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Problems pertaining to evaluation of the interchangeability of drugs with the same international nonproprietary name and a narrow therapeutic index (NTI) are discussed. An analysis of 2073 spontaneous reports in the Russian database for the period 2009 - 2015 revealed information about adverse reactions that occurred upon mutual substitution of NTI drugs. Most communications about adverse side reactions referred to the substitution of calcineurin inhibitors and synthetic hypoglycemic drugs, in particular, cyclosporine (20.4% of the total body of data), tacrolimus (11.3%), and glibenclamide (16.5%). Most disorders with substitution of calcineurin inhibitors were observed in kidneys and the urinary tract; of glibenclamide, in the gastrointestinal tract. Significant percentages of cases referred to ineffective replacement of levothyroxine and warfarin besides glibenclamide. In most cases, the reference drug was tolerated well whereas switching to a generic led to a lack of efficacy and/or the development of adverse reactions. An analysis of the database showed that spontaneous communications can and should be taken into account during post-registration control of drugs that were initially accepted as interchangeable. [ABSTRACT FROM AUTHOR]

The presence of several generics on the pharmaceutical market makes it possible to create a competitive environment and helps to reduce the costs of drug therapy. RF Government Decree No. 1154 of October 28, 2015, 'On the procedure for determining the interchangeability of drugs for medical use' determines largely the fate of generics in Russia. Quality assurance of generics and the creation of a competitive environment for the procurement of pharmaceutical products by regional public health institutions in order to reduce costs were the primary drivers of this decree. However, results from substitution of antiepileptic drugs indicate a number of problems in this field. The present review is devoted to an analysis of the interchangeability problems of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

The presence of granular matter between the sliding blocks (such as for example gouge in rock joints and faults) considerably affects friction. The effect of grain movement and rolling is often modelled by considering them as spherical. This paper investigates the influence of the grain/particle shape. We found that rolling of non-spherical particles leads to an apparent friction reduction related to the effect of the moment equilibrium about a point of contact. The collective behaviour of rolling non-spherical particles is affected by their interaction by the elasticity of the material of the sliding blocks. In the case of identical and symmetrical particles, there exists a uniform solution whereby all particles undergo identical displacements. This solution is, however, unstable; at certain magnitudes of the friction force and the corresponding values of the displacement the solution bifurcates such that different particles show different displacements. When many particles of different sizes are rolling without interaction, the friction force fluctuates, and as the displacement increases, the fluctuations reach a steady state. The amplitudes of the fluctuations depend upon the shape factor; they are the smallest when the particles have a square shape and considerably increase as the period of particle rolling approaches the diameter. [ABSTRACT FROM AUTHOR]

A continuum model of deformation of a transform fault is considered. The fault interior is modelled as a part of a plate fragmented into a large number of angular blocks. The blocks are not joined together by any binder, but are rather held together due to external compression such that they can, in principle, rotate independently. Significant numbers of blocks involved in the deformation process permit a continuum description of the deformation, which in view of the possibility of independent rotations, necessitates the application of the Cosserat theory. The crucial point in the described model is the interconnection between the rotations and the normal stresses associated with the angular shape of the blocks: the rotating blocks `elbow' one another. Furthermore, elbowing produces compressive stresses independent of the direction of rotations. Consequently, the constitutive equations become non-linear involving absolute values of the components of the curvature tensor. The paper analyses a simple shear of a fault under constraining compression acting in the direction normal to the fault. An infinite layer subjected to opposite displacements and zero rotations at the edges is considered. It is shown that block rotations can lead to complex deformation patterns. There exists a displacement threshold proportional to the pressure: for imposed displacements below the threshold, the deformation pattern coincides with the conventional one as predicted for a classical elastic isotropic layer with uniform displacement gradient in the absence of block rotations. When the imposed displacement exceeds the threshold value, boundary zones of non-uniform rotations, displacement gradients and dilatation emerge. It is interesting to note that these features, which could be mistaken for indicators of non-elastic or localisation processes, occur in a situation where only elastic processes are acting at the scale of blocks and no friction or other energy dissipation processes take place. [ABSTRACT FROM AUTHOR]

Rotational degrees of freedom in Cosserat continua give rise to higher fracture modes. Three new fracture modes correspond to the cracks that are surfaces of discontinuities in the corresponding components of independent Cosserat rotations. We develop a generalisation of J- integral that includes these additional degrees of freedom. The obtained path-independent integrals are used to develop a criterion of crack propagation for a special type of failure in layered materials with sliding layers. This fracture propagates as a progressive bending failure of layers – a “bending crack that is, a crack that can be represented as a distribution of discontinuities in the layer bending. This situation is analysed using a 2D Cosserat continuum model. Semi-infinite bending crack normal to layering is considered. The moment stress concentrates along the line that is a continuation of the crack and has a singularity of the power − 1/4. A model of process zone is proposed for the case when the breakage of layers in the process of bending crack propagation is caused by a crack (microcrack in our description) growing across the layer adjacent to the crack tip. This growth is unstable (in the moment-controlled loading), which results in a typical descending branch of moment stress – rotation discontinuity relationship and hence in emergence of a Barenblatt-type process zone at the tip of the bending crack. [ABSTRACT FROM AUTHOR]

- The phenomenon of strain localisation is often observed in shear deformation of particulate materials, e.g., fault gouge. This phenomenon is usually attributed to special types of plastic behaviour of the material (e.g., strain softening or mismatch between dilatancy and pressure sensitivity or both). Observations of strain localisationin situor in experiments are usually based on displacement measurements and subsequent computation of the displacement gradient. While in conventional continua the symmetric part of the displacement gradient is equal to the strain, it is no longer the case in the more realistic descriptions within the framework of generalised continua. In such models the rotations of the gouge particles are considered as independent degrees of freedom the values of which usually differ from the rotation of an infinitesimal volume element of the continuum, the latter being described for infinitesimal deformations by the non-symmetric part of the displacement gradient. As a model for gouge material we propose a continuum description for an assembly of spherical particles of equal radius in which the particle rotation is treated as an independent degree of freedom. Based on this model we consider simple shear deformations of the fault gouge. We show that there exist values of the model parameters for which the displacement gradient exhibits a pronounced localisation at the mid-layers of the fault, even in the absence of inelasticity. Inelastic effects are neglected in order to highlight the role of the independent rotations and the associated additional parameters. The localisation-like behaviour occurs if (a) the particle rotations on the boundary of the shear layer are constrained (this type of boundary condition does not exist in a standard continuum) and (b) the contact moment-or bending stiffness is much smaller than the product of the effective shear modulus of the granulate and the square of the width of the gouge layer. It should be noted however that the virtual work functional is positive definite over the range of physically meaningful parameters (here: contact stiffnesses, solid volume fraction and coordination number) so that strictly speaking we are not dealing with a material instability. [ABSTRACT FROM AUTHOR]

The incidence of bile leaks has increased with laparoscopic cholecystectomy as compared with open cholecystectomy. Minor bile leaks are not infrequent but are clinically insignificant; of the major bile leaks the most common sequela is the biloma, the most serious, bile peritonitis. Early symptoms may be very subtle; all untoward symptoms should be investigated with a HIDA scan to rule out bile leakage. Positive HIDA scans should be followed with endoscopic retrograde cholangiography (ERC) or percutaneous transhepatic cholangiography (PTC). Management of the leakage depends on identification of its source. Prompt identification of ductal injuries permits earlier effective treatment and consequently less morbidity and/or mortality. [ABSTRACT FROM AUTHOR]