[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.

[Changes in general hemostasis in patients with diabetic retinopathy]. / Izmeneniia obshchego gemostaza u bol'nykh diabeticheskoi retinopatiei.

The hemostasis system was analyzed in 106 patients with diabetes mellitus, including 86 patients with diabetic retinopathy. Parameters of coagulogram and thromboelastogram as well as platelets aggregation, stimulated by collagen, were examined in all patients. Besides, the fibrinolytic activity of blood plasma as well as the concentration of plasminogen, fibrinogen and of fibrin-degradation products were evaluated. Essential changes were detected, which correlated with an intensity of diabetic changes in the eye fundus, i.e. generalized hypercoagulation caused by a lower activity of the system antithrombin III-heparin, a higher activity of fibrinogen and activation of the fibrinolytic system. The obtained data denote an important role of impaired hemostasis in the pathogenesis of diabetic retinopathy.

[Homeostasis and its correction in burn patients with gastrointestinal erosive-ulcerative diseases]. / Sostoianie gomeostaza i ego korrektsiia u obozhzhennykh s érozivno-iazvennymi porazheniiami zheludochno-kishechnogo trakta.

Acute erosive ulcerative hemorrhage (EUH) is one of the most grave complications of burn disease, caused by impaired blood rheology, clotting, and protein status. Twenty-three patients with burns of 12-70% body surface were examined, 17-25% of burns being deep. The most pronounced changes in blood rheology and clotting with formation of erythrocyte aggregations, fibrin precipitation and imbalance of visceral proteins were observed during the shock stage (days 1-3), particularly pronounced in patients with acute EUH. Development of septicotoxemia favored secondary increase in blood clotting and rheological parameters, which led to thrombotic complications. The data helped improve the complex of infusion-transfusion therapy for preventing and treating ulcerative and erosive lesions.

[Use of leukinferon for prophylaxis of pyogenic complications in victims with thoracic wounds]. / Primenenie leikinferona dlia profilaktiki gnoinykh oslozhnenii u postradavshikh s raneniiami grudi.

The results of treatment of 131 victims with penetrating wounds of the thorax complicated by profuse bleeding, are presented. 36 of them after surgery to prevent pyogenous complications received 5 injections of leukinferon (test group); 95 patients who were not treated by leukinferon made up control group comparable with the test group by sex, age and character of wounds. Comparative analysis of the results showed that treatment with leukinferon has resulted in decrease of postoperative complications. In the test group the number of complications made up 47.2%, in control group--61%. Al the same time in the former group there was only one pyogenous complication (2.9%), while in control group--10 (10.6%). After the course of leukinferon leucocytic formula of the blood has become normal, the number of patients with immunodeficiency and imbalance of proteins markers of the acuteness of inflammatory process has decreased.

[Hemocomponent therapy of central involution chorioretinal dystrophy]. / Gemokomponentnaia terapiia tsentral'noi involiutsionnoi khorioretinal'noi distrofii.

Hemocomponent therapy was used in 181 patients (347 eyes) with central chorioretinal dystrophy. Activated autoplasma possessing a marked resorptive effect, consisting in resorption of hemorrhages and exudations on the fundus oculi, was used. Vision acuity improved in 75% of examined eyes by an average of 0.2 diopters.

[Alternation of protease inhibitors and hemostasis system in treatment of spontaneous pneumothorax]. / Izmenenie ingibitorov proteaz i sistemy gemostaza pri lechenii spontannogo pnevmotoraksa.

3 groups of 37 patients were examined, in which for treatment of spontaneous pneumothorax drainage of pleural cavity and medicamentous pleurodesis with tetracycline hydrochloride and 4% solution of sodium bicarbonate were used. Interdependence of clinical criteria and level of protease inhibitors were evaluated, as well as the basic components of hemostasis. The best effectiveness of treatment in carrying out chemical pleurodesis was demonstrated, especially when 4% sodium bicarbonate solution was used. At the same time the application of this agent has evoked the most evident changes in values of hemostasis and protease inhibitors. The possibility of use of the above mentioned biochemical in dices together with clinical criteria for the evaluation of effectiveness of treatment of the unspecific spontaneous pneumothorax is stressed.

[Clinical significance of the determination of several hemostatic parameters in the lacrimal fluid of patients with vascular diseases of the retina]. / O klinicheskom znachenii opredeleniia nekotorykh gemostaticheskikh pokazatelei v sleznoi zhidkosti bol'nykh s sosudistymi zabolevaniiami setchatki.

Clinicolaboratory studies of 92 patients with vascular diseases of the retina (retinal vein thrombosis, central chorioretinal dystrophy, retinal hypertensive angiosclerosis) were carried out to assess hemorheologic parameters (platelet and red cell aggregation coefficients, blood viscosity). In parallel with this, lacrimal fluid was analyzed for hemostatic parameters, plasminogen and antithrombin III. A marked increase of plasminogen and antithrombin III levels was found in the lacrimal fluid of patients with retinal vein thrombosis, this increase correlating with pathologic shifts in the studied rheologic characteristics. Central chorioretinal dystrophy and retinal hypertensive angiosclerosis were associated with shifts in some rheologic characteristics. Hence, measurements of lacrimal fluid hemostatic parameters plasminogen and antithrombin III in patients with retinal vascular diseases help assess blood rheology.

[Several components of plasma hemostasis in patients with suppurative processes in the abdominal cavity]. / Izuchenie nekotorykh komponentov plazmennogo gemostaza u bol'nykh s gnoinymi protsessami v briushnoi polosti.

Blood and urine concentrations of antithrombin-III, plasminogen, alpha 2-macroglobulin, alpha 1-antitrypsin, degradation products of fibrinogen-fibrin were studied in patients with abdominal suppuration. Noticeable deviations from the normal values especially marked in the severe process indicated the development of DIC syndrome and renal failure. Heavy combined treatment promoted normalization of the hemostasis shifts and eliminated pyo-inflammatory processes in the abdominal cavity.

[The determination of the concentration of antithrombin III in the urine]. / Opredelenie kontsentratsii antitrombina III v moche.

The authors developed the special enzyme immunoassay technique for the detection of the urinary antitrombin III (AT-III) levels. Sensitivity of the method was 7.8 ng/ml. The study lasted for 2 hrs. The levels of AT-III were studied in the circadian human urine in health, in physiological and nephropathy-complicated pregnancy, as well as in patients with gastroduodenal ulcer-induced bleeding. There was a 34.1-fold increase in the urinary AT-III levels in pregnant females with Stages II-III nephropathy and a 17.3-fold increase in those who sustained the resection of the stomach, which could be explained by proteinuria and abnormal resorption of AT-III in the proximal tubules of the kidney.

[Study of the complement system and the inhibitors of plasma proteolytic enzymes in the erythrocytes during blood preservation]. / Izuchenie sostoianiia sistemy komplementa i ingibitorov proteo- liticheskikh fermentov plazmy krovi v éritrotsitnoi masse pri khranenii.

Changes in the activity of the complement system components C1--C5, and proteinase inhibitors: alpha 1-inhibitor, alpha 2-macroglobulin and antithrombin III were studied in red blood cell pack during storage at 4 degrees C, in comparison with erythroconcentrate. A decrease, detected in the level of C1, C3 and alpha 2-macroglobulin, was more pronounced in the erythroconcentrate than in the red blood cell pack. The data obtained have evidenced that the adequate amount of plasma plays an important role in the red blood cell preservation and prevention of accumulation of undesirable physiologically active substances in the transfusion solutions.

[Pathogenetic factors in thrombosis of the central retinal vein]. / Patogeneticheskie faktory tromboza tsentral'noi veny setchatki.

Studies of the hemorheologic parameters and the hemostasis system components in the blood and lacrimal fluid of 130 patients with thrombosis of a branch of the central retinal vein (CRV) and calibrometry of the CRV have lead the authors to a conclusion that the major factors contributing to the pathogenesis of CRV thrombosis are (1) disordered blood rheology; (2) changes in the local hemostatic potential; (3) impaired blood stream in the corresponding CRV branches. Rationale for the use of drugs normalizing the blood rheology in CRV thrombosis is given.

[Immunoenzyme method of determination of antithrombin III]. / Immunofermentnyi metod opredeleniia antitrombina III.

Immunoenzymatic assay is developed for estimation of antithrombin III (AT-III). Sensitivity of the assay was 7.8 ng of AT-III per 1 ml. The test system developed corresponded to the requirements for serological assays. Estimation of AT-III in blood plasma of healthy persons and in patients with various diseases showed that the assay may be recommended for clinical practice.

[Isolation and characteristics of antithrombin III from human plasma]. / Vydelenie i kharakteristika antitrombina-III iz plazmy krovi cheloveka.

Highly purified preparation of antithrombin III (AT III) was obtained from human blood plasma. Efficiency of the procedure developed was corroborated by studies of physicochemical properties of the preparation. The AT III preparation was used for production of monospecific antiserum. The antisera prepared were analogous to the commercially available antisera in content of specific antibodies, affinity properties and might be used for development of sera for serodiagnostics.