Today, within the context of harmonisation of requirements in the international pharmaceutical market, there is a trend towards development of common standards, including in the field of preclinical studies. The reliability and reproducibility of experimental data obtained in various laboratories using animals cannot be guaranteed unless the 3Rs principles are observed (the principles of humane experimental technique) to ensure the welfare of animals. The present paper analyses Russian and foreign recommendations on different administration routes and administered volumes as applied to mice, rats, guinea pigs, and rabbits – the most frequently used laboratory animals.  The paper systematises literature data on oral/intragastric, subcutaneous, intramuscular, intravenous and intraperitoneal routes of administration. It assesses potential complications of each route of administration, and negative effects on both health and well-being of laboratory animals, as well as on the results of experiments. The paper also touches upon some anatomical and physiological characteristics of laboratory animals, potential opportunities for feed and water deprivation, ways of reducing pain in animals. The results of comparison of administered volumes helped to determine optimal recommended and maximum administered volumes.

Neuropsychological research methods are used to evaluate cognitive functions (CF). Tests used in clinical neuropsychology, in most cases, describe one or more aspects of cognitive domains that are theoretical «constructs» in which several cognitive processes are involved. Neuropsychological tests measure CFs regardless of the medical condition of the test subject. This allows for determination of even minor changes in CFs, including in clinical trials, which is of fundamental importance in studying the efficacy and safety of a given therapy. This article deals with specific aspects of using neuropsychological and screening testing of cognitive functions in individual domains on the basis of foreign experience. It discusses the criteria for selection and application of individual tools, their features, and choice of criteria for evaluating the results of testing in clinical studies in cases of CFs deterioration in various medical conditions accompanied by cognitive impairment. When planning clinical trials, it should also be taken into account that mixed anxiety-depressive disorders are likely to cause forgetfulness, and this calls for differential diagnosis and should be registered in clinical research protocols. The use of subscales and combinations of components of different tools are encouraged based on the objectives of the clinical study, and the tools of neuropsychological research and cognitive function assessment should be validated taking into account the specificity and sensitivity of the method, using statistical analysis methods for specific purposes and tasks. Such a multifaceted approach to the study of cognitive impairments will significantly increase the level of clinical trials conducted and, consequently, will make it possible to put up for sale efficacious and safe medicines for the treatment of cognitive impairment.

Nowadays retrospective analysis of bioequivalence studies of medicinal products that have the same International Nonproprietary Name is becoming particularly relevant. Over the past years we have accumulated a sufficient pool of data in the Russian Federation which make it possible to identify many differences, difficulties and errors associated with bioequivalence studies (especially those of highly variable drugs). Given that inhibitors of angiotensin-converting enzyme (ACE) can be highly variable, we conducted a retrospective analysis of bioequivalence studies of domestically-produced and foreign-made generic enalapril products. This article presents the results of the analysis whose aim was to determine intraindividual coefficients of variation and harmonise approaches to planning and evaluation of enalapril bioequivalence studies. It was demonstrated that enalapril products do not show high variability – both in terms of the original compound and the active metabolite. However, the analysis revealed many differences in the study designs: recruitment of a different number of healthy volunteers; determination of the concentration of either the original compound only, or in combination with the active metabolite; various analytical methods used for determination of analytes; different duration of blood sampling; and different sampling time points. The revealed differences made it possible to standardise the key research parameters, to harmonise them with the current requirements for conducting bioequivalence studies, and to formulate recommendations for planning and evaluation of enalapril studies. With respect to the study design, in addition to the standard conditions, the following can be recommended: at least 18 healthy volunteers should participate in enalapril bioequivalence studies; the pharmacokinetic parameters should be determined for both enalapril and its main active metabolite (enalaprilat); the duration of blood analyte determination should be at least 24 hours; the washout period should be 7 days; blood sampling for estimation of the maximum concentration should be more frequent around one hour after administration for enalapril and after three hours for enalaprilat.

Rheumatoid arthritis (RA) is an autoimmune rheumatic disease of unknown etiology which manifests itself in chronic erosive arthritis (synovitis) and systemic lesions affecting internal organs. The main emphasis in the RA treatment is placed on the pharmacological therapy: non-steroidal anti-inflammatory drugs, ordinary analgesics, glucocorticoids, basic synthetic anti-inflammatory drugs, and targeted therapy drugs which are now represented by genetically engineered biologicals. The choice of rational treatment options for this severe disease is an important challenge facing modern medicine. The study reported in this paper analysed the clinical data registry for basic anti-inflammatory drugs for RA treatment, which was elaborated based on RA classification and diagnostic criteria. It was revealed that a product’s indications for use are formulated in the clinical data registry based on the product’s pharmacological properties and are accompanied with the description of the target population. It is necessary to provide a list of clinical parameters that will be monitored in the study to demonstrate the efficacy of treatment. The main efficacy endpoint may be chosen based on the product’s pharmacological properties. The efficacy is assessed using integrated indicators. Expected endpoints should be in line with the declared indication for use. Trials that confirm efficacy of a product should assess its therapeutic potential to the fullest extent possible. Before a medicinal product is authorised, it is necessary to obtain sufficient data on its safety, taking into account potential risks of long-term use. 

Fluconazole – an antifungal agent belonging to the chemical class of triazole derivatives – is represented in the Russian pharmaceutical market by a large number of generic drugs. An important issue of rational pharmacotherapy is the demonstration of the reference and generic drugs’ equivalence with the aim of assessing their interchangeability. Therefore, the aim of this study was to analyse fluconazole drug dosage forms and routes of administration, as well as qualitative and quantitative composition of active substances and excipients in order to identify characteristics that may affect interchangeability. The analysis of the nomenclature and composition of fluconazole drugs was carried out based on the data contained in the National Register of Medicinal Products of the Russian Federation and the Reference Book of Medicines^®. It was shown that the current nomenclature of fluconazole drugs includes the following types of products: for parenteral use, internal use, and topical use. The generic fluconazole drugs in the form of capsules differ from the reference Diflucan^® in excipients, shelf life, and packaging. The fluconazole substance has a number of specific features, i.e. the presence of polymorphic modifications, their specific characteristics, and the influence of the process parameters and storage on their stability. It was revealed that in many cases the production of fluconazole capsules involved the use of substances purchased from two or more suppliers, which may lead to changes in quality and bioavailability during storage. The obtained data can be used in the future for optimisation of pharmaceutical development and evaluation of interchangeability of fluconazole drugs.

 The use of assay methods with different test conditions for determination of anthracene derivatives in herbal substances and herbal medicinal products requires adjustment of the established limits for total anthracene derivatives content based on the test method used.

The aim of the study was to compare different pharmacopoeial methods of quantitative determination of anthracene derivatives, and established limits for the active substance content, and to analyse the possibility of adjusting the limits based on the test method used.

Materials and methods: the total content of anthracene derivatives was measured in the samples of frangula bark (fragmented bark and powder) and senna leaves (fragmented leaves and powder) using the test methods described in the State Pharmacopoeia of the Russian Federation (XI and XIII editions), and the European Pharmacopoeia.

Results: the analysis of Russian and foreign pharmacopoeial requirements for determination of anthracene derivatives in laxative herbal medicinal products demonstrated differences in extraction solvents, extraction conditions, and calculation methods used. The experiments showed that the optimal extraction solvent was 70 % alcohol solutions, and that an indirect cobaltic chloride reference standard should be replaced by specific absorbance of glucofrangulin A and sennoside B. It was shown that the limits for total anthracene derivatives content should be chosen based on the extraction conditions used.

Conclusions: comparative theoretical research and experimental studies helped to determine optimal assay conditions and respective limits for total anthracene derivatives content to be used in quality control of herbal substances and herbal medicinal products.   

The need to reduce analysis time when controlling impurities in medicinal products remains an urgent challenge.

The aim of the study was to use the example of ciprofloxacin in order to select chromatographic conditions that will significantly accelerate and simplify determination of impurities in medicinal products.

Methods: the study was performed using the Chromolith^® Performance RP-18e 100×4.6 mm and Acquity UPLC BEH C18 1.7 μm, 100×2.1 mm columns and the Agilent 1290 Infinity chromatography system with a diode array detector.

Results: the authors of the study worked out gradient elution modes for determination of ciprofloxacin impurities that involved 15 min run time for fast high-performance liquid chromatography and 12 min run time for ultra-performance liquid chromatography. The identification of impurities was performed based on relative retention times of impurity peaks and their comparison with the reference standard chromatogram.

Conclusions: the study demonstrated the possibility of replacing the thin-layer chromatography method used for determination of fluoroquinolonic acid (ciprofloxacin impurity A) with high-performance liquid chromatography. The proposed test conditions allow for identification of ciprofloxacin impurities specified in well-established pharmacopoeias and manufacturers’ product specification files. The obtained data may be used for further development of rapid methods of ciprofloxacin impurities determination in medicinal products.