persons of retirement age, CVDs accounted for 75,9% and exceeded the proportion of neoplasms in 6,5 times. The aim is to analyze of morbidity and mortality rates of diseases of the CVD among the population of Ukraine and Poltava region, to conduct a comparative analysis of data to identify possible ways to improve the situation. PATIENTS AND METHODS: Materials and methods: A retrospective study of morbidity and mortality rates by age, gender and cause (2014-2018) was conducted and the statistical method was used to analyze dynamic (time) series. RESULTS: Review: An analysis of the dynamics of population mortality indicates significant fluctuations in it`s levels over ten years. At the same time, by the method of alignment of the dynamic series, a tendency to a slight decrease in the mortality rate of the population from 17,1‰ to 16,9 ‰ was established. The mortality of the population of Ukraine in 2018 from diseases of the circulatory system was 1000,8 per 100 thousand people. Data on mortality rate in the Poltava region significantly higher than those in Ukraine. CONCLUSION: Conclusions: The age structure of the population of Poltava region belongs to the regressive type. The mortality rate among the population of Poltava region is slightly decreasing but remains at a very high level (16,9 ‰). In the structure of causes of death, diseases of the circulatory system are at the first place (70,8%), the second place belongs to neoplasm (13,5%), and third are the external causes of death (4,8%).

Comparative analysis of the dynamics of modified risk factors of non-communicable diseases among the population of China and Ukraine.

OBJECTIVE: Introduction: In the modern world, the problem of non-communicable diseases, which nowadays constitute the main cause of social and economic losses, is extremely topical: the main causes of disability and mortality of the working population are caused by non-communicable diseases. The aim is a comparative analysis of the prevalence and dynamics of the risk factors of the NCDs, and the overall mortality rate between the economically developed country - China and the developing country - Ukraine. PATIENTS AND METHODS: Materials and methods: To achieve the set goal, the method of data analysis was used - the alignment of dynamic rows with the definition of increasing rates, the determination of reliability between two unrelated aggregates, triangulation. Material: annual reports of the State Statistics Service of Ukraine and the National Bureau of Statistics of China. RESULTS: Review: As a result of the study, it was found that with the tendency to reduce the mortality rate, the mortality rate in Ukraine exceeds the rate in China, especially among men (2.5-3 times); the percentage of smoking is 6 times higher among Ukrainian women; an increase in malnutrition is observed in Ukraine, while in China it is constantly decreasing; in both countries there is an increase in the frequency of obesity in both sexes, but in Ukraine the prevalence is 4-6 times higher. CONCLUSION: Conclusions: Thus, using the obtained data, one can conclude that, despite the difference in the level of economic development between countries, behavioral risk factors remain an extremely important problem.

Familial heterozygous hypercholesterolemia: a case report.

OBJECTIVE: Іntroduction: Familial hypercholesterolemia (FH) is an autosomal dominant disorder, caused by the defect of the gene, encoding the structure and function of the receptor for the apoprotein B/E. Patients with FH are predisposed to premature development of atherosclerosis and clinically manifested forms of cardiovascular diseases, in particular coronary heart disease (CHD). The aim of our article is informing the general practitioners about the diagnosis and management of patients with familial heterozygous hypercholesterolemia. PATIENTS AND METHODS: Materials and methods: The data of domestic and foreign literature were analyzed. The case report of familial heterozygous hypercholesterolemia (FHH) was present in this article. Diagnostic criteria, current approaches to the management of patients with hereditary disorders of lipid metabolism are considered. CONCLUSION: Conclusions: Familial heterozygous hypercholesterolemia is one of the most common genetic disorders, but this pathology is not well-known to practitioners and is often underdiagnosed. Early diagnosis and aggressive contemporary hypolipidemic therapy is crucial for patients with signs of hereditary lipid disorders.

Planning of effective evaluation of the activities of hospital district at the example of poltava region.

OBJECTIVE: Introduction: Increasing of the availability and quality of health care in rural areas is one of the priority directions of public health and regional development policy. The need for reforming of the network of secondary health care facilities is due to the fact, that they are unable to meet the needs of the population in this specialized type of medical care in the conditions of the existing structure and funding system. The aim: to analyze the existing legislation regulating the establishment and operation of hospital districts; to determine the methodology for monitoring and evaluating of the activity of the hospital district on the example of the Poltava region. PATIENTS AND METHODS: Materials and methods: In this work a set of methods is used: system approach, bibliosemantic, legal, logical modeling. RESULTS: Review: A managerial tool capable of tracking the process and demonstrating the impact of projects, programs and development policies is monitoring and evaluation. The basis of evaluation is the creation of different indicators and indexes. The system of these indicators provides an opportunity to assess the social, medical, economic and environmental aspects of development of hospital district. The monitoring and evaluation program should include monitoring of implementation (contributions and activities) and monitoring of the results of work of the hospital districts (short-term and long-term). CONCLUSION: Conclusions: Hospital districts are created with the aim of optimizing of the organization and functioning of the network of health facilities. The Management Board's decision should be based on valid, reliable information on the development of the hospital district. Compliance with the monitoring and evaluation methodology makes it possible to provide the health care system with qualitative and timely data at all stages of its reformation.

A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy.

OBJECTIVES: To compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: This is a phase III, randomised, double-blind, parallel-group, multicentre study with a 24-week primary endpoint. Patients with moderate to severe RA despite MTX treatment were randomised to receive weekly dose of 50 mg of subcutaneous SB4 or ETN. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 24. Other efficacy endpoints as well as safety, immunogenicity and pharmacokinetic parameters were also measured. RESULTS: 596 patients were randomised to either SB4 (N=299) or ETN (N=297). The ACR20 response rate at week 24 in the per-protocol set was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted treatment difference was -9.41% to 4.98%, which is completely contained within the predefined equivalence margin of -15% to 15%, indicating therapeutic equivalence between SB4 and ETN. Other efficacy endpoints and pharmacokinetic endpoints were comparable. The incidence of treatment-emergent adverse events was comparable (55.2% vs 58.2%), and the incidence of antidrug antibody development up to week 24 was lower in SB4 compared with ETN (0.7% vs 13.1%). CONCLUSIONS: SB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was well tolerated with a lower immunogenicity profile. The safety profile of SB4 was comparable with that of ETN. TRIAL REGISTRATION NUMBERS: NCT01895309, EudraCT 2012-005026-30.

52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis.

Objective: To compare the 52-week efficacy and safety of SB4 [an etanercept biosimilar] with reference etanercept (ETN) in patients with active RA. Methods: In a phase 3, randomized, double-blind, multicentre study, patients with moderate to severe RA despite MTX treatment were randomized to receive 50 mg/week of s.c. SB4 or ETN up to week 52. Efficacy assessments included ACR response rates, 28-joint DAS, Simplified and Clinical Disease Activity Indices and changes in the modified total Sharp score (mTSS). Safety and immunogenicity were also evaluated. Results: A total of 596 patients were randomized to receive either SB4 (n = 299) or ETN (n = 297) and 505 (84.7%) patients completed 52 weeks of the study. At week 52, the ACR20 response rates in the per-protocol set were comparable between SB4 (80.8%) and ETN (81.5%). All efficacy results were comparable between the two groups and they were maintained up to week 52. Radiographic progression was also comparable and the change from baseline in the mTSS was 0.45 for SB4 and 0.74 for ETN. The safety profile of SB4 was similar to that of ETN and the incidence of anti-drug antibody development up to week 52 was 1.0 and 13.2% in the SB4 and ETN groups, respectively. Conclusion: Efficacy including radiographic progression was comparable between SB4 and ETN up to week 52. SB4 was well tolerated and had a similar safety profile to that of ETN. Trial registration number: ClinicalTrials.gov NCT01895309, EudraCT 2012-005026-30.

Medical evaluation of efficiency of optimized models for early detection and primary prevention of cardiovascular diseases.

INTRODUCTION: Nowadays cardiovascular disease occupies a leading place in the structure of the prevalence, incidence, disability causes and mortality of the adult population in Ukraine and in the whole world. The prevalence of hypertension in the adult population ranges from 25 - 40%, coronary heart disease is almost 20% of people aged 50-59 years while 24.3% of them have a form of silent coronary artery disease. The feasibility of study is justified by the need to perform health institutions Law of Ukraine dated 07.07.2011 year №3611-VI ≪On Amendments to the Basic Laws of Ukraine on health care on improvement of care" and MoH of Ukraine from 24.07.2013 № 621/60 "On the system of cardiac care in health facilities of Ukraine" therefore extremely important is to develop an optimized model of early detection and primary prevention of cardiovascular diseases at primary level of health care. The aim of the research is to develop methods and evaluation models optimized for early detection and primary prevention of cardiovascular diseases at a general practitioner of family medicine. MATERIAL AND METHODS: The methodical apparatus is of complex of medical and social research methods that meet the requirements of public health: bibliosemantyc, systematic approach and analysis, statistical, expert evaluations. To determine the effectiveness of medical evaluation was conducted in its 33 clinics of general practice in Poltava region, including 7 urban and 26 rural. In expert opinion is taken 825 patients, of which 175 urban and 650 in rural areas. The results of the study found that 193 patients (23.4%) achieved target blood pressure through the implementation of the recommendations concerning the optimization behavior towards of risk factors, lifestyle.

Determine the effectiveness of lipid-lowering therapy in patients with chronic obstructive pulmonary disease combined with coronary heart disease.

INTRODUCTION: In complex treatment of chronic obstructive pulmonary disease (COPD) combined with ischemic heart disease (IHD) more and more attention is drawn to pleiotropic effect of statins. The aim of our researches became determining the effectivity of utilization of rosuvastatin (CRESTOR®, IPR PHARMACEUTICALS, Inc.) in complex treatment of COPD combined with IHD. MATERIALS AND METHODS: Basing on pulmonology department of Poltava regional clinical hospital, 30 patients with COPD combined with IHD have been examined (stable effort angina FC II) aged from 51 to 67 y.o. (average age was 57,03 ± 3,51). The patients were divided into two age compatible groups. Patients of the main group (n = 15) underwent regular COPD and IHD treatment, addind 20 mg of rosuvastatin per night. The observed group (n = 15) didn't receive rosuvastatin. The examination of patients was held before and half year of treatment, included the estimation of respiratory symptoms of the disease, the degree of intensity of dyspnea (Medical Research Council Dyspnea Scale). The tolerance to physical exercise was studied with 6 minute walking test. The cholesterine level, HDL, LDL, function of ventilation have been tested as well. The average frequency of aggravations during the year was estimated through retrospective examination of anamnesis. RESULTS: After the treatment the improvement of clinical state has been noticed at both groups due to decrease of intensity of respiratory symptoms of the disease, such as cough, amount of expectoration, dyspnea and also increase of tolerance to physical exercise and improvement of laboratory-instrumental indexes. Though the patients of the main group were noticed to have significantly less amount of expectoration and cough. The distance covered in 6 minutes was positively longer (р < 0,05). It has to be noted that the patients of the main group had positive decrease of wheezing after treatment, due to increase of FEV1, GI (р < 0,01). The retrospective studying of the anamnesis revealed that the frequency of arrogations during the year was 1-2 times a year (1,6 ± 0,48). CONCLUSIONS: Including rosuvastatin into the treatment scheme allows to decrease and stabilize the main clinical symptoms of this constellation of diseases, improving the quality of life, reduce the frequency of exacerbations.

Intensifying approach to the therapy of patients with constellation of the diseases: chronic obstructive pulmonary disease and osteoarthritis.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of 21st century. About 210 million people all over the world are suffering with COPD, and annually 3 million people die of it. Under the influence of different factors, such as smoking, air prolusion, evaporation of chemicals, poisoning effect of chemical firings, inflammation processes take place in lungs, and if it is prolonged and take place simultaneously with morphological changes in the lungs, it it provide the de4velopment of the systemic inflammation process. At present systemic inflammation is regarded to be an essential component of COPD pathogeneses capable to become risk factor in developing and progressing multiple complications of the disease. The development of osteoporoses as the basis for the development of osteoarthritis (OA) is often considered one of a great amount of COPD complications and systemic effects. In the course of complex approach to treating patients for COPD, especially in the case when it is accompanied with OA, resolving therapy is more and more often referred to nowadays, namely, to the use of fenspirid hydrochloride. The aim of the article is to depict the results of the study of the effectiveness of fenspirid hydrochloride (EurespalR, ≪Servier≫ France) included in complex therapy in treating patients for COPD accompanied with OA. MATERIALS AND METHODS: Hospitalized in the Pulmonology Department of Poltava regional clinical hospital named after N.V. Sklifosovsky served as the bases for the research, the investigation being carried out in the Institute of genetic and immune studies of development of pathology and pharmocogenetics of Ukrainian Higher State Educational Establishment "Ukrainian Medical Stomatological Academy of Poltava". Under investigation there were 33 patients (the average age of them was 54.4±3.1) suffering from exacerbation of COPD (clinic group B-GOPDII), accompanied with OA - basic group. Patients of the basic group were divided into two representative subgroups - A and B. The patients of A subgroup were restricted to basic therapy COPD according to the running protocol, while in B subgroup the basic therapy was accompanied with fenspirid hydrochloride hydrochloride per 80 mg twice a day 12 days running. Check group included 25 practically healthy people of the identical age. Results obtained showed that regress of the illness (cough decreasing) among the patients of the subgroup with COPD accompanied with OA, who were given fenspirid hydrochloride together with the basic therapy, 2.9±0.4 days earlier, dyspnoea 2.3±0.33 comparing to another subgroup ( p<0.05), the quality of the patients' life was getting better, the ability to endue more physical assignment increased. By the end of the treatment the sharpened forced exhalation FEV1level within the A subgroup patients equaled 57.1 ±4.2% (before the treatment it was 53.4±3.9 %), while within the B subgroup patients it became 59.9 ±3.9 (before the treatment it was 53.9±4.0 %). Repayments of bronchial obstruction in both groups became a bit higher- in A subgroup by 3.2±0.7%, and in B subgroup - by 3.6±0.5%. Concentration of IL-1ß in blood serum of basic group patients was 14.6 times higher than that of practically healthy people. After the therapy the level of IL-1ß within the A subgroup patients became 1.7 times lower (p < 0.01). After the basic therapy being accompanied with fenspirid hydrochloride to B subgroup patients the level of lowering was more vivid, and equelled 2.8 times ( p < 0.001). Decrease of the concentration of other mediators of inflammatory process under the influence of fenspirid hydrochloride was evident in other researches as well. Strong negative correlation ( r = -0.812; p < 0.05) between the level of IL-1ß in blood serum of basic group patients and their sharpened forced inhalation/exhalation. Forced expiratory volume (FEV)1 level before the treatment became moderately negative within the patients of A subgroup ( r= - 0.681; p < 0.05) and week within the patients of B subgroup ( r= -0.475; p <0.05). The term of treatment of A subgroup patients was 14.3 ± 0.4 days, and that of B subgroup patients it was a bit less, namely, 12.9 ± 0.5 days. An important result of the therapy with additional use of fenspirid hydrochloride was determining the periods between the case when next COPD exacerbation occurs because it is the frequency of the disease exacerbation that predicts the disease. Within A subgroup this time was 10.3±0.9 months, and within B subgroup it was 15.7±1.1 months. CONCLUSION: All this made it possible to draw the conclusion that usage of fenspirid hydrochloride hydrochloride in addition to complex therapy essentially reduces the level of IL-1ß in blood serum in compereson to the cases when only basic remedy was used, favours reduction of cases and intensity of systemic inflammations associated with increasing the duration of remission within this type/constellation of patients.

Churg-strauss syndrome: a case report.

A clinical case of Churg-Strauss syndrome has been reported on the 53-year-old female patient Ts. with bronchial asthma and allergic rhinitis. The main clinical signs and syndromes depending on the stage of the disease are presented, as well as therapeutic treatment of patients with this disease.

Myocardial capacity of mitochondrial oxidative phosphorylation in response to prolonged electromagnetic stress.

Introduction: Mitochondria are central energy generators for the heart, producing adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) system. However, mitochondria also guide critical cell decisions and responses to the environmental stressors. Methods: This study evaluated whether prolonged electromagnetic stress affects the mitochondrial OXPHOS system and structural modifications of the myocardium. To induce prolonged electromagnetic stress, mice were exposed to 915 MHz electromagnetic fields (EMFs) for 28 days. Results: Analysis of mitochondrial OXPHOS capacity in EMF-exposed mice pointed to a significant increase in cardiac protein expression of the Complex I, II, III and IV subunits, while expression level of α-subunit of ATP synthase (Complex V) was stable among groups. Furthermore, measurement of respiratory function in isolated cardiac mitochondria using the Seahorse XF24 analyzer demonstrated that prolonged electromagnetic stress modifies the mitochondrial respiratory capacity. However, the plasma level of malondialdehyde, an indicator of oxidative stress, and myocardial expression of mitochondria-resident antioxidant enzyme superoxide dismutase 2 remained unchanged in EMF-exposed mice as compared to controls. At the structural and functional state of left ventricles, no abnormalities were identified in the heart of mice subjected to electromagnetic stress. Discussion: Taken together, these data suggest that prolonged exposure to EMFs could affect mitochondrial oxidative metabolism through modulating cardiac OXPHOS system.

Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naïve Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study.

OBJECTIVES: The aims were to demonstrate pharmacokinetic (PK) similarity between DRL_RI, a proposed rituximab biosimilar, and two reference innovator products (Rituxan® [RTX-US] and MabThera® [RTX-EU]) and compare their pharmacodynamics (PD), efficacy, safety, and immunogenicity in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)-based therapy and no prior biologic administration. METHODS: In this randomized, double-blind, parallel-group study, 276 patients with moderate-to-severe active RA were randomized to receive DRL_RI, RTX-US, or RTX-EU on days 1 and 15. The primary PK end points included area under the concentration-time curve from time 0 to 336 h after first infusion (AUC0-14 days, first infusion), AUC from day 1 through week 16 (AUC0-∞, entire course), and AUC from time 0 to time of last quantifiable concentration after the second dose (AUC0-t, second infusion). Secondary end points included other PK parameters, such as maximum concentration (Cmax), time to Cmax after each infusion, terminal half-life, systemic clearance, and volume of distribution after the second infusion; PD parameters and efficacy until week 24; safety and immunogenicity at week 24 and 52; and B cell recovery until week 52. AUC from time 0 to time of last quantifiable concentration after the first dose and over the entire course from day 1 through week 16 (AUC0-t, entire course) was analyzed as an exploratory end point. RESULTS: The 91% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the primary end point of AUC0-∞, entire course were within the bioequivalence limits of 80-125% for all comparisons: DRL_RI versus RTX-US 100.37% (92.30-109.14), DRL_RI versus RTX-EU 93.58% (85.98-101.85), and RTX-US versus RTX-EU 93.24% (85.62-101.54). PD outcomes (peripheral blood B-cell depletion and mean change in Disease Activity Score [28 joints]-C-reactive protein), efficacy, safety, and immunogenicity were also comparable between DRL_RI and the reference products. CONCLUSION: DRL_RI, a proposed biosimilar, demonstrated three-way PK similarity with RTX-EU and RTX-US, the reference innovator products, with comparable efficacy, PD, safety, and immunogenicity. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02296775.

Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a randomised, phase 2b, dose-ranging study.

BACKGROUND: The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We aimed to evaluate the efficacy, safety, and key patient-reported outcomes related to pain in patients with active rheumatoid arthritis receiving otilimab. METHODS: This phase 2b, dose-ranging, multicentre, placebo-controlled study was done at 64 sites across 14 countries. Patients aged 18 years or older with rheumatoid arthritis who were receiving stable methotrexate were randomly assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor, and patients were assigned to treatment by interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was the proportion of patients who achieved disease activity score for 28 joints with C-reactive protein (DAS28-CRP) <2·6 at week 24. Patients who were not in the otilimab 180 mg group, without a good or moderate European League Against Rheumatism response (week 12) or with DAS28-CRP >3·2 (week 24) escaped to otilimab 180 mg. Patients who escaped were treated as non-responders in their original assigned group. Safety endpoints were incidence of adverse events and serious adverse events, infections, and pulmonary events. Efficacy and safety outcomes were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02504671. FINDINGS: Between July 23, 2015, and Dec 29, 2017, 222 patients were randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180 mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of patients with DAS28-CRP <2·6 was two (5%) of 37 in the otilimab 22·5 mg group, six (16%) of 37 in the 45 mg group, seven (19%) of 37 in the 90 mg group, five (14%) of 37 in the 135 mg group, five (14%) of 37 in the 180 mg, and one (3%) of 37 in the placebo group. The largest difference was achieved with otilimab 90 mg (16·2%; odds ratio [OR] 8·39, 95% CI 0·98-72·14; p=0·053). Adverse events were reported pre-escape in 19-24 (51-65%) patients and post escape in 10-17 (40-61%) patients across otilimab dose groups and in 18 (49%) of 37 and 22 (67%) of 33 in the placebo group. The most common adverse event was nasopharyngitis: 3-9 (8-24%) in otilimab groups and one (3%) in the placebo group pre-escape and 1-3 (4-10%) in otilimab groups and seven (21%) in the placebo group post escape. Pre-escape serious adverse events were foot fracture (otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90 mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), and uterine leiomyoma (otilimab 135 mg). Post-escape serious adverse events were ankle fracture (placebo) and rheumatoid arthritis (otilimab 135 mg). There were no deaths or pulmonary events of clinical concern, and rates of serious infection were low. INTERPRETATION: Otilimab plus methotrexate was well tolerated and, despite not achieving the primary endpoint of DAS28-CRP remission, there were improvements compared with placebo in disease activity scores. Of note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in rheumatoid arthritis. FUNDING: GlaxoSmithKline.