Репозиторий Университета

© 2018 Elsevier B.V. Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188-coated PLGA nanoparticles enabled a 30-fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.

Copyright © 2018 Institute of Computer Science. The paper proposes a mathematical model for the therapy of glioma, taking into account the blood-brain barrier, radiotherapy and antibody therapy. The parameters were estimated from experimental data and the evaluation of the effect of parameter values on the effectiveness of treatment and the prognosis of the disease were obtained. The possible variants of sequential use of radiotherapy and the effect of antibodies have been explored. The combined use of radiotherapy with intravenous administration of mab Cx43 leads to a potentiation of the therapeutic effect in glioma. Radiotherapy must precede chemotherapy, as radio exposure reduces the barrier function of endothelial cells. Endothelial cells of the brain vessels fit tightly to each other. Between their walls are formed so-called tight contacts, whose role in the provision of BBB is that they prevent the penetration into the brain tissue of various undesirable substances from the bloodstream. Dense contacts between endothelial cells block the intercellular passive transport. The mathematical model consists of a continuous part and a discrete one. Experimental data on the volume of glioma show the following interesting dynamics: after cessation of radio exposure, tumor growth does not resume immediately, but there is some time interval during which glioma does not grow. Glioma cells are divided into two groups. The first group is living cells that divide as fast as possible. The second group is cells affected by radiation. As a measure of the health of the blood-brain barrier system, the ratios of the number of BBB cells at the current moment to the number of cells at rest, that is, on average healthy state, are chosen. The continuous part of the model includes a description of the division of both types of glioma cells, the recovery of BBB cells, and the dynamics of the drug. Reducing the number of well-functioning BBB cells facilitates the penetration of the drug to brain cells, that is, enhances the action of the drug. At the same time, the rate of division of glioma cells does not increase, since it is limited not by the deficiency of nutrients available to cells, but by the internal mechanisms of the cell. The discrete part of the mathematical model includes the operator of radio interaction, which is applied to the indicator of BBB and to glial cells. Within the framework of the mathematical model of treatment of a cancer tumor (glioma), the problem of optimal control with phase constraints is solved. The patient's condition is described by two variables: the volume of the tumor and the condition of the BBB. The phase constraints delineate a certain area in the space of these indicators, which we call the survival area. Our task is to find such treatment strategies that minimize the time of treatment, maximize the patient's rest time, and at the same time allow state indicators not to exceed the permitted limits. Since the task of survival is to maximize the patient's lifespan, it is precisely such treatment strategies that return the indicators to their original position (and we see periodic trajectories on the graphs). Periodic trajectories indicate that the deadly disease is translated into a chronic one.

© 2018 Istituto Superiore di Sanita. All Rights Reserved. Parkinson disease is one of the common age-related motor neurodegenerative diseases, in which dopamine neurons degeneration is considered to be pathognomic for the development of motor disfunction. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which is considered to be a key regulator of neuronal plasticity. BDNF, being a large molecule, does not pass through the blood-brain barrier (BBB). Synthetic polymer nanoparticles (NP), covered by surfactant, provide the phenomenon of “Trojan hoarse” and enable BDNF to penetrate into the brain tissue. For modelling of parkinsonism we used an intraperitoneal (i.p.) injection of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was injected to the C57BL/6 mice with subsequest treatment with normal saline (group 1), BDNF (group 2), nanoparticulate BDNF (group 3) and surfactant-coated nanoparticulate BDNF (group 4). After 90 min, 24 hours, 72 hours and 7 days manifestations of parkinsonism were evaluated using behavioural tests of open field, rota-rod, assessment of the tremor, length of the body and pace. At the end of experiment the brain was sampled for histological evaluation of changes in the striatum and midbrain and concentration of BDNF in the brain tissues. The results of the experiments demonstrated that nanoparticulate BDNF covered with surfactant significanltly reduced rigidity of the skeletal muscles, oligokinesia and tremor, and also significantly increased BDNF concentration in the brain tissues.