The s-process branching at 185W

The neutron capture cross section of the unstable nucleus 185W has been derived from experimental photoactivation data of the inverse reaction 186W(gamma,n)185W. The new result of sigma = (687 +- 110) mbarn confirms the theoretically predicted neutron capture cross section of 185W of sigma = 700 mbarn at kT = 30 keV. A neutron density in the classical s-process of n_n = (3.8 +0.9 -0.8} * 1e8 cm-3 is derived from the new data for the 185W branching. In a stellar s-process model one finds a significant overproduction of the residual s-only nucleus 186Os.Comment: ApJ, in pres

Perturbed Three Vortex Dynamics

It is well known that the dynamics of three point vortices moving in an ideal fluid in the plane can be expressed in Hamiltonian form, where the resulting equations of motion are completely integrable in the sense of Liouville and Arnold. The focus of this investigation is on the persistence of regular behavior (especially periodic motion) associated to completely integrable systems for certain (admissible) kinds of Hamiltonian perturbations of the three vortex system in a plane. After a brief survey of the dynamics of the integrable planar three vortex system, it is shown that the admissible class of perturbed systems is broad enough to include three vortices in a half-plane, three coaxial slender vortex rings in three-space, and `restricted' four vortex dynamics in a plane. Included are two basic categories of results for admissible perturbations: (i) general theorems for the persistence of invariant tori and periodic orbits using Kolmogorov-Arnold-Moser and Poincare-Birkhoff type arguments; and (ii) more specific and quantitative conclusions of a classical perturbation theory nature guaranteeing the existence of periodic orbits of the perturbed system close to cycles of the unperturbed system, which occur in abundance near centers. In addition, several numerical simulations are provided to illustrate the validity of the theorems as well as indicating their limitations as manifested by transitions to chaotic dynamics.Comment: 26 pages, 9 figures, submitted to the Journal of Mathematical Physic

Planning of clinical trial programmes for medicines for the treatment of obesity

Scientific relevance. Obesity is a significant public health problem. Currently, the Russian Federation and the other Member States of the Eurasian Economic Union (EAEU) do not have regulatory documents and recommendations for planning clinical trials (CTs) of new (original) medicines for the treatment of obesity.Aim. The study aimed to provide recommendations on the basic principles of planning and conducting CTs of medicines for the treatment of obesity.Discussion. The authors reviewed the requirements for conducting CTs of medicines for the treatment of obesity set forth by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). In addition, the authors analysed approaches to CTs providing for a reliable evaluation of the efficacy and safety of medicines for the treatment of obesity. The primary endpoint of such CTs is a statistically significant loss of at least 5% of the baseline weight after 12 months of treatment. Secondary endpoints include assessments of abdominal obesity reduction, subcutaneous and visceral fat reduction, and the medicinal product’s effect on maintaining a reduced body weight.Conclusions. In addition, CTs should investigate the effects of treatment on cardiovascular risk factors and cardiovascular morbidity/mortality. A CT protocol should define the intercurrent events that should be considered in the analysis of trial results. When investigating the safety of medicines for the treatment of obesity, studies should focus on neuropsychiatric safety, the potential for abuse/addiction and withdrawal reactions, and the development of valvulopathy and pulmonary hypertension. These recommendations may be of use to experts evaluating clinical development programmes or marketing authorisation submissions for medicines for the treatment of obesity

INFLUENCE OF SEX DIFFERENCES ON PHARMACOKINETICS OF DRUGS WITHIN THE FRAMEWORK OF BIOEQUIVALENCE STUDIES OF GENERIC MEDICINAL PRODUCTS

Background. Evidence of the effect of sex on the pharmacokinetics of drugs and, accordingly, on the clinical response is significantly accumulated, because of a growing number of clinical studies of the early development of original drugs, which include female subjects. The number of bioequivalence studies of replicated drugs involving both sexes is also growing. Of particular importance for the bioavailability of oral medications are differences in the anatomy and physiology of the digestive system. Along with this factor, the differences may be due to the dosage form of the reproduced drug, which may differ from that of the reference (original). The aim of the study was to identify the effect of sex differences on the pharmacokinetics of drugs and to propose an algorithm for assessing their detection. Materials and methods. The article presents a general analysis of the works devoted to the pharmacokinetics of medicines in men and women and includes literature data. Results. The main factors influencing the pharmacokinetics of drugs (absorption, distribution, metabolism, excretion) are identified. Examples of medicinal products for which differences in pharmacokinetics in men and women are revealed are given. The article describes the main international requirements for conducting clinical trials and bioequivalence studies with regard to the choice of gender of subjects and their number to be included in the clinical study. It is suggested that there is a need to further study of the effect of sex differences on bioequivalence results in carrying out relevant studies. Conclusion. An algorithm for estimating the detection of sex differences and their effect on the results of bioequivalence studies of generic drugs is proposed

Current Approaches to Demonstration of Therapeutic Equivalence of Locally-Acting Gastrointestinal Drugs

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU

Development of an Approach to the Assessment of Changes to Approved Biological Products

The need to strengthen the post-approval regulation of biological products stems from their increasing role in the treatment of serious human diseases. Until recently, there were open questions on the classification of changes and supporting data necessary to confirm the comparability of a biological medicinal product before and after any changes, as well as on the procedures and deadlines for the submission and approval of variations. In October 2017 the WHO Expert Committee on Biological Standardisation developed and published the «Guidelines on procedures and data requirements for changes to approved biotherapeutic products». The WHO recommendations are primarily aimed at resolving the complexities and current problems in the global life cycle management of biotherapeutic products. Guidelines suggest approaches that ensure continued quality, efficacy, and safety of this group of products, as well as continuity in supply and access. The purpose of this paper was to analyse the WHO recommendations on post-approval changes to biotherapeutic products in order to develop harmonised approaches to the assessment of post-approval changes to biological medicinal products in the Russian Federation. The categories of quality changes, supporting data, conditions to be fulfilled, procedures and deadlines set forth in this paper can serve as a basis for further improvement of the national regulatory and methodological framework

The breakdown of the mean-field description of the Nagaoka phase

We discuss the relevance of the improved mean-field slave-fermion theory to describe the Nagaoka ($U=\infty$) limit of the Hubbard model. In this theory the crucial on-site constraint of no double electron occupancy is taken into account rigorously prior to the mean-field approximation. At one-loop approximation the effective mean-field action shows a long-range ferromagnetic order over the whole doping range. This indicates that the slave-fermion mean-field theory does not constitute an appropriate framework to describe the physics of the Nagaoka phase. We discuss the drawbacks of this mean-field theory and present some results on the derivation of a low-energy effective spin action to describe the Nagaoka phase beyond the mean-field approximation.Comment: 10 pages, revised and extended version. To be published in Phys. Rev.