[The efficacy and safety of eculizumab biosimilar in patients with paroxysmal nocturnal hemoglobinuria. Results of a phase III randomized open-label comparative clinical trial].

AIM: To establish the equivalent efficacy and comparable safety profile of biosimilar Acveris and referent eculizumab product Soliris used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). MATERIALS AND METHODS: Were included in the phase III multicenter 28 PNH patients, open-label clinical trial. Participants were randomized (1:1) into 2 treatment groups: investigational product (Acveris, n=14) and referent product (Soliris, n=14). Patients received eculizumab as the intravenous infusion 600 mg once a week during the first 4 weeks, 900 mg at week 5 and then 900 mg every 14 days (2 days) up to week 27 of the study. The efficacy, pharmacokinetics, pharmacodynamics, safety and immunogenicity of the compared products were analyzed after the end of 27 weeks of the study. The primary efficacy endpoint was the area under the curve LDH concentrationtime (AUCLDH) throughout the study period weeks 527. RESULTS: The difference between the mean AUCLDH values between the Acveris and Soliris groups was 5380.0 [-38 773.87; 49 533.87] U/ldays. The 95% CI limits for the difference in mean AUCLDH values between the groups fit the preset 95% CI [-146 500.9146 500.9] U/ldays and establish the equivalent efficacy of the biosimilar and referent product according to the primary efficacy endpoint. The safety profile of both Acveris and Soliris was expected and comparable according to the proportion of patients with adverse events. The formation of binding antibodies to eculizumab was not detected in both the groups. CONCLUSION: The study established the equivalent efficacy of biosimilar product Acveris and referent eculizumab product with the evidence of effective suppression of intravascular hemolysis in PNH patients along with a comparable favorable safety profile.

[The morbidity of medical personnel of mobile teams of emergency medical care].

The medical personnel of mobile teams of emergency medical care are exposed to factors of working environment that affect health state and results in development of occupational diseases. The purpose of study is to analyze morbidity of medical personnel of mobile teams of emergency medical care according data of temporary disability and results of medical check-ups. The analysis was made according information from certificates of incapacity for work and the final acts of periodic medical examinations for five-year period. The study established significant increase of rate and duration of primary and general morbidity with increase of age and length of service of workers, higher susceptibility to diseases of physicians as compared with paramedics and employees of pediatric teams and specialists of other clinical profiles. In the structure of morbidity according to results of medical examinations, diseases of the eye and its accessory apparatus, the circulatory system and the musculo-skeletal system prevailed.

[Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy].

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab. AIM: To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH. MATERIALS AND METHODS: The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks. RESULTS: During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity. CONCLUSION: The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.

Gene Polymorphism of Xenobiotic Biotransformation Enzymes in Patients with Classical Ph-Negative Myeloproliferative Neoplasms.

The correlation of gene polymorphisms rs4025935 (large deletion), rs1695 (313A>G), rs71748309 (large deletion), and rs1800566 (609C>T) of GSTM1, GSTT1, and NQO1 genes encoding glutathione-S-transferases (GST) M1, P1, and T1 and NADPH-quinone oxidoreductase with the risk of development of classical Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) was studied in the Caucasian ethnicity population of Vyatka region of the Russian Federation. It was found that NQO1*609T allele, NQO1*609T genotypes, and homozygous carriage of a deletion (null) allele of GSTT1 gene are associated with the risk of development of myeloproliferative neoplasms (OR=1.29, 95%CI=1.02-1.64, p=0.04; OR=1.39, 95%CI=1.04-1.85, p=0.03; and OR=1.48, 95%CI=1.03-2.12, p=0.03, respectively). However, no influence of GSTM1 and GSTP1 gene polymorphisms on the risk of development of myeloproliferative disorders was registered.

[Interpretation of the results of immunohematological tests in hematological patients.]

The correct determination of the blood types of the recipient and the donor is very importante for the choice of blood components for transfusion. As a result of the study, it was established that 18.0% of patients, admitted to the hematology clinic, have difficulties in interpreting of the results of immunohematological tests. Most often, a double population of red blood cells was detected when determining antigens of the Rhesus system (10.9%), auto- (3.9%) and alloantibodies (2.8%). The proposed algorithm for the selection of donor red blood cells in difficult diagnostic cases helps to prevent the development of post-transfusion complications.

[Expirience introduction of quantitative analysis of chimerism after allogenic stem cell transplantation by real-time PCR with InDel polymorphism.]

Using data obtained from domestic and foreign sources, we formed a set of primers and fluorogenic probes for analyzing twentysix specific sequence polymorphisms and one reference gene. In the course of evaluating the effectiveness of real-time PCR, using the example of one of the markers (S01a), we obtained the optimal amount of DNA per reaction (70 ng), providing a resolution of at least 0.1% of the method with the ability to estimate linear chimerism. Formed panel of primers for genetic polymorphisms - InDel has a high degree of informational content for donor-recipient pairs of Russia. From January 2018 to June 2019, a quantitative assessment of the level of linear (CD3 +, CD34 +) and general chimerism was carried out for 28 patients of the clinic of the Institution. Finally, we analyzed patients who received allografts and present 4 different clinical situations that illustrate the informativity level of this method.

[Autologous hematopoietic stem cell transplantation as late high-dose consolidation in adult patients with T-cell lymphoblastic leukemias: Results of a Russian multicenter study].

AIM: To analyze the efficiency of the ALL-2009 protocol (ClinicalTrials.gov NCT01 193933) in patients with T-cell leukemias, particularly the role of autologous hematopoietic stem cell transplantation (auto-HSCT) after non-myeloablative BEAM conditioning, followed by maintenance therapy. SUBJECTS AND METHODS: Since 2009, the ALL-2009 study has enrolled 90 patients with T-cell acute lymphoblastic leukemia (T-ALL), the treatment results were assessed in 86 patients: 6 and 28 patients underwent allogeneic HSCT and auto-HSCT, respectively. A landmark analysis was used to compare survival rates in patients who had undergone auto-HSCT and in those who had not. For this, the median time from complete remission to the date of auto-HSCT was determined (the median was 6 months). Then to compare with the auto-HSCT group, only 27 patients who had been in complete remission for 6 months or more were included in a chemotherapy group. RESULTS: The achievement of complete remission in patients with thymic T-ALL (100%) was significantly higher than in those with early (85.7%) or mature (70%) variants. The patients with early and mature T-ALL as compared to those with thymic T-ALL showed high death rates in the remission induction (7.4 and 10% versus 0) and the patients with mature T-ALL had a.higher proportion of refractory forms (20% versus 0). The 5-year overall and relapse-free survival rates in all the T-ALL patients were 66 and 76%, respectively. After auto-HSCT, the risk of recurrence was 0% versus 21% after chemotherapy (p=0.03). The relapse-free survival rates significantly differed in the auto-HSCT and non-auto-HSCT groups: 100 and 66%, respectively (p=0.047). CONCLUSION: The long-term survival rates obtained during this multicenter study in the T-ALL patients treated according to the ALL-2009 protocol, the basis for which is the principle of continuity of cytostatic effects, are exclusively optimistic. Late consolidation with auto-HSCT following non-myeloablative BEAM conditioning, followed by maintenance therapy, considerably reduces the risk of recurrence.

[The immediate and long-term results of sylvinite speleoclimatotherapy in the children presenting with pollinosis].

The present open randomized comparative study had the objective to compare the effectiveness of two strategies for the treatment of early spring pollinosis in 23 children at the age varying from 2 to 17 years in the phase of exacerbation. The patients of the study group underwent 10 sessions of sylvinite speleoclimatotherapy 60 min in duration each in addition to conventional pharmacotherapy. The children included in the control group were treated by traditional medicamental therapy alone. The estimation of clinical symptoms on day 10 after the onset of the treatment with the use of a scoring system has demonstrated a marked decrease in the severity of allergic rhinitis (p = 0.003), conjunctivitis (p = 0.01), and the total number of signs and symptoms of the disease (p = 0.002) in the children managed with the use of sylvinite speleoclimatotherapy. Positive dynamics in the patients of the control group was less pronounced (p < 0.05). The aeropollinological data are presented giving evidence of the absence of a high pollen concentration in the air of the speleoclimatic chamber and its high content in the atmospheric air at the height of thepollen season of early spring allergens. The clinical manifestations of the allergic conditions were shown to depend on the concentration in the atmospheric air of the causative allergens from their principle plant sources (r = 0.66, p = 0.039 in the control patients in comparison with r = 0.42, p = 0.22 in the children treated by sylvinite speleoclimatotherapy. It is concluded that the results of the present study confirm the clinical effectiveness of sylvinite speleoclimatotherapy used in the acute phase of pollinosis. The combination of this modality with traditional medicamental therapy accelerates elimination of clinical symptoms of allergic rhinitis and conjunctivitis; moreover, it reduces the frequency of recurrent respiratory disorders.

[Modern approach to the rehabilitation of children with fractured long tubular bones].

An optimized therapeutic rehabilitation program involved 393 patients with fractured long bones (humeral, radial/ulnar, femoral, crural) admitted to the Orthopedic Department of the Stavropol Regional Children's Clinical Hospital and the Rehabilitation Centre for Handicapped Children and Adolescents. Rehabilitation was performed in three consecutive stages, viz. immobilization, functional recovery and training. The proposed approach ensured rather fast functional recovery of the affected extremity even in cases with compound fractures. The rehabilitation program included polyenzyme therapy with wobenzym during 3-4 weeks after injury or surgical repositioning of bone fragments. Pain and oedema syndromes resolved twice as fast as after traditional treatment. The use of this program permitted to avoid development of contracture and disturbances of locomotary activity; moreover, it improved the quality of life in children with fractures of long tubular bones.

[Enzyme therapy of patients with pyo-inflammatory disease of maxillofacial area].

Conditions of activity of medical service of the Armed Forces of RF predetermines the necessity of utilizing new methods of organization of the process of access of medical-technical models and medical equipment, including complex equipment. The article presents several definitions, connected with aterm "medical technics and equipment". Medicine chest, wallets, complexes of medical equipment and medical tool kits could be accessed to the purchasing of medical service of the Armed Forces and cold be added to the normative documents after their state registration according to the right legal way.