Vol 92, No 12 (2020)

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Chronic intestinal pseudo-obstruction
Parfenov A.I., Krums L.M., Bykova S.V., Ahmadullina O.V.

Chronic intestinal pseudo-obstruction a rare violation of the motor skills of the gastrointestinal complex, similar to mechanical obstruction, but without a mechanical obstacle. The development of chronic intestinal pseudo-obstruction is caused by a disturbance on the part of the smooth muscles and the nervous system of the gastrointestinal system. Common symptoms include constipation, abdominal pain, nausea, vomiting, bloating. Violation of peristalsis leads to food stagnation in the hinges of the small intestine, their dilation, the development of bacterial insemination syndrome. Eating disorders, bacterial contamination syndrome (CDDs) lead to impaired suction syndrome, cahexia. Treatment is aimed at providing adequate nutrition, the use of drugs that activate motor skills, suppress the growth of microbes in the small intestine, the implementation of intestinal decompression. Surgical treatment: resection of the affected segment of the gut. In the refractory course of the disease – intestinal transplantation.

Terapevticheskii arkhiv. 2020;92(12):4-9
Pericarditis in contemporary therapeutic clinic: nosological spectrum, approaches to diagnosis and treatment
Blagova O.V., Nedostup A.V., Sedov V.P., Kogan E.A., Alijeva I.N., Sorokin G.Y., Sarkisova N.D.

Aim. To analyze the register of pericarditis in a therapeutic clinic, to evaluate their nosological spectrum, to optimize approaches to diagnosis and treatment.

Materials and methods. For the period 2007–2018, the register includes 76 patients with the diagnosis of “pericarditis” (average age 53.1±15.7 years, 20–85 years, 46 female). Patients with hydropericardium were not included in the register. Diagnostic puncture of pericardium was carried out in 5 patients, pleural puncture – in 11 patients. Morphological diagnostics included endomyocardial/ intraoperative biopsy of myocardium (n=4/2), thoracoscopic/intraoperative biopsy of pericardium (n=1/6), pleural puncture (n=5), transbronchial (n=1), thoracoscopic biopsy of intrathoracic lymph nodes (n=2), lung (n=1), supraclavicular lymph node biopsy (n=1), salivary gland (n=1), subcutaneous fat and rectum biopsy per amyloid (n=6/1). The genome of cardiotropic viruses, level of anti-heart antibodies, C-reactive protein, antinuclear factor, rheumatoid factor (antibodies to cyclic citrullinized peptide), antibodies to neutrophil cytoplasm were determined, extractable nuclear antigens (ENA), protein immunoelectrophoresis, diaskin test, computed tomography of lungs and heart, cardiac magnetic resonance imaging, oncologic search.

Results. The following forms of pericarditis were verified: tuberculosis (14%, including in combination with hypertrophic cardiomyopathy – HCM), acute / chronic viral (8%) and infectious immune (38%), including perimyocarditis in 77%, pericarditis associated with mediastinum lymphoma/sarcoma (4%), sarcoidosis (3%), diffuse diseases of connective tissue and vasculitis (systemic lupus erythematosus, rheumatoid arthritis, diseases of Horton, Takayasu, Shegren, Wegener, 12%), leukoclastic vasculitis, Loeffler’s endomyocarditis, AL-amyloidosis, thrombotic microangiopathy (1% each), HCM (8%), coronary heart disease (constriction after repeated punctures and suppuration; postinfection and immune, 4%), after radiofrequency catheter ablation and valve prosthetics (2%). Tuberculosis was the main causes of constrictive pericarditis (36%). Treatment included steroids (n=39), also in combination with cytostatics (n=12), anti-tuberculosis drugs (n=9), acyclovir/ganclovir (n=14), hydroxychloroquine (n=23), colchicine (n=13), non-steroidal anti-inflammatory drugs (n=21), L-tyroxine (n=5), chemotherapy (n=1). In 36 patients different types of therapy were combined. Treatment results observed in 55 patients. Excellent and stable results were achieved in 82% of them. Pericardiectomy/pericardial resection was successfully performed in 8 patients. Lethality was 13.2% (10 patients) with an average follow-up 9 [2; 29.5] months (up to 10 years). Causes of death were chronic heart failure, surgery for HCM, pulmonary embolism, tumor.

Conclusion. During a special examination, the nature of pericarditis was established in 97% of patients. Morphological and cytological diagnostics methods play the leading role. Tuberculosis pericarditis, infectious-immune and pericarditis in systemic diseases prevailed. Infectious immune pericarditis is characterized by small and medium exudate without restriction and accompanying myocarditis. Steroids remain the first line of therapy in most cases. Hydroxychloroquine as well as colchicine can be successfully used in moderate / low activity of immune pericarditis and as a long-term maintenance therapy after steroid stop.

Terapevticheskii arkhiv. 2020;92(12):10-18
Detection of kidney dysfunction potential biomarkers with hypertension in the persons of 25–45 years
Kovalkova N.A., Khudyakova A.D., Kashtanova E.V., Polonskaya Y.V., Shcherbakova L.V., Ragino Y.I.

Aim. To assess the significance of symmetrical dimethylarginine (SDMA), uromodulin, retinol-binding protein 4 (RSB-4), transforming growth factor b1 (TGF-b1), plasminogen activator inhibitor 1 (PAI-1) as kidney dysfunction potential biomarkers persons with hypertension in persons 25–45 years old.

Materials and methods. The study included 147 people. Hypertension was recorded with blood pressure (BP)≥140/90 mm Hg, renal dysfunction – with GFRCKD-EPI<90 ml/min/1.73 cm2. Four groups were formed: 1 – individuals with hypertension and GFR<90 ml/min/1.73 cm2; 2 – with hypertension and GFR≥90 ml/min/1.73 cm2; 3 – with BP<140/90 mm Hg and GFR<90 ml/min/1.73 cm2; 4 – with BP<140/90 mm Hg and GFR≥90 ml/min/1.73 cm2. The groups were comparable by gender, age, and number of respondents. Creatinine, SDMA, uromodulin, RSB-4, TGF-b1, PAI-1 levels were examined in all individuals in the serum.

Results. The maximum values of SDMA were determined in the 1st and 3rd groups (1.30 and 1.36 μmol/l). In the 1st group, an association was found between SDMA and GFR (r=-0.324; p=0.048). In the 1st group, the minimum values of uromodulin were recorded, in the 4th group – the maximum values (164.86 and 188.90 ng/ml; at the same time р=0.921). The level of RSB-4 was the highest in the 1st group, the lowest – in the 4th group (88.64 and 80.05 µg/ml; p=0.011). The association of RSB-4 with SDMA in the 3rd group (r=0.400; p=0.017), the 4th group (r=0.403; p=0.018) was detected. The level of TGF-b1 was 1.5 times higher in the 1st group than in the 3rd (23.16 and 15.99 µg/ml; p=0.026), the association of TGF-b1 with GFR in the 1st group had the opposite direction (r=-0.452; p=0.005). The study of similar indicators of PAI-1 did not reveal its relationship with renal dysfunction in hypertension.

Conclusion. The results of the study made it possible to consider SDMA, RSB-4, TGF-b1 as potential biomarkers of renal dysfunction in hypertension in persons 25–45 years old.

Terapevticheskii arkhiv. 2020;92(12):19-24
Association of rs3025058 polymorphism with the development of stroke in patients with cardiovascular pathology
Nikulina S.Y., Shulman V.A., Chernova A.A., Prokopenko S.V., Nikulin D.A., Platunova I.M., Tretyakova S.S., Semenchukov A.A., Marilovtseva O.V., Lebedeva I.I., Maksimov V.N., Gurazheva A.A.

Aim. To study the association of single-nucleotide polymorphism rs3025058 (5а/6а) with the development of stroke in patients of the East Siberian population with cardiovascular pathology and risk factors for its development.

Materials and methods. The study involved 260 patients with stroke (age [57.0; 51.0–62.0]) and 272 patients of the control group (age [55.0; 51.0–62.0]). Among the patients who underwent stroke, 157 men and 103 women. The control group included 170 men and 102 women. The examination of the main group included: collection of complaints, anamnesis, clinical examination, computed tomography of the brain, electrocardiography, echocardioscopy, ultrasound duplex scanning of the extracranial brachiocephalic arteries, 24-hour monitoring of blood pressure and heart rate, analysis of the blood coagulation system. The patients of the main group had the following cardiovascular pathology and risk factors: arterial hypertension, paroxysmal supraventricular tachycardias, dyslipidemia, atherosclerosis of extracranial brachiocephalic arteries, disorders of the hemostasis system. The control group was examined within the framework of the international project HAPIEE. Molecular genetic research was carried out by real-time PCR. Statistical processing of the material was carried out using the Statistica for Windows 7.0, Excel and SPSS 22 application software.

Results. The study established statistically significant associations between the 5a/5a genotype and the 5a allele and stroke in the general group of patients, as well as in the subgroup of men, subgroups of patients with extracranial brachiocephalic arteries atherosclerosis and dyslipidemia. In the subgroup of patients with cardiac arrhythmias, statistically significant results were obtained only for allele 5a, and in the subgroup of women with stroke, subgroups of patients with arterial hypertension and hypercoagulation, no significant associations of rs3025058 (5a/6a) polymorphism with stroke were found.

Conclusion. Genotype 5a/5a and allele 5a of the single-nucleotide polymorphism rs3025058 (5а/6а) increase the risk of stroke in individuals from the East Siberian population, including those in the presence of such risk factors as extracranial brachiocephalic arteries atherosclerosis and dyslipidemia.

Terapevticheskii arkhiv. 2020;92(12):25-30
Clinical and prognostic value of metabolic disorders in non-alcoholic fatty liver disease
Vakhrushev Y.M., Suchkova E.V., Lukashevich А.Р.

Aim. A comprehensive assessment of metabolic parameters in patients with non-alcoholic fatty liver disease and based on them the development of prognostic criteria for the development of liver fibrosis.

Materials and methods. 288 patients with non-alcoholic fatty liver disease at the stage of steatosis were examined. The patients underwent ultrasound examination of the hepatobiliary system using the SONIX OP apparatus (Canada), the FibroMax test, and liver elastography using the AIXPLORER apparatus (France). The parameters of anthropometry, lipid spectrum, protein and pigment metabolism, cytolysis, cholestasis, bilirubin, insulin in the blood serum were evaluated. The methods of statistical forecasting are used.

Results. The clinical picture in patients with non-alcoholic fatty liver disease at the stage of steatosis was nonspecific and was due to the presence of concomitant diseases of the digestive system and the cardiovascular system. A kettle index of up to 30 was observed in 26.5% of patients, from 30 to 34.9 in 37.5%, from 35 to 39.9 in 29.7% of patients, more than 40 in 6.3% of patients. The results obtained during the biochemical analysis of blood serum indicate the presence of atherogenic dyslipidemia, an increase in the level of total protein, bilirubin, transaminases, gamma-glutamyl transpeptidase and a decrease in alkaline phosphatase in relation to the control group. Against the background of elevated glucose levels, an increase in basal insulin levels was observed (p=0.001). HOMA-IR insulin resistance was increased in patients (p=0.01). When analyzing the results of the study, the main prognostic criteria (body mass index and atherogenicity coefficient) in the diagnosis of non-alcoholic fatty liver disease in the stage of steatosis with high specificity (97.8%) and sensitivity (96.2%) were determined. In determining the risk of progression of non-alcoholic fatty liver disease into liver fibrosis, the model of prognostic criteria included insulin and triglycerides with a specificity of 93.8% and a sensitivity of 85.7%.

Conclusion. Among many variable factors, we have identified the main prognostic criteria that are highly likely to diagnose non-alcoholic fatty liver disease at an early stage and determine the risk of progression to liver fibrosis.

Terapevticheskii arkhiv. 2020;92(12):31-35
Resected bowel syndrome: clinical course and treatment options
Hatkov I.E., Kuzmina T.N., Sabelnikova E.A., Parfenov A.I.

The current concepts of the “short bowel syndrome” and “malabsorption after intestinal surgery” are generally accepted, but do not fully reflect the patient’s condition, making it difficult to diagnose and treat it.

Aim. The purpose of the study is to analyze the clinical course of the patients after bowel resection, to create a classification based on the variants identified to allow for a differentiated treatment and to introduce the concept of the “resected bowel syndrome”.

Materials and methods. We observed 239 patients (96 men and 143 women) aged 18 to 80 who underwent intestinal resection for 1 month to 16 years (from 2002 to 2018). The 1st group included 96 patients with small bowel resection (40 men and 56 women). The 2nd group included 39 men and 58 women with small bowel resection, including the resection of the ileocecal valve and the right-hand side of the colon (n=97). The 3rd group included 17 men and 29 women with the resection of the right-hand side of the colon or colectomy (n=46). The survey included the NRS-2002 (Nutritional Risk Screening 2002) screening test to identify nutritional risk, a clinical assessment of the symptoms that occurred after the surgery, instrumental methods (esophagogastroduodenoscopy, colonoscopy with biopsy, ultrasound of the abdominal cavity organs and the kidneys, a plain radiography of the abdominal cavity organs, an X-ray examination of the small intestine and the intestinal passage), serum citrulline and short-chain fatty acids in faeces.

Results. Based on the analysis of the clinical symptoms and the nutritional status of the patients, a new concept is proposed – the resected bowel syndrome – with two variants of its progression: either with or without the development of nutritional insufficiency of three types: the dehydration type, the protein-energy insufficiency type and a mixed type. Type 1 requires the use of antimicrobials with the control of SCFA concentrations in faeces. Type 2 requires the introduction of an optimal amount of easily digestible protein to correct protein-energy deficit. The 3rd (most severe) mixed type requires prescription of a parenteral nutrition component with the control of citrulline concentration in the blood serum.

Conclusion. The proposed concept – the resected bowel syndrome – makes it possible to improve its diagnosis, take into account the variants of its progression and allow for a differentiated treatment.

Terapevticheskii arkhiv. 2020;92(12):36-42
The prevalence of sarcopenia in patients with chronic pancreatitis: a meta-analysis
Maev I.V., Andreev D.N., Kucheryavyy Y.A., Levchenko A.I.

Aim. Systematization of data on the prevalence of sarcopenia in patients with chronic pancreatitis (CP).

Materials and methods. MEDLINE/PubMed, EMBASE, Cochrane, the Russian Science Citation Index (RSCI) through June 2020 were searched to identify studies evaluating the prevalence of sarcopenia in CP. Additionally, a search for relevant abstracts was carried out in the electronic databases of the conferences of the European Pancreatic Club (EPC), the International Association of Pancreatology (IAP) and the European Congress of Radiology (ECR). For the final analysis, publications were selected that used validated muscle mass assessment tests with detailed descriptive statistics to enable the resulting data to be included in the meta-analysis.

Results. The final analysis included 7 studies involving 604 patients with CP. The pooled prevalence of sarcopenia in patients with CP was 42.09% (95% confidence interval – CI 27.845–57.055). There was significant heterogeneity between the results (p<0.0001; I2=90.81%). When studies with a total sample of less than 50 patients were excluded from the meta-analysis, the overall prevalence of sarcopenia in patients with CP was 22.24% (95% CI 15.475–29.847).

Conclusion. The present meta-analysis demonstrated that sarcopenia is a common complication of CP and is observed in about 2 out of 5 patients with this inflammatory disease of the pancreas. Given the high incidence of adverse outcomes associated with sarcopenia, it is necessary to promptly diagnose this pathological condition in patients with CP.

Terapevticheskii arkhiv. 2020;92(12):43-47
Anemia as a risk factor of contrast-associated acute kidney injury
Mironova O.I., Deev A.D., Lakotka P.G., Fomin V.V.

Aim. The aim of our study was to assess the role of anemia as a risk factor of contrast-associated acute kidney injury (CA-AKI) in patients with stable coronary artery disease.

Materials and methods. 1023 patients with chronic coronary artery disease were enrolled in a prospective, open, cohort study (ClinicalTrials.gov ID NCT04014153). 83 patients had anemia. CA-AKI was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dl or more in serum creatinine from baseline value, assessed at 48 hours following the administration of the contrast. The primary endpoint of the study was the development of CA-AKI according to KDIGO criteria.

Results. CA-AKI developed in 12 (14.5%) patients with anemia according to the relative increase of the level of serum creatinine (25% and more from the baseline). With using the absolute increase of the level of serum creatinine the prevalence of CA-AKI was 2 (2.4%) patients. Patients with anemia had higher rate of CA-AKI than the overall population of the study (14.4% versus 12.7%). Although our results were not statistically significant (р=0.61, odds ratio 1.19, 95% confidence interval 0.63–2.24).

Conclusion. The prevalence of CA-AKI was higher in the group of patients with anemia, but didn’t meet statistical significance and needs further evaluation in larger studies.

Terapevticheskii arkhiv. 2020;92(12):48-52
Prevalence of small bowel bacterial overgrowth in patients with functional dyspepsia: a meta-analysis
Kucheryavyy Y.A., Andreev D.N., Maev I.V.

Aim. Systematization of data on the frequency of detection of the syndrome of bacterial overgrowth in the small intestine (SIBO) in patients with functional dyspepsia (FD).

Materials and methods. MEDLINE/PubMed, EMBASE, Cochrane, Google Scholar, the Russian Science Citation Index (RSCI) through July 2020 were searched to identify studies evaluating the prevalence of SIBO in FD. In addition, a search for relevant abstracts was carried out in the electronic databases of the United European Gastroenterology Week (UEG), American College of Gastroenterology (ACG), International Conference on Nutrition and Food (ICNF). For the final analysis, publications were selected that used validated tests for the assessment of SIBO (hydrogen breath test using glucose or lactulose) with detailed descriptive statistics, allowing the resulting data to be included in the meta-analysis.

Results. The final analysis included 7 studies with 1248 patients with FD. Overall pooled prevalence of SIBO in patients with FD was 34.73% (95% CI 24.807–45.383). There was significant heterogeneity between the results (p<0.0001; I2=89.91%). When excluded from the meta-analysis of a study in which the incidence of SIBO was studied in patients with refractory FD, the pooled prevalence was 38.98% (95% CI 28.964–49.490).

Conclusion. This meta-analysis has demonstrated that SIBO is often associated with FD and is observed in about every third patient with this functional gastrointestinal tract disease.

Terapevticheskii arkhiv. 2020;92(12):53-58
Testing and validation of the Russian version of quality of life questionnaire in patients with GERD – GERD-HRQL
Ionova T.I., Zinkovskaya A.V., Mayevskaya E.A., Nikitina T.P., Porfirieva N.M., Cheremushkina N.V., Shaburov R.I., Kucheryavyy Y.A., Maev I.V.

Aim. This study aimed to test the Russian version of GERD-HRQL in the focus group of patients with GERD, as well as to evaluate its psychometric properties – reliability, validity and sensitivity.

Materials and methods. The total of 57 patients with GERD (mean age – 45.8±12.4 years, 72% – women, 68% – patients with not erosive reflux disease, 84% had esophageal manifestations of GERD) were enrolled into the study. All the patients filled out the Russian version of GERD-HRQL and generic quality of life questionnaire RAND SF-36 during the routine visit to the gastroenterologist. According to the results of testing of GERD-HRQL, it was clear and easy to complete for patients and reflected the main concerns specific for GERD patients. The most frequent and bothersome symptoms/problems which interfered with quality of life in GERD patients were heartburn (100% of patients) and bloating (84% of patients). During the validation procedure, the high reliability and validity of the Russian version of GERD-HRQL were demonstrated. It was shown that the tool was sensitive both to changes over time and to clinically determined differences in patients’ status.

Results. The Total GERD-HRQL Score was significantly higher (worse quality of life) in the following groups: a) patients who had esophageal manifestations of GERB vs those without esophageal manifestations of GERB; b) patients with GERD complications vs those without GERD complications, c) patients with comorbidities of upper gastrointestinal tract vs without those comorbidities; d) patients with erosive esophagitis vs with non-erosive reflux disease (p<0.05).

Conclusion. The developed Russian version of the GERD-HRQL questionnaire proved to have high psychometric properties and may be used in the Russian population of GERD patients both in research studies and in a real clinical practice.

Terapevticheskii arkhiv. 2020;92(12):59-66
Vascular remodeling with violations of intracardiac hemodynamics in patients older age category, combined with the clinical-cluster, neurocognitive and biomarker heterogeneity in multifocal atherosclerosis
Khasanov A.K., Bakirov B.A., Davletshi R.A., Novikova L.B., Kudlay D.A.

Aim. Study of the remodeling of the carotid arteries with violation of intracardiac hemodynamics in patients with MFA, and the estimation of the main parameters of dyslipidemia, apoptosis, and oxidative stress in patients with high vascular risk older age group (61–75 years) in a Regional vascular center of Ufa.

Materials and methods. Depending on the predominant lesion of the vascular pool, patients were divided into 3 clusters by the method of hierarchical analysis of categorical variables according to the clinical manifestation of atherosclerotic lesions of the heart, brain and lower limb arteries confirmed by coronary angiography, ultrasound Doppler of the main arteries of the head and lower extremities. 96 of them were IPA with a primary lesion of the heart (1st cluster), the 96 – IPA with a predominance of lesions of the carotid arteries (2nd cluster), 96 patients with ischemia of lower extremities (3rd cluster). At the hospital stage, electrocardiography, echocardiography, magnetic resonance imaging of the chest and abdomen, ultrasound of the OBP and kidneys, if necessary, ultrasound of the pelvis were performed. Determination of 8-ON-deoxyguanosine, annexin-5 (An-5) and Aan-5 in blood by ELISA was performed in all patients with MFA, as well as standard biochemical screening for lipidogram examination.

Results. We have found that most often in different combinations and with different degrees of severity according to our data are observed:

Clinical manifestation of atherosclerotic heart disease (cluster 1) mainly due to its history in combination with stage III hypertension with increasing thickness of intima-media complex and stenosis of the right WASP, left ventricular dilatation, as well as a higher concentration of Aan-5IgMand LP-A as a risk factor for coronary heart disease, atherosclerosis, atherothrombosis. 2. Hemodynamically significant violations of the main arteries of the head in patients of the 2nd cluster mainly with acute ischemic cerebral circulation, in which there was a development of left ventricular hypertrophy with an increase in the size of the left atrium and the presence of atherosclerotic plaque of the right and left WASP. The higher prevalence of stroke was combined with a marked cognitive deficit among patients of cluster 2 with the lowest level of An-5, an increase in total cholesterol and low-density lipoprotein cholesterol. 3. The total severity of the condition in patients with hemodynamic ischemia with clinical manifestation of vascular lesions of the lower extremities was accompanied by a predominant increase in stable angina with FC2, lerish syndrome with occlusion of the iliac, superficial femoral arteries, the presence of insulin-independent type 2 diabetes, which in this group was established in 59.4% of cases, combined with a higher concentration of the marker of oxidative stress 8-ON-deoxyguanosine and hypertriglyceridemia.

Conclusion. The construction of a three-cluster model in patients at high vascular risk of the elderly age category showed the interaction of cardio-carotid comorbid background on the clinical diversity of systemic vascular lesions in MFA with the development of remodeling of the main arteries and disorders of intracardiac hemodynamics associated with laboratory changes in the assessment of the main parameters of dyslipidemia, apoptosis markers, oxidative stress.

Terapevticheskii arkhiv. 2020;92(12):67-74
Antiresorptive activity of pharmacological chondroitin sulfate in the older age group
Shavlovskaya O.A., Zolotovskaya I.A., Prokofyeva Y.S.

The prevalence of osteoarthritis (OA) increases in proportion to age, so in the population of people over 65 years of age. The pathogenesis of OA is based on inflammation of the cartilage tissue of the joint, which leads to damage to the cartilage, activation of signaling pathways and increased levels of cytokines.

Aim. To study the literature data on bone and cartilage remodeling with the development of resorptive processes and discuss possible algorithms and recommendations for the management of patients with OA on the background of chondroprotective therapy.

Materials and methods. A comprehensive analysis of data presented in open sources, published and available on such resources as PubMed, EMBASE, Cochrane, and Library.

Results. According to the available recommendations and the opinion of experts, among the methods of OA therapy, drugs containing pharmaceutical chondroitin sulfate are currently being discussed, which in a number of studies has demonstrated high antiresorptive effectiveness.

Conclusion. The use of drugs based on pharmaceutical chondroitin sulfate (Chondroguard) contributes not only to the reduction of pain in OA, but also has a positive effect on the processes of inflammation, including those associated with age-related changes in the body.

Terapevticheskii arkhiv. 2020;92(12):75-79
Advantages and limitations of initial combination therapy in pulmonary arterial hypertension patients in Russia
Shmalts A.A., Gorbachevsky S.V.

Pulmonary arterial hypertension (PAH) is severe and often times rapidly progressive disease with fatal outcome. The concept of initial combination of PAH-specific therapies in high risk patients at baseline was first described in the European guidelines on pulmonary hypertension (PH) in 2009, and in low or intermediate risk patients at baseline in 2015. Interestingly, that in Cologne Experts Consensus, and then in the 6th World Symposium on PH medical community started considering initial combination therapy as one of the most important pillars in PAH treatment algorithms in 2018. As of August 2020, as many as 8 formulations of 7 reference PAH-specific drugs are licensed for medical use in the Russian Federation. On top of that, 6 abbreviated drugs (generics) have also become available few years ago. Unfortunately, intravenous and subcutaneous prostacyclin analogs (PCA) and tadalafil are not approved for PH patients treatment in the Russian Federation. In this narrative review paper we attempted to describe studies on initial dual combination therapy with PAH-specific drugs registered in Russia, i.e. ambrisentan and riociguat, macitentan and riociguat, macitentan and sildenafil in low or intermediate risk patients at baseline, as well as iloprost inhaled and sildenafil, iloprost inhaled and bosentan in high risk patients. Some beneficial pharmacological effects due to the synergy between ambrisentan plus riociguat, and inhaled iloprost plus sildenafil appear to be interesting and require further clinical confirmation. Other initial combinations of PAH-specific agents require large-scale clinical trials as well.

Terapevticheskii arkhiv. 2020;92(12):80-85
Diagnosis and treatment of hereditary angioedema with normal C1-inhibitor level
Emelyanov A.V., Leshenkova E.V., Kameneva G.A.

Hereditary angioedema (HAE) with normal C1-inhibitor level is a rare potentially life-threatening disorder with autosomal dominant inheritance which was first described in 2000. Its clinical presentation is similar to HAE with C1-deficiency. The review is summarized data about its prevalence, mechanisms, genetics and diagnostic criteria. Different subtypes and treatment options (on demand, short term and long-term prophylaxis) are discussed. We describe family clinical cases of 2 female patients with normal C1-inhibitor and plasminogen gene mutation. Their features were late diagnosis (in 10 and 25 years after the onset of symptoms), family history (similar genetic mutation in 3 female members of the same family, including 1-asymtomatic) and combination of face, tongue, larynx and abdominal angioedema in patient and her sibling.

Terapevticheskii arkhiv. 2020;92(12):86-90
Mixed steatohepatitis: more questions than answers (Part 1)
Raikhelson K.L., Kondrashina E.A., Pazenko E.V.

The term «steatohepatitis» is used for a heterogeneous group of diseases of various etiologies, characterized by a similar morphological picture. Earlier the diagnosis of non-alcoholic fatty liver disease implied the exclusion of other causes of steatohepatitis, in recent years it has been suggested that a combination of various etiological variants of steatohepatitis is possible. The review considers the terminological, epidemiological and pathogenetic aspects of the most common combination: metabolic and alcoholic genesis, the issues of the mutual influence of etiopathogenetic factors and the identification of the predominant process. Issues of existing and prospective pathogenetic and symptomatic therapy are discussed in detail. Treatment of steatohepatitis is based on the elimination of known causal factors and lifestyle modification; therapy includes medications, that have been proven to be effective in certain types of steatohepatitis and symptomatic therapy as well.

Terapevticheskii arkhiv. 2020;92(12):91-96
Rebamipide: evidence base for use in gastroenterology
Andreev D.N., Maev I.V.

Rebamipide is a cytoprotective drug that has been used in practical gastroenterology for 30 years. This article summarizes the main results of the most relevant clinical studies of rebamipide in diseases of various parts of the gastrointestinal tract, including the esophagus, stomach, small and large intestine.

Terapevticheskii arkhiv. 2020;92(12):97-104
Recommendations for the Protocol of functional examination of the anorectal zone and disorders classification: the International Anorectal Physiology Working Group consensus and Russian real-world practice
Fomenko O.Y., Morozov S.V., Scott S., Knowles H., Morozov D.A., Shelygin Y.A., Maev I.V., Nikityuk D.B., Shkoda A.S., Kashnikov V.N., Bordin D.S., Isakov V.A., Biryukov O.M., Belousova S.V., Pimenova E.S., Rumiantsev A.S., Fedorov E.D., Gvozdev M.Y., Trukhmanov A.S., Storonova O.A., Indeykina L.H., Biryukova M.G., Andreev D.N., Kucheryavyy Y.A., Achkasov S.I.

This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high-resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Aim – to provide information about methods of diagnosis and new classification of functional anorectal disorders to a wide range of specialists – general practitioners, therapists, gastroenterologists, coloproctologists – all who face the manifestations of these diseases in everyday practice and determine the diagnostic and therapeutic algorithm. Current paper provides agreed statements of IAPWG Consensus and comments (in italics) of Russian experts on real-world practice, mainly on methodology of examination. These comments in no way intended to detract from the provisions agreed by the international group of experts. We hope that these comments will help to improve the quality of examination based on the systematization of local experience with the use of the methods discussed and the results obtained. Key recommendations: the International Anorectal Physiology Working Group protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia.

Terapevticheskii arkhiv. 2020;92(12):105-119
Autoimmunity and autoinflammation in pathogenesis of immunoinflammatory diseases
Shilkina N.P., Masina I.V., Dryazhenkova I.V., Vinogradov A.A., Yunonin I.E.

Rheumatic diseases relate to the group of the immunoinflammatory diseases (IID), in pathogenesis of which have a value both autoimmune and autoinflammatory processes.

Aim. To present the heterogeneous pathogenesis of inflammation in IID.

Materials and methods. It is inspected 260 patients (pts) with IID: 242 pts with systemic autoimmune diseases (SAD): 65 systemic lupus erythematosis, 50 systemic sclerosis, 127 systemic vasculitides (SV) and 18 patients with autoinflammatory diseases (AID): 8 Behcet’s disease, 2 periodic disease, 5 familial cold fever, 2 idiopathic lobular panniculitis and 1 relapsing polychondritis. Is carried out a study of complement, antigen of von Willebrand factor (FW:AG), antinuclear antibodies, antibodies to DNA, anti-endothelial antibodies, antibodies to topoizomeraze I (anti-Scl-70), antineutrophilic cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aCL IgG and aCL IgM), cryoglobulins, VS, CRP.

Results. SAD were characterized by the synthesis of wide antibodies spectrum. As the basic serological marker at the screening it follows to consider antinuclear antibodies (75%). Practically in all groups it took place hypcomlemetemia with reduction of C3 and C4 complement. With systemic lupus erythematosis are revealed antibodies to DNA (71%), with ANCA-associated SV-ANCA (94%), aKL (14%); with SSD – aScl-70 (17%). At Wegener granulomatosis ANCA are determined in 94% patients in the active stage. It is noted correlation ANCA with the index of the clinical activity of vasculitis. In the remaining SV groups ANCA were separated in the single cases. Cryoglobulins are noted in all patients with cryoglobulinemic vasculitis. aCL IgG and aCL IgM were the markers of antiphospholipid syndrome. Аnti-endothelial antibodies had significant oscillation spectrum. High indices FW:AG are noted with all above nosologic forms indicated, especially with Wegener granulomatosis and vasculitis hemorrhagic. Among the laboratory tests of inflammatory activity should be considered the determination of VS, CRP and FV:AG, which is also considered the marker of vascular wall defeat. Is given clinical characteristic and changes in the laboratory indices at AID:

Conclusion. Isolation from the group IID of patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy. Isolation from the group SAD patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy.

Terapevticheskii arkhiv. 2020;92(12):120-125
The relationship between Sjogren’s syndrome, systemic sclerosis and lymphoproliferative diseases
Vasil'ev V.I., Chal'tsev B.D., Gorodetskii V.R., Pal'shina S.G., Shornikova N.S., Anan'eva L.P., Gaiduk I.V., Kokosadze N.V., Probatova N.A., Pavlovskaia A.I., Rodionova E.B., Safonova T.N., Balabina A.A.

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature.

Aim. To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogren’s syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkin’s lymphomas (NHL), developing in patients with these rheumatic diseases (RDs).

Materials and methods. In 1998–2018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkin’s lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD.

Results. Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands – 7, disseminated MALT lymphoma – 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) – 1]. RDs debuted with Raynaud’s phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score >4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median – 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies – 60%, antibodies to ribonucleoprotease III – 30%, Pm/Scl – 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La – 70%, RF (rheumatoid factor) – 90%), were detected in patients with a combination of these RDs.

Conclusion. pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

Terapevticheskii arkhiv. 2020;92(12):126-136
Immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation
Allazova S.S., Novikova M.S., Kotenko O.N., Shilov E.M.

Aim. To analyze the modes of immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation (NODAT) in kidney recipients.

Materials and methods. The retrospective analysis included data from 1367 recipients (755 men and 612 women) who lived more than one year after NODAT and were observed at the Moscow City Nephrology Center from January 1989 to December 2018. NODAT was established for 178 (13%) patients based on criteria from the World Health Organization and the American Diabetes Association. The modes of immunosuppressive therapy using cyclosporin A (CSA), tacrolimus (Tac), mTOR inhibitors, glucocorticoids in patients with NODAT and without NODAT were evaluated. To assess the impact of risk factors, descriptive statistics methods were used, the odds ratio (OR) and the 95% confidence interval (CI) were calculated.

Results. NODAT was diagnosed in 105 men and 73 women. The OR for men was 1.19 (95% CI 0.87–1.64), the OR for women was 0.84 (95% CI 0.61–1.15). At the time of transplantation, the average age of the kidney recipients in the NODAT group was higher than in the group without NODAT: 51 [43; 57] and 43 [32; 52] years, respectively (p=0.0001). Most patients with NODAT (82%) were older than 50 years, while in the group without NODAT, the proportion of patients of the same age was 48.5% (p=0.0001). Among patients without NODAT, transplantation of a kidney from a living donor was significantly more often compared with the group with NODAT+ (7.1% vs 1.1%; p=0.001). Among the recipients who received the regimen with CSA, diabetes developed in 75 (42.1%), those who received Tac in 102 (57.3%; p>0.05). The chance (risk of development) of NODAT in patients receiving i-mTOR + Tac was 3.2 (95% CI 1.47–6.78; p=0.032), and for patients receiving i-mTOR + cyclosporin A, the chance of development NODAT was 1.95 (95% CI 0.88–4.35; p=0.044).

Conclusion. 13% of recipients developed de novo kidney diabetes after allograft. Age at the time of allotransplantation, gender, as well as the use of tacrolimus in combination with i-mTOR are the most significant risk factors for the development of NODAT.

Terapevticheskii arkhiv. 2020;92(12):137-141
Comparative capabilities of the speckle-tracking echocardiography technologiesin two-dimensional and three-dimensional modes in the detection of subclinical cardiotoxicity in patients with breast cancer
Saidova M.A., Avalyan A.A., Oshchepkova E.V., Shitov V.N., Chazova I.E.

Aim. The study was to assess the deformation properties of the left ventricle (LV) myocardium in patients with breast cancer initially and after anthracycline chemotherapy according to 2D and 3D speckle-tracking echocardiography (STE).

Material and methods. the study included 99 patients with triple negative breast cancer with hypertensionandnormotension. All patients underwent standard transthoracic echocardiography with assessment of systolic function of the LV. To assess the indicator of global longitudinal strain (GLS), as a marker of cardiotoxicity, STE was used in two-and three-dimensional modes. In the three-dimensional STE mode, a new strain parameter, the global area strain (GAS) was evaluated.

Results. The study showed that in patients with breast cancer for a more accurate assessment of LV systolic function (ejection fraction) it is advisable to use 3D-echocardiography. A comparative analysis revealed statistically significantly lower values of the GLS according to the three-dimensional mode of STE compared to two-dimensional. The study also evaluated a new strain parameter – GAS (%). In patients with breast cancer during ROC analysis with a value of ³≥-14.0, the GAS indicator for the development of subclinical cardiotoxicity showed a sensitivity of 81.5% and a specificity of 73.3%.

Сonclusion. the advantage of the STE in the three-dimensional mode, in contrast to the two-dimensional mode, is the simultaneous and more accurate assessment of LVEF. The value of the additional parameter of LV deformation – the area of deformation requires further study.

Terapevticheskii arkhiv. 2020;92(12):142-147
Experience of olokizumab use in COVID-19 patients
Antonov V.N., Ignatova G.L., Pribytkova O.V., Sleptsova S.S., Strebkova E.A., Khudyakova E.A., Simakov A.I., Rabets S.Y., Tikhonova E.P., Kurmaeva D.Y., Petrushin M.A., Mashkov A.S., Gayazova E.V., Yasheva I.V., Andreev M.A., Khinovker V.V., Karpunin A.Y., Berezhanskiy B.V.

Most subjects with the COVID-19 experience mild to moderate symptoms, but approximately 10% of cases suffer from severe course of disease. IL-6 inhibitors are actively used to neutralize and prevent the «cytokine storm». Olokizumab is a humanized monoclonal antibody belonging to the G4/Kappa immunoglobulin isotype that selectively binds to human IL-6 and effectively neutralizes it.

Aim. To evaluate the efficacy and safety of Artlegia (olokizumab) for the treatment of subjects with a disease caused by the SARS-COV-2 virus in a real-world clinical setting.

Materials and methods. The analysis included data of 610 subjects aged 55.08±12.68 years who received olokizumab at a single dose of 160 mg/mL – 0.4 mL subcutaneously as a preemptive anti-inflammatory therapy. The comparison group included 511 subjects aged 55.23±11.23 years who received standard therapy without IL-6 inhibitors. Control Endpoints: 1. Positive clinical changes on Day 7. 2. Changes in the CRP levels on Days 1, 2, and 7. 3. Duration of oxygen therapy. 4. Number of days in hospital. 5. Number of adverse events. 6. Disease outcome.

Results. If a «cytokine storm» occurs, immune regulatory events will trigger the development of either a protective immune response or an exacerbated inflammatory response. The use of preemptive anti-inflammatory therapy has both a short-term and, most importantly, a long-term effect on the T and B parts of the immune process. These aspects definitely require further research and observation.

Conclusion. The use of olokizumab to treat the new COVID-19 coronavirus disease has demonstrated a positive effect on clinical and laboratory parameters. Primarily, it affects the severity of clinical parameters by improving the general condition already on the first day of observation, and decreasing body temperature to normal values. The changes in the C-reactive protein levels show a significant effect of the IL-6 inhibitor on the systemic inflammatory response.

Terapevticheskii arkhiv. 2020;92(12):148-154
Evaluation of the clinical efficacy of local antibacterial therapy in the treatment of acute bacterial rhinosinusitis
Banashek-Meshcheriakova T.V., Semyonov F.V.

Aim. To evaluate the clinical efficacy of Polydexa with phenylephrinum in the complex treatment of moderate acute bacterial rhinosinusitis.

Materials and methods. The article presents the results of a clinical study of 100 patients with moderate acute bacterial rhinosinusitis – 37 (37%) men, 63 (63%) women aged 15 to 53 years. The patients were randomized into 2 groups of 50 people each. In the study group, patients received systemic antibiotic therapy and a topical nasal spray of Polydexa with phenylephrinum. The control group received systemic antibacterial therapy and long-acting local decongestants. The evaluation criteria were statistically significant differences in clinical and laboratory parameters of the control and main groups.

Results and conclusion. The pronounced anti-inflammatory, antimicrobial effects of the drug were confirmed; conclusions were drawn about the clinical efficacy, tolerability, safety of Polydexa with phenylephrinum and allows to achieve complete resolution of the pathological process in more cases.

Terapevticheskii arkhiv. 2020;92(12):155-159
The practice of using a domestic antiviral drug in the etiotropic therapy of acute respiratory viral infection
Lioznov D.A., Tokin I.I., Zubkova T.G., Sorokin P.V.

Aim. Evaluation of efficacy, safety, tolerability, and determination of the optimal dose of riamilovir in patients diagnosed with acute respiratory viral infection (ARVI).

Materials and methods. The study included 270 patients with uncomplicated ARVI of mild and moderate severity (with a laboratory-confirmed PCR method for the presence of ARVI antigens, absence of influenza virus antigens). Patients were included in the study after signing an informed consent. Patients were randomized into 3 groups in a 1:1:1 ratio of 90 patients in each group. Completed the study in accordance with the Protocol: 267 patients. The study involved patients diagnosed with ARVI.

Results. Confirmed the efficacy, safety and tolerability of the drug riamilovir. Adverse drug reactions associated, in the opinion of the doctor, with taking the drug and resulting in discontinuation of the drug, were not noted in this study.

Conclusion. As a result of clinical study, the effectiveness of both ARVI treatment regimens with drug riamilovir has been shown. There were no differences in the effectiveness and safety of the proposed treatment regimens. Practical use of both treatment regimens is recommended. However, according to the authors, taking the drug 3 times a day is much more convenient for patients, improves the quality of life and adherence to therapy.

Terapevticheskii arkhiv. 2020;92(12):160-164
Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе
Khokhlov A.L., Mariandyshev A.O., Shcherbakova V.S., Ozerova I.V., Kazaishvili Y.G., Igumnova O.V., Bolgarina A.A., Rudoy B.A.

Introduction. Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs.

Aim. Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form – a dispersible tablet for preparation of oral solution.

Materials and methods. Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated.

Results. The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) – from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) – from 16.8 to 29 mg/l.

It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.5¥10-6 cm/s in the forward direction from the apical to basolateral cell membrane, and 1.5¥10-6 cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented.

Discussion. The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented.

Conclusion. In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Terapevticheskii arkhiv. 2020;92(12):165-171
Clinical and economic comparison of utilization of reslizumab, mepolizumab and benralizumab in the treatment of severe eosinophilic asthma
Zyryanov S.K., Avdeev S.N., Ivanov D.A., Zhuravleva M.V., Kniajeskaia N.P., Matveev N.V., Nenasheva N.A., Fomina D.S., Frolov M.I.

During last few years, the approaches to the management of patients with severe asthma have been revised. Monoclonal antibodies (MABs), inhibitors of interleukin-5 (reslizumab, mepolizumab, benralizumab) have been recently introduced for the treatment of severe eosinophilic asthma. The mentioned drugs were approved in Russia and included into the list of Vitally Essential Drugs.

Aim. The aim of this study was to compare the clinical and economic consequences of the use of biological agents that antagonize IL-5 in the treatment of severe eosinophilic asthma in adults.

Materials and methods. Two methods of clinical and economic research were used: assessment of the cost-effectiveness ratio and analysis of the budget impact. The effectiveness of the drugs was assessed using indirect comparison; special attention was paid to comparability of the patient groups in the studies chosen for such an assessment. Two approaches were used for calculation of the cost of therapy for severe asthma: using DRGs (applicable to most regions of Russia), and without the use of DRGs, which is relevant only for few Russian regions.

Results. Basing on the data obtained from a budget impact study without the use of DRG, it was shown that reslizumab was dominating for patients with body mass of up to 70 kg, while for the patients with body mass of 70 to 110 kg, mepolizumab was dominating, while utilization of reslizumab appeared to be somewhat more expensive. In the group of patients with body mass over 110 kg, mepolizumab also was dominating. The calculation of the cost-effectiveness ratio (CER) showed that reslizumab appeared to be dominating over two other MABs,

The results of the study using the DRG demonstrated that the cost of an annual course of benralizumab in most cases in Russia would exceed the amount that can be compensated by Territorial Funds for Mandatory Medical Insurance to a healthcare institution for therapy of bronchial asthma in one adult patient with genetically engineered drugs. Therefore, further comparisons were made for reslizumab and mepolizumab only. Analysis of the impact on the budget demonstrated that treatment with reslizumab and mepolizumab would represent a similar burden for the budget. When applying cost-effectiveness analysis, reslizumab was more cost-effective than mepolizumab (regardless of patient body mass).

Conclusion. Thus, the results of the clinical and economic study suggested that, basing on the cost-effectiveness analysis, reslizumab appeared to be the dominant IL-5 antagonist (regardless of body mass if DRG approach was used and in patients with body mass up to 110 kg, if such an approach was not used). Basing on budget impact analysis, calculations without use of DRG approach showed superiority of reslizumab over mepolizumab and benralizumab for the patients with body mass up to 70 kg and the DRG-based approach showed equal burden for the budget for reslizumab and mepolizumab for the patients with any body mass.

Terapevticheskii arkhiv. 2020;92(12):172-179
Clinical case of combined genetic pathology in a patient
Losik E.A., Yakushina I.I., Skhirtladze M.R., Balahonova N.P., Kerchev V.V., Garanina I.A.

Family hypercholesterolemia (HSX) is a form of genetically deterministic increase in blood lipid levels associated with a high risk of cardiovascular disease, usually at a young age. HSX is a common genetic disease found in the general population in most countries in 1:500 people. Clinically xantomas are found in achilles tendor and wrist flexors, lipoid arc of the cornea, concentration of total cholesterol and low-density lipoproteins is 4.9–11.6 mmol/l. Gilbert’s syndrome is a hereditary benign hyperbilirubinium, associated with a decrease in the functional activity of the liver enzyme uridinfosfat-glucuronosil transferase. Clinically, this syndrome appers in intermittent jaundice, which is provoked by physical activity, consumption of alcoholic beverages, insulation and an increase in the level of indirect bilirubin within 20–100 micromol/ml. The article presents a rare clinical case of genetic combination of HSC SSC and Gilbert syndrome a young patient has and discusses the elevated bilirubin levels protective role in the atherosclerosis progression in Gilbert syndrome.

Terapevticheskii arkhiv. 2020;92(12):180-184
Adrenal incidentaloma. Part 1. Computed tomography of adrenal incidentaloma: the possibilities and difficulties of differential diagnosis
Buryakina S.A., Tarbaeva N.V., Volevodz N.N., Karmazanovsky G.G., Kovalevich L.D., Shestakova M.V., Dedov I.I.

The adrenal incidentaloma is a lesion of a different etiology and found incidentally in patients who underwent a diagnostic study not about the disease of this organ. Lesions can be both hormonally inactive and hormonally active, can arise from different zones of the adrenal gland or have non-specific organ affiliation, can be benign or malignant. Computed tomography characterization of these lesions, especially the differential diagnosis of benign and malignant, is extremely important for the correct diagnosis in order to provide adequate management of the patient. The article presents the key computed tomography criteria that allow radiologist to characterize the lesion most accurately and consider appropriate diagnosis.

Terapevticheskii arkhiv. 2020;92(12):185-194
BCG, muramylpeptides, trained immunity (part I): linkages in the light of the COVID-19 pandemic
Kalyuzhin O.V., Andronova T.M., Karaulov A.V.

It has long been known that Bacillus Calmette–Guérin (BCG) vaccine provides nonspecific protection against many non-mycobacterial infections, which has been discussed in the last decade through the prism of the concept of trained immunity. Within the framework of this concept, a persistent increase in resistance to various pathogens, which occurs after an infectious disease or exposure to certain microbial agents, is associated with epigenetic reprogramming of innate immune cells and their bone marrow progenitors. The COVID-19 pandemic has drawn attention of scientists and practitioners to BCG as an inducer of trained immunity. A number of epidemiological studies have suggested a negative association between the coverage of the population with BCG vaccination and the burden of SARS-CoV-2 infection. A series of independent clinical studies of the effectiveness of this vaccine in non-specific prevention of COVID-19 has been initiated in different countries. Recently, the key role of cytosolic NOD2 receptors in BCG-induced trained immunity has been proven. This actualizes the search for effective immunoactive preparations for prevention of respiratory infections in the pandemic among low molecular weight peptidoglycan fragments of the bacterial cell wall, muramylpeptides (MPs), which are known to be NOD2 agonists. The review highlights the proven and proposed linkages between BCG, MPs, NOD2 and trained immunity in the light of the COVID-19 pandemic. Analysis of the data presented indicates the prospects for preclinical and clinical studies of MPs as potential drugs for nonspecific prevention of SARS-CoV-2 infection and/or other respiratory infections in risk groups during the pandemic. First of all, attention should be paid to glucosaminylmuramyl dipeptide, approved for clinical use in Russia and a number of post-Soviet countries for the complex treatment and prevention of acute and recurrent respiratory infections.

Terapevticheskii arkhiv. 2020;92(12):195-200
Insulin therapy is a personalized approach to glycemic management in diabetes
Demidova T.Y., Titova V.V.

Type 2 diabetes is characterized by chronic hyperglycemia and varying degrees of insulin resistance and insulinopenia. Achieving targeted glycemic control in diabetic patients is important to reduce the risk of late complications, and many patients with type 2 diabetes ultimately require insulin therapy to maintain adequate glycemic control. Timely administration of insulin can prevent the progression of diabetes, reduce the development of complications, and have fewer side effects. Basal insulin is the preferred option in most cases when glycemic control is not achieved. However, there is considerable therapeutic inertia in clinical practice, both with respect to initiation of insulin therapy and titration of the basal insulin dose. The longer duration of action, reduced glucose variability and a lower risk of hypoglycemia seen with the latest generation of basal insulin analogs compared to the previous generation simplify titration and may increase patient compliance.

Terapevticheskii arkhiv. 2020;92(12):201-206
Diagnosis of thrombotic thrombocytopenic purpura
Galstyan G.M., Klebanova E.E.

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease, disease, characterised by microangiopathic hemolytic anaemia, consumption thrombocytopenia, and organ dysfunction. The pathogenesis of TTP is attributed to the deficiency in the activity of the metalloproteinase ADAMTS13, specific von Willebrand factor cleaving protease. TTP is suspected when detecting microangiopathic hemolytic anemia, thrombocytopenia, damage to various organs. Diagnosis of TTP is confirmed by the detection of ADAMTS13 activity in plasma less than 10%. Plasma samples for the study of ADAMTS13 activity should be taken before the start of plasma transfusions or plasma exchange. In patients with severe ADAMTS-13 deficiency autoantibodies anti-ADAMTS13 and inhibitor ADAMTS13 should be investigated. Anti-ADAMTS13 antibodies belonging to IgG not always have inhibitory effects. The inhibitory effect of anti-ADAMTS13 antibodies is confirmed by mixing test. All patients with the first established diagnosis of TTP should be examined for mutations of the ADAMTS13 gene.

Terapevticheskii arkhiv. 2020;92(12):207-217

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