A comparative dissolution kinetics test (CDKT) related to proton-pump inhibitors (PPIs), particularly omeprazole, using dissolution media with pH 1.2 and 6.8 does not take into account the impact of common pathophysiological factors on these acid-labile drugs, in particular pharmacological acid suppression of intragastric contents in patients with acid-dependent diseases. The stability of enteric dosage forms in moderately acidic environments (pH 4.0) should be studied to solve this problem because they simulate the gastric content during a course of PPIs, i.e., they themselves organize stress testing of their own membranes after several days of a course of PPIs, the results of which can be predictively assessed in CDKT studies. ACDKT was performed on a model of pharmacological acid suppression using the drugs OMEZ® (20 mg enteric capsules, Dr. Reddy’s Laboratories LLC, Spain) and omeprazole enteric capsules (20 mg) produced in Russia with a stated bioavailability of 30 – 40

Тест сравнительной кинетики растворения (ТСКР) на сегодняшний день остается незаменимым инструментом исследования поведения лекарственных препаратов in vitro. Это метод, целью которого является установление эквивалентности профиля растворения в условиях, близких к физиологическим в желудочно-кишечного тракте. С помощью двухэтапного ТСКР, моделирующего патологический дуоденогастральный рефлюкс и состояние фармакологической кислотосупрессии, изучена стабильность таблеток референтного (РП) и воспроизведенных препаратов рабепразола натрия (Разо® и ВЛС1) в моделируемых условиях. Количественное определение рабепразола натрия проводили на жидкостном хроматографе Agilent 1200 со спектрофотометрическим детектором. По результатам сравнительной кинетики растворения и расчета фактора сходимости выявлена эквивалентность профилей растворения препаратов РП и Разо® в среде растворения с рН 7 после 2-часовой экспозиции в средах с рН 1,2 и 4,5. Препарат ВЛС1 признан неэквивалентным по профилю растворения препарату РП в связи с существенными различиями в динамике высвобождения действующего вещества в изучаемые среды растворения. Использованная модель патологического дуоденогастрального рефлюкса показала, что лекарственная форма ВЛС1 не обеспечивает сохранность молекул рабепразола в моделированных патофизиологических условиях, характерных для пациентов с кислото- зависимыми заболеваниями.

Helicobacter pylori infection can serve as one of indications to clarithromycin prescription. H. pylori eradication is performed commonly as a treatment for diseases caused by this pathogen and conditions with an increased risk of complications (precancerous changes of the gastric mucosa, unspecified iron deficiency anemia, idiopathic thrombocytopenic purpura, long-term NSAIDs use, anti-platelet drugs use etc). A number of H. pylori functional characteristics determines specific requirements for eradication schemes: high sensitivity of the pathogen, the ability of antibacterial drugs to penetrate and accumulate in gastric tissue and mucous,a stimulation of microorganism’s reproduction and protection of acid-resistant drugs by reducing gastric acid production as well. If the latter is provided by the use of proton pump inhibitors, then clarithromycin fully provides the other issues above. In Russia, standard triple therapy is used as the first-line treatment of H. pylori infection due to current clarithromycin resistance less than 15%. The article gives detailed reasoning and factual evidence of commitment to the first-line therapy under the increasing prevalence of the most recent antibiotic resistance (local resistance to levofloxacin has reached 20%), the high potential for multi-drug resistant H. pylori strains appearing, low ensuring medical facilities with relevant resistance test-systems, a role of generic drugs (clarithromycin and proton pump inhibitors) with compromised pharmaceutical characteristics in creation and erroneous interpretation of a pseudoresistance to clarithromycin.

Among the defecating disorders with constipation or diarrhea, there is a group of major intestinal disorders defined by the Rome IV Diagnostic Criteria (2016): irritable bowel syndrome, functional constipation, functional diarrhea. The presence of several updates of the Rome criteria is due to the current lack of objective signs of the listed disorders while many options for describing subjective sensation by patients from different countries. It calls for their terminological multilingual standardization. Both constipation and diarrhea can be caused by a variety of exogenous and endogenous factors and have different pathogenetic mechanisms, but they cannot be identified properly using modern clinical and laboratory methods for functional intestinal disorders. However, the high prevalence of these syndromes, characterized by the presence of complaints that reduce patients’ quality of life, necessitates their correction. The drug choice for defecation disorders and abdominal pain is often limited by contradictions from international clinical guidelines and national regulations.Therefore, the Recommendations of the Russian Gastroenterological Association for the treatment of functional intestinal diseases contain many instructions on general therapeutic and dietary measures. The pain syndrome treatment is based on the spasmolytics. Among the laxatives that have long been used in the treatment of chronic constipation, sodium picosulfate has long been successfully used. This drug has high efficacy and safety profiles; the instructions for its medical use allow to prescribe it in patients suffered from irritable bowel syndrome with constipation. The use of sodium picosulfate for IBS is regulated by many clinical recommendations. However, this drug may be ineffective against abdominal pain. It is incorrect to assign the mission of pain relief to a laxative because of multifactorial pathogenesis of IBS pain with constipation or diarrhea and uncertainty of methods for its pharmacological control.

Тест сравнительной кинетики растворения (ТСКР), проводимый в отношении ингибиторов протонной помпы (ИПП), в частности, омепразола, с применением сред растворения с pH 1,2 и 6,8, не учитывает влияния на эти кислотонеустойчивые препараты промежуточных значений pH, которые возникают в желудке при курсовом применении ИПП не учитывает влияния на эти кислотонеустойчивые препараты обычных патофизиологических факторов, в частности, фармакологической кислотосупрессии внутрижелудочного содержимого у больных с кислотозависимыми заболеваниями. Для решения данной проблемы целесообразно изучать стабильность кишечнорастворимых лекарственных форм в умеренно-кислых средах (pH 4,0), поскольку они моделируют содержимое желудка при курсовом применении ИПП. То есть через нескольких дней курсового применения ИПП сами организуют стресс-тестирование собственных оболочек, результаты которого можно предиктивно оценить в исследованиях ТСКР. В работе проведен ТСКР с моделью фармакологической кислотосупрессии препаратов ОМЕЗ®, капсулы кишечнорастворимые 20 мг (ООО «Др. Редди’с Лабораторис», Испания) и кишечнорастворимые капсулы омепразола 20 мг российского производства с заявленной биодоступностью 30 – 40 % (Омепразол*). Установлено, что при экспозиции в растворе с pH 6,8 после двухчасовой инкубации в среде с pH 1,2 препараты ОМЕЗ® и Омепразол* оказались фармацевтически эквивалентными. Однако при экспозиции в растворе с pH 4,0 наблюдалось разрушение пеллет препарата Омепразол* с вероятной деградацией выделившегося кислотонеустойчивого действующего вещества в умеренно кислой среде; при перемещении частично разрушенных пеллет в раствор с pH 6,8, имитирующий тонкокишечную среду, доля высвободившегося действующего вещества не превышала 24,0 %, по сравнению с 82,4 – 88,1 % действующего вещества, высвободившегося из пеллет препарата ОМЕЗ®. Следовательно, кишечнорастворимые пеллеты препарата Омепразол*, в отличие от пеллет препарата ОМЕЗ®, разрушились в умеренно кислой среде с pH 4,0, соответствующей pH среды желудка, при курсовом применении ингибиторов протонной помпы с падением концентраций кислотонеустойчивого действующего вещества омепразола в средах, имитирующих среды желудка и тонкой кишки.

The article deals with the current problems of the prevalence, diagnosis and treatment of acid-related disorders in children. The administrative and legal aspects of the state regulation of measures aimed at diagnosing Helicobacter pylori infection, procurement of drugs for its treatment in the Russian Federation are discussed. The article also focuses on the standards of treatment of H. pylori infection in children with regard to age restrictions for the administration of the recommended drugs. A detailed account of the mechanisms of the developing H. pylori resistance to modern antibacterial drugs is given. The above problems necessitate the use of highly effective and safe drugs with low H. pylori resistance and approved for administration in children. The article indicates the already established and hypothesised factors of the pathogen’s low resistance to bismuth preparations. The multifactor, predominantly local, pharmacodynamic effect of bismuth tripotassium dicitrate in children ≥ 4 years of age is described. Data on the clinical effectiveness and high safety of this compound in H. pylori eradication therapy in paediatric population are also presented. Key words: acid-related disorders, Helicobacter pylori, standards for diagnosis and treatment of H. pylori in children, antibiotic resistance, bismuth tripotassium dicitrat

The current data about patient management strategy of dyspepsia syndrome at outpatient stage are reported in the review.

Modern therapy, aimed at eradication of H.pylori, includes a set of antisecretory and antibacterial drugs and sometimes bismuth preparations. A feature of modern eradication schemes is the 14-day use of antibiotics, prescribed in high daily doses and selected mainly based on microorganism resistance to clarithromycin and metronidazole in the respective region. However, each component of eradication scheme can have rather serious sode effects, as well as affect the bioavailability, biotransformation, excretion, and the potentiation of the effects of the drugs that the patient can take simultaneously with anti H.pylori therapy. The article lists the most serious and common variants of drug-drug interactions of the eradication schemes' components, it gives a description of the mechanism of their development, when applicable. Before the approval official of practical recommendations for the prevention of drug-drug interactions of drugs included in the eradication schemes, commonly available databases containing information about such interactions should be used.

The article highlights modern concepts of inflammatory diseases in adults and children in terms of genetic possibilities for diagnosing Crohn's disease and ulcerative colitis. It names the main candidate genes, which, in the presence of their specific polymorphisms, indicate the occurrence of a high risk of inflammatory bowel disease. The principles of modern therapy, the possibilities of pharma-cogenetic testing in predicting the effectiveness or risks of reducing the safety of drug therapy are described. The article focuses on modern trends and perspectives in ulcerative colitis and Crohn's disease treatment.

Main groups of antisecretory drugs used in the treatment of acid-dependent diseases, including gastroesophageal reflux disease (GERD), are described in a review. Mechanisms of activation, degradation and inactive metabolites formation of proton pump inhibitors (PPIs) – final elements of acid production blockage – are considered in detail. Special attention is paid to the presence of PPIs’ derivatives with different functional activity: inactive derivatives, active and inactive metabolites. Topographic description of these derivatives, their significance in terms of an effect on bioavailability, clinical effectiveness and a potential of PPIs interactions with other administered drugs. The combined decision-making algorithm in the presence of gastroesophageal reflux disease symptoms is presented, compiled on the basis of the most authoritative current recommendations. This algorithm provides for the use of PPIs in standard doses once a day for 4–8 weeks with a possible dose escalation in a case of ineffectiveness. If treatment with high doses of PPIs is ineffective, a set of measures is needed to identify the causes of this inefficiency and to choose additional medical strategy. Depending on the clinical situation, after erosions epithelization the treatment can be stopped, used on demand, prolonged in the intermittent or supportive forms. Particular attention is paid to the Panum® drug, which has proven its effectiveness in patients with different degrees of reflux esophagitis. The availability of dosage forms for prescription and over-the-counter leave allows ensuring its comfortable and unhindered purchase by patients and eliminating excessive burden on the healthcare system.

This review aims at describing clinical benefits and characteristics of the main highly effective disease modifying drugs (DMD) for multiple sclerosis (MS): alemtuzumab, cladribine tablets, ocrelizumab, natalizumab, fingolimod based on the efficacy and safety. The authors highlight that all MS DMDs have certain benefits and features that shall be considered in prescribing pharmacotherapy. Cladribine in tablets are comparable by the efficacy to other modern highly effective second-line drugs, have a high level of evidence and a favorable safety profile, as well as the most preferred benefit/risk ratio among other MS DMDs indicated for the treatment of highly active MS, which offers an advantage to the drug. The use of cladribine in tablets will contribute to further study of the efficacy and safety of this highly efficient drug for MS treatment.

Introduction. Patients with surgical menopause have a risk for osteopenic syndrome (OS). Menopausal hormone therapy (MHT) in combination with calcium and vitamin D promotes increase in bone mineral density (BMD). The expression level of vitamin D receptor in mononuclear fraction cells (MNFC) of blood can be considered as a predictive marker of effectiveness of OS therapy. Aim. To search a molecular predictive marker of the effectiveness of OS treatment. Materials and methods. The study included 100 women aged 4055 years with a duration of surgical menopause from 12 months to 6 years. The criterion for including patients in the study was the absence of contraindications to the use of MHT. The subject of the study was the determination of BMD by dual-energy X-ray absorptiometry, polymerase chain reaction diagnostics of the level of expression of vitamin D genes, estradiol and progesterone receptors, determination of 25-OH vitamin D in the blood. Results. Analysis of 12-month OS therapy effectiveness evaluated with a surrogate marker BMD. The increase in BMD up to 34% per year was treated as absence of negative dynamics, more than 4% per year as positive one. Significant effect of combination therapy compared with MHT on BMD in patients with surgical menopause with a low baseline level of BMD (due to hypovitaminosis D) is associated with the anti-inflammatory, bone-protective effect of vitamin D. In both groups of patients not responding; to the prescribed therapy we were able to conduct a comparative analysis of expression level of the target molecules in the MNFC before the start of treatment. The efficacy of MHT and combination therapy for BMD disorders is positively associated with the expression level of vitamin D receptors in MNFC before treatment. Therefore, the vitDR mRNA level is a potential predictive marker of the effectiveness of OS treatment. The expression levels of nuclear estradiol beta receptor and membrane receptor for progesterone in MNFC before treatment showed an upward trend in women responding to therapy. Conclusion. The expression level of the vitamin D receptor in MNFC of blood is significantly lower in the group of women with no/insufficient effect on 12-month combined therapy. This indicator can be considered as a predictive marker of the effectiveness of OS therapy.

Выполнен тест сравнительной кинетики растворения, моделирующий воздействие патологического дуоденогастрального рефлюкса и лекарственной кислотосупрессии на устойчивость препаратов эзомепразола 3 разных производителей. После экспозиции в растворах с pH (1,2 ± 0,05) или (4,0 ± 0,05) препараты перемещались в среду с pH (7,0 ± 0,05), откуда забирались аликвоты через 0, 4, 10, 15, 20, 30, 45, 60 мин для определения в них концентраций эзомепразола. Время воздействия патологического дуоденогастрального рефлюктата на лекарственную форму эзомепразола равно 4 мин. Показано, что в заданных тестом условиях ВЛС1 и ВЛС2 не являются эквивалентными референтному препарату (РП), лекарственная форма РП, вероятно, подвержена влиянию патологического дуоденогастрального рефлюкса в желудке, ВЛС2 полностью разрушается в умеренно кислой среде с pH 4,0, что свидетельствует о возможном негативном воздействии его основного антисекреторного фармакодинамического эффекта на стабильность в желудке собственной лекарственной формы и действующего вещества.

Aim: The aim of this work is to assess the organizational risks of H. pylori eradication therapy and the control methods of antibiotic resistance by a clinico-pharmacological analysis of the purchases structure in Russian state-funded medical facilities. Materials and methods: A legal framework in the fields of purchases of products, works, services for state and municipal needs, open contract bids, schedule and annual procurement plans for 2017, the Ministry of Health of Russian Federation statistical materials were explored. Results: According to Russian and international guidelines, current purchases of products, works, services are mainly related to a primary H. pylori identification not its eradication control. “Quasi-reference” H. pylori diagnostic methods with lower sensitivity in comparison to reference ones and extremely low specificity are relatively popular. Conclusion: Information related to the structure of products, works and services purchases for H. pylori diagnostics on the Federal Acts No. 44 and 223 united information web-system (http://zakupki.gov.ru) shows no rational assessment of effective eradication therapy while H. pylori is recognized as a microorganism with a high potential for adverse drug reactions and drug-to-drug adverse interactions development. WHO made H. pylori a priority pathogen for antibiotics research and development.

Current risks from resistance, adverse drug reactions, and drug – drug interactions of clarithromycin used as a component of Helicobacter pylori eradication therapy are reviewed. The acid sensitivity of clarithromycin i responsible for the dependence of its pharmacological properties on the efficacy of proton-pump inhibitors, which could be one reason for the resistance of H. pylori to the macrolide. The potential for clarithromycin drug – drug interactions is related to its metabolism by CYP3A4 and strong inhibition of this enzyme.

A comparative dissolution kinetics test was performed to model the actions of pathological duodenogastric reflux and therapeutic acid suppression on the stability of esomeprazole formulations from three different manufacturers. After exposure to solutions pH (1.2 ±0.05) or (4.0 ±0.05), formulations were transferred to medium pH (7.0 ±0.05), from which aliquots were collected at 0, 4, 10, 15, 20, 30, 45, and 60 min for estimation of esomeprazole concentrations. The duration of exposure of the medicinal formulation of esomeprazole to pathological duodenogastric refluxate was 4 min. In these test conditions, Generic-1 and Generic-2 were found not to be equivalent to the reference drug (RD); the medicinal formulation of the RD was probably influenced by pathological duodenogastric reflux in the stomach, while Generic-2 was completely degraded in moderately acidic medium pH 4.0, which is evidence of the possible adverse influence of its main antisecretory pharmacodynamic effect of the intragastric stability of the medicinal formulation and the active substance.

В обзорной статье описаны современные риски резистентности, нежелательных лекарственных реакций и лекарственных взаимодействий кларитромицина при его применении в качестве компонента терапевтических схем эрадикации H. pylori. Кислотонеустойчивость кларитромицина в кислой среде определяет зависимость фармакологических свойств препарата от эффективности ингибиторов протонной помпы, что может быть одной из причин резистентности возбудителя к макролиду. Потенциал лекарственных взаимодействий кларитромицина связан c его способностью метаболизироваться с помощью CYP3A4 и мощно ингибировать этот фермент.

В обзоре литературы освещено современное состояние проблемы оценки безопасности одного из наиболее широко применяемых в клинической практике прокинетика и антиэметика — домперидона. Особое внимание уделено потенциальной кардиотоксичности препарата, механизмов ее развития и факторов риска. Для снижения риска развития дозозависимых побочных эффектов препаратов созданы новые лекарственные формы, обеспечивающие поддержание концентрации действующего вещества в плазме крови в пределах терапевтического диапазона. Другим способом повышения эффективности и безопасности является использование эффекта потенцирования. В качестве примера приведен домперидон в составе фиксированной лекарственной комбинации с омепразолом (Омез-ДСР), в которой прокинетик представлен формой модифицированного высвобождения, обеспечивающей равномерное поступление действующего вещества в системный кровоток без развития высоких «пиковых» концентраций, сопряженных с повышенным риском дозозависимых нежелательных лекарственных реакций.

Aim: To develop evidence-based recommendations for primary care physicians and general practitioners (GP) on choosing the proper management tactics and making valuable & quick diagnostic decisions at outpatient phase for patients with symptoms of dyspepsia, and also reveal possible oncology on time. Summary of recommendations: Approximately 40% of the patients in Russia presenting to primary care with symptoms of dyspepsia. A doctor has to focus on the warning signs, which may require an urgent additional examination & the consultation with a surgeon/onco-surgeon or other specialists if required. With regard to a risk of cancer, a doctor should be more cautious in patients over 45 years of age. Early diagnosis of oncology depends mainly on cautiousness of GP, primary care physicians and their knowledge, future tactics with regard to the patients. From the mandatory diagnostic tests during the first visit, esophagogastroduodenoscopy and H. pylori diagnostics helps to exclude any organic esophagus and stomach pathology, possible oncology. While waiting for endoscopy results, a physician should use the preliminary diagnoses “Uninvestigated Dyspepsia” (ICD-10 К 31.9) (disease of stomach and duodenum, unspecified). After exclusion of all warning signs, therapy of dyspepsia should be in accordance to the order of the Ministry of Health No 248 which gives an option to use proton pump inhibitors (omeprazole or rabeprazole 20 mg daily) in combination with prokinetic (domperidone 30 mg daily). Fixed drug combination of omeprazole 20 mg and modified-release domperidone 30 mg/daily (Omez® DSR) is medically reasonable. Conclusion: The introduction of this recommendation into clinical practice will help clinicians to prevent diagnostic mistakes, unreasonable use of expensive diagnostic examinations and inappropriate treatment leads to improvement in the overall prognosis and quality of life for the patients.