Development Of Adverse Reactions Research Articles

Research Progress on the Influence of Blood Tumor Microen-vironment on the Efficacy and the Adverse Reactions of CAR-T Cell Immunotherapy--Review

The application of chimeric antigen receptor T cell (CAR-T) immunotherapy has ushered in a new era in cancer therapy, especially in the treatment of many kinds of refractory malignant tumors. The curative effect is significant for refractory/recurrent hematologic malignancies, such as acute leukemia, lymphoma, and multiple myeloma (MM). Tumor microenvironment (TME) is closely related to the efficacy and adverse reactions of CAR-T therapy. TME not only affects the activity of CAR-T cells, reduces their anti-tumor ability, but also directly involved in the occurrence and development of CAR-T cell therapy-related adverse reactions, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Therefore, a deeper understanding of the role of blood TME in the process of CAR-T immunotherapy and the occurrence and development of adverse reactions is helpful for the application of CAR-T therapy in hematological malignancies. In this review, the influence of blood TME on the efficacy and adverse reactions of CAR-T immunotherapy was briefly summarized, aiming to provide evidence-based support for the clinical optimization of therapeutic regimen of refractory/recurrent hematologic malignancies.

CBD in the Treatment of Epilepsy.

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.

Relationship between CYP2C19 genotypes and proton pump inhibitorsʹs pharmacokinetics and pharmacodynamics: review

The purpose of this review is to provide clinicians with information and a concise interpretation of the results of pharmacogenetic testing for the cytochrome P450 2C19 (CYP2C19) genotype when choosing a proton pump inhibitor (PPI) dosage. PPIs are widely used for the treatment and prevention of common gastrointestinal diseases, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, and other hypersecretory conditions. Most PPIs are metabolized predominantly by cytochrome P450 2C19 (CYP2C19) to form inactive metabolites, and the CYP2C19 genotype determines the action of PPIs, their efficacy and possible side effects. In clinical practice, a gastroenterologist or therapist is faced with problems of insufficient effectiveness or the development of adverse reactions when prescribing PPIs. Thus, consideration of CYP2C19 genotype appears to be necessary to determine the optimal PPI dosing regimen. The above served as a reason for generalizing in the presented review of literature data on the prescription of PPIs depending on the CYP2C19 genotype.

Overview of Antibiotic Prophylaxis in Orthopaedic and Cardiac Procedures.

Antibiotic prophylaxis (AP) in surgical procedures is commonly used to prevent infections that may occur after operations. There are multiple factors that can contribute to increased risk of postsurgical complications that include prolonged hospitalization, reoperation, and readmissions. One of the strategies of decreasing the risk of bacterial contamination and developing infections is preprocedural antibiotic administration. When selecting an appropriate antibiotic, it is important to take into account surgery type and patient's characteristics which would also impact timing of administration and prophylaxis duration. Although surgical AP is significant for avoiding bacterial complications, it is also associated with some drawbacks such as increased antibiotic resistance and development of adverse reactions. Therefore, it is important to assess risks and benefits and select the most appropriate antibiotic regimen before initiating AP.

Switching biological disease-modifying antirheumatic drugs and Janus kinase inhibitors in patients with rheumatoid arthritis

The goal of treatment of rheumatoid arthritis (RA) is to achieve remission or low disease activity. A wide range of disease-modifying antirheumatic drugs is used for the treatment of RA, including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). However, even with the use of bDMARDs and JAKi, this goal can be achieved only in 40–60% of patients. Insufficient response to bDMARs and JAKi is the reason for switching to other drugs from the same group, such as tumor necrosis factor-α inhibitors, and to drugs with a different mechanism of action. The need to change therapy may be associated with its ineffectiveness due to various immune, genetic and epigenetic mechanisms, with the development of adverse reactions, as well as with comorbid pathology. To date, there is no certain predictors of effectiveness of a particular bDMARDs and JAKi and of the need and strategy for changing the therapy.The review considers the effectiveness of various classes of bDMARDs and JAKi in RA, the frequency and risk factors associated with the need to switch patients to other drugs, the role of chemokines as promising markers of response to RA treatment.

P017 Increased Level of Immunoglobulin G in the Development of Adverse Reactions in Patients With Ulcerative Colitis.

Goal: To identify the relationship between the level of immunoglobulins G and E and the development of adverse reaction (AR) in patients with ulcerative colitis (UC) receiving original infliximab (IFХ) and infliximab biosimilar (BS). 35 UC patients with moderate to severe course of the disease (according to Truelove-Witts) who received maintenance therapy with IFХ at a standard dose of 5 mg/kg of body weight for a year were retrospectively analyzed. There were 16 men (45.7%), 19 women (54.3%). The average age is 34±4.2 years. The duration of the anamnesis was from 3 to 7 years. Patients were divided into 3 groups depending on the development of AR and the received biological drug, without taking into account concomitant anti-inflammatory therapy. The 1st group (n=14) alternated the introduction of the original IFХ and its BS; The 2nd group (n=7) consisted of patients alternating between the original IFХ and BS, in whom AR was registered; the 3rd group (n=14) received BS by one trade name. Using enzyme immunoassay, the level of immunoglobulins in the groups of patients was assessed. In the 1st and 3rd groups, AR was not observed. AR in 2nd group was characterized by: bronchospasm 3 (42.8%), Quincke's edema 1 (14.3%), urticaria 1 (14.3%), rhinitis 1 (14.3%), anaphylactic shock 1 (14.3%). In patients of 1st group, the level of IgE is 44.8 ± 5.1 IU/ml, IgG is 16.5 ± 1.7 g/l. In 2nd group -IgE-44.5 ± 11.7 IU / ml, IgG-26.1 ± 2.1 g/l, while in patients in group 3-IgE - 31.5 ± 3.04 IU/ml, IgG - 9.46 ± 1.01 g/l. It was reliably established that the highest level of IgG was observed in the 2nd group, while in the 3rd group it was minimal (p < 0.05). The IgG level in 1st group is higher than in 3rd group, although in both groups the IgG level was within the reference values. In all groups, the IgE value remained normal. AR on the background of therapy with IFL and biosimilars are not associated with an increase in the level of IgE, but are caused by an increase in the level of IgG. The alternation of the original drug and the biosimilar increases the risk of developing AR due to increased IgG levels. Treatment with a biosimilar by one trade name does not increase the risk of developing AR.

The problem of hypersensitivity to vitamin preparations

ABSTRACT. The problem of the development of adverse reactions as a result of the use of diagnostic and medicinal products (drugs) is becoming increasingly important. Patients more often report reactions to local anesthetics (43.2 % of cases), antibiotics (18.8 %), nonsteroidal anti-inflammatory drugs (9.7 %), other drugs (28.4 %), B vitamins (4-5 %). It is important to understand that hypersensitivity (HS) to vitamin preparations (VP) is very common, according to patients, but not so often confirmed by their in-depth allergy examination. Basic data on HS before the VP were obtained in the 80-90s of the 20th century, but since then the situation has changed radically. The frequency of HS on these drugs is based on medical history when patients use multicomponent VP for oral administration, allergens in which may be other components (shell tablets and capsules, metal salts, flavors, sweeteners, dyes, preservatives). The causative allergens in the injectable forms of VP can also be auxiliary ingredients of the drug, in particular lidocaine and benzyl alcohol. There are only a few scientific publications with the appropriate evidence base for HS to individual VP, more often B vitamins. The clinical picture of HS reactions to VP is diverse (systemic, cutaneous, respiratory, rarely other visceral manifestations). They can develop both immediately and in a delayed type. Part of the VP (B vitamins, vitamin K) can cause the development of anaphylaxis with fatal consequences. VP, as a rule, do not belong to vital drugs therefore it is possible for this reason till now in real clinical practice insufficiently developed methods of allergodiagnostics both in vivo (skin, provocative tests), and in vitro (laboratory tests) among patients with suspicion for the development of HS to VP. It is not possible to perform allergy diagnostics in persons who have taken complex VP, so there is a problem of hyperdiagnosis of drug allergy to them. Therefore, the problem of determining the true allergic reaction in patients who report the development of a history of HS to VP remains relevant. As a rule, after the development of any adverse reaction during the reception of VP on the patient hangs the label “allergy to vitamins” for life without further allergy examination. That is why the problem of HS to VP needs further study.

Особенности течения милиарного туберкулеза у подростков

Особенностью течения туберкулеза в подростковом возрасте является склонность к прогрессированию, некротическим реакциям. Наиболее тяжелым исходом милиарного специфического процесса является развитие менингита, что нередко может быть его терминальной стадией. Цель работы — изу­чить особенности течения милиарного туберкулеза в сочетании с менингитом туберкулезной этиологии у подростка на примере клинического случая. Особенностями течения милиарного туберкулеза в сочетании с менингитом туберкулезной этиологии у подростка были: развитие побочных реакций на длительный прием комплексного противотуберкулезного лечения и гормонотерапии (токсический гепатит, болезнь Иценко — Кушинга вторичного генеза); осложнение туберкулезного менингита ишемическим инсультом в подкорковых отделах левой гемисферы большого мозга и нисходящей атрофией зрительных нервов положительная динамика при правильно подобранном режиме противотуберкулезной химиотерапии как проявлений милиарного туберкулеза, так и специфического менингита.

Frequency of detection of allergic reactions to food in children with atopic dermatitis and pathology of the gastrointestinal tract

Background. In recent years, there has been a worldwide tendency to steady increase in the incidence of adverse reactions caused by food. Therefore, at the present stage, the investigation of the prevalence of the main causative factors of the development of food hypersensitivity is still a challenging task for researchers. The purpose was to study the range of food products, which are the most likely allergy-causing for children of the Poltava region, who had a history of unwanted allergic reactions to food. Materials and methods. The study involved 242 children aged from 6 to 15 years, who had a history about adverse reactions caused by food. The basic group included 128 patients with inflammatory diseases of the upper gastrointestinal tract; the comparison group involved 114 children with atopic dermatitis. The detection of the frequency of allergic reactions to food was investigated by using a questionnaire, allergic anamnesis and findings obtained by skin prick tests with food, epidermal, household and pollen allergens. Results. The study has demonstrated that the factors significantly increasing risks of skin and gastrointestinal allergies in the examined children are as following: maternal hereditary burden of allergic diseases; non-compliance in pregnancy, when mothers of examined children neglected to stick to the hypoallergenic diet; early mixed and bottle feeding and improper introducing of solid food. The findings obtained by questionnaire and skin allergic tests demonstrated a higher level of food sensitization in the children of the basic group. It has been also found out that the development of adverse reactions, regardless of skin or gastrointestinal manifestations, is the most often observed when taking cow’s milk, eggs and fish. Conclusions. Thus, the conducted studies have contributed in finding out main risk factors for the development of food hypersensitivity in children and in identifying the most etiologically significant food products that can provoke the development of allergic and gastroenterological diseases.

Antirheumatic drugs and COVID-19: frustrations and hopes

In accordance with current views on the pathogenesis of the new coronavirus infection, some antirheumatic drugs are considered as therapeutic agents for suppressing the hyperinflammatory response in severe COVID-19. The review presents literature data on the efficacy and safety of certain basic anti-inflammatory and genetically engineered drugs in patients with COVID-19. Hydroxychloroquine is not indicated for the treatment of SARS-CoV-2 infection of any severity due to the lack of therapeutic benefits, the likelihood of a worse prognosis in more severe patients and the development of adverse reactions, especially when used concomitantly with azithromycin. The use of systemic glucocorticoids (GC) in patients with COVID-19 who require oxygen support leads to a decrease in mortality and an improvement in the prognosis of the disease. However, the optimal time of administration, dose and duration of HA administration remain the subject of further research. Despite the encouraging data, it is too early to draw final conclusions about the feasibility of using tocilizumab in COVID-19, since no randomized clinical trials have demonstrated a clear advantage of the drug in terms of reducing mortality. The use of anakinra does not reduce the need for noninvasive / invasive lung ventilation or the mortality of patients with COVID-19. Two drugs from the group of tumor necrosis factor inhibitors - infliximab and adalimumabare currently being considered as possible treatment options for COVID-19. The use of a combination of baricitinib and remdesivir for the treatment of COVID-19 patients requiring oxygen support has been approved. New RCTs are needed to study the effectiveness of other anti-rheumatic drugs in COVID-19.

Prevention of the development of adverse reactions in the treatment of tuberculosis in combination with diabetes mellitus

Background. In recent decades, tuberculosis (TB) and its resistant forms have become an increasing problem in lowincome countries, especially in countries with epidemics of HIV infection and insulin-dependent diabetes mellitus (DM). DМ has been shown to adversely affect TB treatment outcomes. Low treatment outcomes for TB/DM comorbidity are associated with age, weight gain, or poor glycemic control, and it is the increased duration of DM treatment that may be the best strategy for improving outcomes in TB/DM patients. In the formation of the development of polyneuropathy, one of the components is increasing ischemia and intracellular hypoxia, which is characteristic of TB/DM. Decreased blood flow contributes to the destabilization of cell membranes and neuronal death. The interconnected components of the immune and other systems, namely pro-inflammatory cytokines, play an important role in the formation and progression of these processes.&#x0D; Results and discussion. Our clinical assessment of the general condition of patients with TB/DM (23 patients) showed that 91.5 % of the examined patients complained of persistent cough with sputum production, 78 % had shortness of breath, weight loss of more than 5 kg – 89.8 %, thirst – 80 %, 75 % – tingling and numbness of the lower extremities, pain in the legs at night – 85.5 % of people. Sub-febrile temperature (37.4-37.9 °C) was registered in 52.2 % of the examined patients. The general condition of moderate severity prevailed in 49.5 % of patients. Intoxication syndrome (IS) in TB/DM patients by clinical and paraclinical signs was observed in all patients, respectively, pronounced (manifest) IS was recorded in 79.5 %. Body mass index is on average 15.6 kg/m2 (p&lt;0.001). To prevent the development of polyneuropathy, patients with TB/DM was prescribed anti-TB drugs, insulin and additionally pathogenetic therapy according to the scheme: Neuromax, 2 ml intravenously, intramuscular once a day for 7 days, followed by the administration of the drug 2 times a week for 3 weeks, and with the subsequent transition to the tablet form – 1 tablet per day (until the end of the intensive phase of treatment), then Dialipon 3 % solution of 20 ml was prescribed intravenously drip for 7 days (the contents of the ampoule are diluted in 250 ml of 0.9 % sodium chloride solution), with the subsequent transition to a tablet form of 300 mg – 2 tablets once a day for a month.&#x0D; Conclusions. The proposed method makes it possible to effectively prevent adverse reactions in the treatment of TB in combination with DM, reduce the manifestations of peripheral polyneuropathy, provide better tolerance to anti-TB drugs, normalize clinical blood parameters, accelerate the rate of normalization of the content of some pro (IL-6, IL-18) and anti-inflammatory (IL-10) cytokines in the blood plasma of patients, which, in turn, reduces the percentage of refusals from the treatment of comorbid pathology.

Prognostic value of methylation status of MGMT gene promoter in patients with glioblastoma after combination treatment.

e14025 Background: The effectiveness of radiation therapy in the classical and stereotactic treatment regimens of the primary glioblastoma multiforme was analyzed and compared. Methods: 87 patients with primary glioblastoma multiforme were hospitalized during the study period. 17 patients of them were in the treatment group (stereotactic radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.1 cm - group 1), and 70 patients were in the control group (conventionally fractionated radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.5 cm - group 2). Patients of both groups were treated with alkylating agents as the third stage of complex treatment. MGMT methylation was evaluated by pyrosequencing. Results: The use of stereotactic radiation therapy allowed to conduct a full course of treatment without interruption, whereas in the second group, due to the development of adverse reactions, the course was interrupted for 7 patients (10%). The advantage of stereotactic radiation therapy was a less pronounced increase and rapid regression of neurological deficits during treatment, manifested by better local control for 6 months. Hypermethylation of MGMT was detected in 39% of glioblastoma cases and was not detected in non-tumor tissue. The presence of promoter methylation disrupts DNA repair and is associated with longer survival in glioblastoma patients receiving alkylating agents. Note that the median survival of patients with MGMT hypermethylation in the group 1 was 285 days (IQR = 323.75), and in the group without hypermethylation was significantly more than 338.5 days (IQR = 476) (p = 0.045). A similar trend was observed in the second group: in patients with hypermethylated MGMT, the median survival was 271 days (IQR = 337), the result is different from patients without hypermethylated MGMT – 342 days (IQR = 493) (p = 0.039). Conclusions: As a result, the application of the stereotactic approach of radiation therapy in the complex treatment of patients with glioblastoma and their classification by the MGMT methylation status with a cut-off point of 10% has the basis for improving the effectiveness and tolerability of radiation therapy and contributes to the overall survival of patients.

Pharmacogenetic markers of antipsychotic-induced weight gain: leptin and neuroepeptide Y

Antipsychotic drugs are a critical modality in managing of schizophrenia. Although medications can be highly effective, response varies and some patients derive considerably less benefit than others. Long-term use of antipsychotic drugs is associated with the development of adverse reactions. Te safety advantages of the atypical drugs havebeen questioned because of their propensity to induce weight gain and alter glucose and lipid metabolism. Antipsychotic-induced weight gain is a common cause of self-discontinuation of treatment and a significant deterioration in the quality of life in patients with schizophrenia. Te severity of adverse reactions when taking antipsychotics in different patients varies, which be associated with genetic factors. Antipsychotic induced weight gain is a major health concern and unfortunately, there is no predictive tool to identify who are high risk individuals. Te LEP, LEPR and NRY genes represents a compellings candidates for genetic studies of antipsychotic-induced weight gain. Candidate gene selection should rely on current knowledge on the molecular pathways to weight gain, antipsychotic pharmacokinetics and pharmacodynamics, as well as possible disease-related genetic links to the side effects under study. Pharmacogenetics will provide rational treatment based on matching antipsychotics to a patient’s DNA profile, thus, potentially providing effective treatment with minimal side effects to outliers and mean responders to a given antipsychotic medication.

Effect of Intravenous Ibuprofen on Ischemia-Reperfusion Injury Following Perioperative Tourniquet in Patients Undergoing Total Knee Arthroplasty

Oxidative stress occurs in the organism with ischemia due to tourniquet use and subsequent reperfusion. Oxidative stress increases postoperative morbidity. Some Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) perform their anti-inflammatory effects in part by binding or inhibiting their formation of active oxygen radicals at the site of inflammation. In this study, we aimed to evaluate the effect of IV ibuprofen on ischemia-reperfusion injury (IRI) in patients undergoing total knee arthroplasty over oxidative stress parameters. The patients were randomly divided into two groups. Each patient’s protocol number, age, sex, body mass index (BMI), additional disease, drug use, tourniquet time, hemoglobin value, additional analgesic requirement and application, adverse reaction development on the first postoperative day were recorded in the research follow-up form. Both groups of patients; before anesthesia, 45 minutes after tourniquet application, 5 minutes after tourniquet lowering, 20 minutes after tourniquet lowering and at 24th-hour post-op; TOS, TAS, paraoxonase, arylesterase, myeloperoxidase, catalase, ceruloplasmin, albumin, IMA, thiol-disulfide balance tests were studied. Statistical analysis of test results was performed. We observed that antioxidants decreased and oxidants increased on the first postoperative day in both groups in patients who underwent total knee arthroplasty. The decrease in antioxidant parameters was higher in IV ibuprofen doses compared to the control group in the case group; these doses indicate that the drug adversely affects the organism in the fight against oxidative stress, which is an undesirable effect. To evaluate this negative effect of IV ibuprofen which is increasingly used in postoperative analgesia, studies with different doses of drugs and different surgeries may be needed.

Risk management strategy for preventing the reduced treatment effectiveness from the position of drug interactions and polypharmacy in patients with coronary heart disease

Introduction: In modern clinical practice, various drug combinations are widely used, especially in cardiological pa­tients. The existing clinical recommendations necessitate using organ protective agents, especially with a patient having a comorbid pathology and with an ineffective monotherapy. In some cases, drug interaction decreases the effectiveness of pharmacotherapy and increases the risk of developing adverse events (AE).&#x0D; The purpose of the study was to analyze the modern pharmacotherapy of patients with coronary heart disease (CHD), identify polypharmacy of treatment, evaluate its significance for the treatment process, and determine ways to solve the problem of using a multi-component system of pharmacotherapy risk management.&#x0D; Materials and methods: The study involved 156 patients with CHD, among whom 39 received more than 8 drugs at a time.&#x0D; Results and discussion: In these patients, the evaluation of drug interactions revealed 580 variants (48 were danger­ous, 428 – significant, 104 – insignificant). The administration of a therapy to comorbid patients, taking into account possible changes in the activity of cytochrome P450 isoenzymes, is one of the promising ways to improve the safety of a combined pharmacotherapy.&#x0D; Conclusion: It was revealed that with a mutated cytochrome P450 most of processes of drug biotransformation occurs. And there is a greater risk of developing AE against the background of polypragmasia in polymorbid patients, which makes it possible to individually adjust the dose of beta-blockers, thus affecting the frequency of their development. The choice of management measures should be determined considering all the areas of personalized medicine, includ­ing pharmacogenetic predictors, pharmacoepidemiological data, pharmacoeconomic effectiveness, the development of adverse reactions, polypragmasia, and medical and social risk factors.

AB0920 APPLICATION OF THE EULAR 2016 GUIDELINES FOR URATE-LOWERING THERAPY IN CLINICAL PRACTICE (DATA OF A SIX-MONTH PROSPECTIVE STUDY)

Background:The EULAR 2016 guidelines on gout management provide for a consecutive regimen of urate-lowering medications; however, the possibility of reaching the target uric acid level when using the regimen has not been studied in clinical practice.Objectives:To assess the possibility of reaching the target uric acid level when following the EULAR 2016 guidelines on gout management with use of different xanthine oxidase inhibitors available in Russia.Methods:This monocentric prospective study included 83 gout patients (79 (95%) male and 4 (5%) female patients) with the mean age of 51.3±10.9 years old. The inclusion criterion was indications for urate-lowering therapy in accordance with the EULAR 2016 guidelines. The exclusion criteria were the following: absolute contraindications to all of the study drugs, GFR &lt;30ml/min/1.73m2, and NYHA class III-IV heart failure.At urate-lowering therapy initiation, the patients were prescribed allopurinol with the starting dose of 100mg/day; the dose was titrated until the target uric acid level was reached (maximum up to 900mg/day), and in the patients with GFR between 30 and 60ml/min/1.73m2 – up to 300mg/day. In case of insufficient efficacy of allopurinol (unachieved target uric acid level of &lt;360µmol/L, for the patients with severe gout of &lt;300µmol/L) or development of adverse reactions, allopurinol was replaced with febuxostat with the starting dose of 80mg/day and dose titration up to 120mg/day if necessary. The laboratory tests included serum creatinine level, uric acid level, AST, ALT, creatine phosphokinase, glucose; clinical blood test. The following parameters were assessed: possibility of reaching the target uric acid level when following the suggested regimen, and frequency of development of adverse reactions when using allopurinol and febuxostat.Results:37 (45%) patients had the target uric acid level of &lt;360µmol/L and 46 (55%) pts – of &lt;300µmol/L. The recommended therapy regimen allowed 77 (93%) patients under study to reach their target uric acid level.The target uric acid level was achieved by 44 (53%) out of 79 patients on allopurinol, of whom 36 (82%) received 100-600mg/day, and 8 (18%) – 700-900mg/day. Of the patients with GFR of &gt;60ml/min/1.73m2, 32 (73%) patients achieved their target uric acid level and of those with GFR &lt;60ml/min/1.73m2 – so did 12 (27%).Then the patients on allopurinol with unachieved target uric acid level were prescribed febuxostat (in 30 (77%) cases because of inefficacy of the allopurinol therapy, in 9 (33%) patients because of their development of adverse reactions where 5 pts had a more than doubled level of transaminase (ALT, AST), 2 pts had skin itch and 2 pts had hives).In total, 39 patients received febuxostat, of whom 4 pts were with initial intolerance for allopurinol in past history, and 35 pts after therapy with maximum dose of allopurinol. A febuxostat dose of 80mg/day was associated with achievement of the target uric acid level in 14 (42%) patients and that of 120mg/day – in 19 (58%) patients, therefore, total 33 (85%) patients reached their target uric acid level. Four patients on febuxostat developed adverse reactions: 3 patients had a more than doubled serum transaminase level (ALT, AST) and 1 patient had hives. Also, an insignificant increase in the mean GFR was registered from 73±21.4ml/min/1.73m2 to 78.4±22.5ml/min/1.73m2 which did not differ between the two drugs.Conclusion:The recommended regimen of xanthine oxidase inhibitors in their maximal doses secures reaching the target uric acid level in 93% patients. In 47% patients, allopurinol in maximal doses (up to 900mg/day) does not significantly increase the possibility of reaching the target uric acid level, even though it demonstrates high tolerance.Disclosure of Interests:Maria Chikina: None declared, Maxim Elisеev Speakers bureau: Novartis, Menarini Group, Alium, Olga Sheliabina: None declared

Adherence to nine-month isoniazid for latent tuberculosis infection in healthcare workers: a prospective study in a tertiary hospital

Poor adherence to medication can lead to treatment failure in healthcare workers (HWCs) with latent tuberculosis infection (LTBI) who are at high risk of developing active tuberculosis. However, the factors associated with non-completion of nine-month LTBI treatment with isoniazid (9 H) have not been well studied. We investigated the completion rate and factors affecting adherence to LTBI treatment with 9 H among HCWs. A prospective cohort study of 114 HCWs who were diagnosed with LTBI by QuantiFERON-TB Gold In-Tube tests were performed in a single university hospital between June 2016 and December 2017. All patients received the 9 H LTBI treatment. At each visit, treatment adherence and development of adverse reactions to isoniazid were evaluated via a standard questionnaire. To evaluate the impact of the severity of hepatotoxicity on non-completion of LTBI treatment, we classified hepatotoxicity into two groups: severe hepatotoxicity was defined as alanine aminotransferase >3.0 times the upper normal limit (UNL) with symptoms or = 5.0 times the UNL. Mild hepatotoxicity was defined as alanine aminotransferase>UNL, but not meet the definition of severe hepatotoxicity. Overall, 71 HCWs (62.3%) completed LTBI treatment with 9 H while 43 HCWs (37.7%) discontinued their treatment. Most discontinuation (81.4%, 35/43) occurred during the first three months of treatment. There were no significant differences in age, sex, occupation, or comorbidities between the HCWs who completed and those who discontinued LTBI treatment. However, HCWs who discontinued LTBI treatment had more hepatotoxicity than those who completed treatment (44.2% vs. 11.3%, P < 0.001). Cox proportional hazard analysis revealed that hepatotoxicity is the only factor significantly associated with discontinuation of 9 H LTBI treatment (unadjusted HR = 2.89, 95% CI = 1.62–5.46). In multivariable analysis, not only severe hepatotoxicity (adjusted HR = 7.99, 95% CI = 3.05–20.94) but also mild hepatotoxicity was significantly associated with discontinuation of LTBI treatment (adjusted HR = 2.34, 95% CI = 1.05–5.21). The completion rate of 9 H LTBI treatment was 62.3% among HCWs. While age, sex, occupation, and pretreatment comorbidities were not associated with treatment completion, isoniazid-induced hepatotoxicity significantly affected adherence.

SOME ASPECTS OF MANAGEMENT OF HIV-INFECTED PATIENTS WITH PATHOLOGY OF DIGESTIVE SYSTEM IN CONTEXT OF FAMILY MEDICINE PRACTICE

Introduction. In the current situation of the HIV-infection epidemic, every 100-th citizen of Ukraine aged between 15 and 49 is infected with HIV. It is one of the highest rates among countries in the European Region. The issue of retaining HIV-positive patients in the medical surveillance system and support for adherence to ART treatment are becoming particularly relevant. At the same time, the comorbidity of HIV-infection with digestive system lesion is one of the main elements of pathological changes, both in the progression of HIV infection and in the occurrence of various complications leading to interruptions or failure to receive continuous antiretroviral therapy (ART). The purpose of the study is to examine the features of the digestive system lesions of HIV-infected patients and their impact on the effectiveness of antiretroviral therapy. Materials and methods. The study was conducted on randomly selected 215 HIV-infected patients in compliance with the bioethical and scientific standards, in accordance with industry standards and clinical guidelines approved by the Ministry of Health of Ukraine. Results and Discussion. Patients were divided into two comparison groups: the main group (MG) had 158 (73.5%) of HIV-infected persons with pathology of the digestive system, the controlled group (СG) had 57 (26.5%) of HIV-infected patients with no signs of gastric lesions of the gastrointestinal tract. Among the lesions of the digestive system in HIV-infected patients, hepatitis of viral and/or toxic genesis, chronic inflammatory diseases of the esophagus and gastroduodenal zone, chronic pancreatitis and cholecystitis were most often observed. In 61.4%, the pathology of the digestive tract was combined. When evaluating the efficacy of ART, no statistical difference was found between MG and CG in the frequency of the virologic response and the level of viral load at the beginning of the study and at 6 months of follow-up. However, MG patients had a worse immunologic response compared to CG, they were significantly more likely to switch the initial ART regimen, have breaks in treatment and development of adverse reactions. Patients treated for comorbid digestive system disorders had ART replacements less frequently and after 6 months of treatment they had an average level of CD4 + lymphocytes, which corresponded to the normal value. Conclusions. A significant majority of the examined patients with HIV-infection had digestive system lesions (73.5%). HIV-infected patients with digestive system pathology had more treatment interruptions, switch of ART regimens, and a worse immunological response, compared with the controlled group. Untreated diseases of the digestive system could be predictors of an increased break rate of ART, switch of treatment regimens, and decreased treatment efficacy. The introduction of an integrated, patient-oriented approach to the management of these nosologies in family medicine practice is proposed.

Predicting gastrointestinal drug effects using contextualized metabolic models.

Gastrointestinal side effects are among the most common classes of adverse reactions associated with orally absorbed drugs. These effects decrease patient compliance with the treatment and induce undesirable physiological effects. The prediction of drug action on the gut wall based on in vitro data solely can improve the safety of marketed drugs and first-in-human trials of new chemical entities. We used publicly available data of drug-induced gene expression changes to build drug-specific small intestine epithelial cell metabolic models. The combination of measured in vitro gene expression and in silico predicted metabolic rates in the gut wall was used as features for a multilabel support vector machine to predict the occurrence of side effects. We showed that combining local gut wall-specific metabolism with gene expression performs better than gene expression alone, which indicates the role of small intestine metabolism in the development of adverse reactions. Furthermore, we reclassified FDA-labeled drugs with respect to their genetic and metabolic profiles to show hidden similarities between seemingly different drugs. The linkage of xenobiotics to their transcriptomic and metabolic profiles could take pharmacology far beyond the usual indication-based classifications.

Effect of different approaches to thoracolumbar interfascial plane block on analgesic efficacy after lumbar spinal fusion

Objective To evaluate the effect of different approaches to thoracolumbar interfascial plane (TLIP) block on the analgesic efficacy after lumbar spinal fusion. Methods Seventy-five patients of both sexes, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, aged 40-70 yr, with body mass index ≤40 kg/m2, undergoing posterior median approach to lumbar spinal fusion, were divided into 3 groups (n=25 each) using a random number table method: patient-controlled intravenous analgesia (PCIA) group (group P), medial approach to TLIP combined with PCIA group (group MP) and lateral approach to TLIP combined with PCIA group (group LP). TLIP block was performed by advancing the block needle in a lateral to medial direction and injecting 0.5% ropivacaine 20 ml locally between the bilateral multifidus and longissimus muscles in group MP.TLIP block was performed by advancing the block needle in a medial to lateral direction and injecting 0.5% ropivacaine 20 ml locally between the bilateral longissimus and iliocostalis muscles in group LP.The identification rate and distinction score between multifidus and iliocostalis muscles obtained from ultrasonic images were recorded before block in MP and LP groups.All the patients received PCIA until 48 h after surgery.PCIA solution contained sufentanil 100 μg and tropisetron 10 mg diluted to 100 ml with 0.9% normal saline.The PCA pump was set up with a 2 ml bolus dose, a 15-min lockout interval and background infusion at a rate of 1 ml/h.When visual analogue scale score at rest >4 after surgery, parecoxib 40 mg was intravenously injected for rescue analgesia.The development of adverse reactions such as nausea and vomiting was recorded within 48 h after surgery. Results The identification rate and distinction score of the iliocostalis was significantly higher than that of the multifidus (P 0.05). There was no significant difference in the parameters mentioned above between group MP and group LP(P>0.05). Conclusion Ultrasound-guided medial and lateral approaches to TLIP block is helpful in achieving low-dose opioid anesthesia mode and more helpful in enhancing the efficacy of PCIA when used for lumbar spinal fusion. Key words: Nerve block; Fascia; Analgesia, patient-controlled