Low-molecular-weight heparin was synthesized by depolymerization of high-molecular-weight heparin with nitrous acid. Preparative chromatography was used to isolate low-molecular-weight heparins with narrow molecular-weight distributions, as confirmed by size-exclusion HPLC. The average molecular weight of the products according to capillary viscometry decreased with synthesis time (4 h) from 14.0 to 3.4 kDa. Fractions with molecular-weight characteristics, ratios of sulfo- to carboxyl groups, and specific activities corresponding to those of low-molecular-weight heparin isolated from commercially available Fragmin ® were isolated among the products. Low-molecular-weight heparins with characteristics analogous to those of Dalteparin and Nadroparin substances could be obtained depending on the treatment time of high-molecular- weight heparin with nitrous acid in acidic medium.

The inclusion complex of the antiepileptic drug carbamazepine with hydroxypropyl-β-cyclodextrin was prepared by co-dissolution in practically quantitative yield with losses <1% to increase its solubility and bioavailability. The complex was studied by PMR spectroscopy and differential scanning calorimetry. Acomparison with initial carbamazepine and hydroxypropyl-β-cyclodextrin confirmed that the inclusion complex formed without covalent chemical bonds. The physicochemical properties of the inclusion complex were studied. Its solubility in water was determined as 5・105 mg/L (at 25°C). The anticonvulsant activity of the resulting drug form was assessed after intraperitoneal and intranasal administration to mice. The results indicated that the complex could be used effectively as an anticonvulsant agent at a dose of 20 mg/kg.

Деполимеризацией высокомолекулярного гепарина азотистой кислотой получен низкомолекулярный гепарин. Методом препаративной хроматографии из него выделены узкие по молекулярной массе фракции низкомолекулярных гепаринов, что подтверждено методом эксклюзионной ВЭЖХ. Средняя молекулярная масса продуктов, по данным капиллярной вискозиметрии, уменьшается за время синтеза (4 ч) с 14,0 до 3,4 кДа. Среди полученных продуктов выделены фракции, молекулярно-массовые характеристики, соотношение сульфо- и карбоксильных групп, а также специфическая активность которых соответствует показателям для низкомолекулярного гепарина, выделенного из промышленно выпускаемого препарата Фрагмин®. Показано, что в зависимости от продолжительности обработки высокомолекулярного гепарина азотистой кислотой в кислой среде возможно получение низкомолекулярных гепаринов, аналогичных по своим характеристикам субстанциям Дальтепарин и Надропарин.

The esterification stage of low-molecular-mass heparin (enoxaparin) production by hydrolytic depolymerization of unfractionated heparin was studied and consisted of treating previously synthesized benzethonium heparinate with benzyl chloride. The content of benzyl moieties in the synthesized heparin benzylates and their degree of benzylation were determined using HPLC, PMR, and 13C NMR methods. A carboxylic-acid content of 0.13 ± 0.01 mol/g in the starting heparin was calculated from these results. A new method for estimating the degree of heparin benzylation from PMR and HPLC data was proposed. The benzyl content in the heparin benzylates increased with increasing molar excess of benzyl chloride.

The first step of low-molecular-mass heparin (enoxaparin) preparation by hydrolytic depolymerization of unfractionated heparin was investigated. The step involved chemical reaction of starting heparin and benzethonium chloride in aqueous saline solutions. The number of acid equivalents in unfractionated heparin was shown to increase as the NaCl concentration increased. This was probably related to effects of the solution ionic strength on the heparin macromolecular conformation, which was confirmed using dynamic light scattering. The average size of the observed light-scattering centers in aqueous heparin solutions decreased with increasing NaCl concentration. Rinsing with H2O and not NaCl solutions and application of ultrasonication were recommended to accelerate purification of benzethonium heparinate from starting materials and to reduce the amount of rinse water. The compositions of the produced and purified benzethonium heparinate samples were confirmed using PMR spectroscopy.

Based on main principles of porous silicon (por-Si) formation the research of producing containers for drug delivery systems was launched. Nanoparticles for loading medicine were obtained.

It is established that the crystallographic orientation of a single-crystal silicon substrate affects the nucleation, shape, and evolution of silicon pores during its electrochemical etching. The shape, spatial orientation, and initiation of silicon pores is demonstrated to depend on both the etchant-solution properties caused by an etching-ion structure and the Si lattice symmetry.

The article deals with main principles of the formation of porous silicon (por-Si) to produce containers for drug delivery systems. Most important por-Si characteristics to produce nanocontainers with required parameters are determined.

Обзор посвящен актуальной проблеме получения низкомолекулярных гепаринов, известных в качестве антикоагулянтов, а также проявляющих широкое политерапевтическое действие. Охарактеризованы молекулярная структура и свойства эндогенного нефракционированного гепарина, а также низкомолекулярных гепаринов на его основе и их заменителей. Обсуждены основные методы синтеза низкомолекулярных гепаринов, сводящиеся к процессам окислительной, гидролитической, радикальной и ферментативной деполимеризации под действием неорганических или органических реагентов и катализаторов, ферментов или радиационного излучения. Представленные сведения могут служить основой для направленного выбора и усовершенствования методов синтеза низкомолекулярного гепарина целевого назначения.

A mechanism is suggested for pore formation in n-type Si through the stage of nucleation in the most probable places.

The results of many years of scientific research in the field of physico-chemical biology and its most important direction - lipidology, conducted by the leading scientific school under the leadership of Academician RAS Vitaly I. Shvets, are reported. On the creation of synthetic, biotechnological methods for obtaining lipids, with the possibility of their practical use by designing on this basis effective diagnostic and medicinal products and application in practical medicine. The further development and use of methods of bionanotechnology for the development of modern medicines for directed action on the basis of increasing the effectiveness of classical drugs by their incorporation into nanocontainers is described. It is reported on the development of technologies for obtaining nanoscale forms of drugs, the study of their pharmacological properties and use in medical practice. Information is provided on the preparation of liposomal antitumor, hepatoprotective, anti-tuberculosis, cardiac preparations based on the proposed echnologies, the study of properties and the use for therapeutic purposes. The technologies for obtaining and conducting biological studies of nanoforms based on copolymers of lactic and glycolic acids of antineoplastic, anti-inflammatory, antibacterial and a number of other drugs have been developed: It has been shown that the use of nanosized drugs can lead to a significant increase in the pharmacological effect due to various factors. It was noted that during the construction of the drug for the treatment of Parkinson's disease, the contents of liposomes loaded with dopamine pass through the blood-brain barrier almost 100 times better than individual dopamine molecules. Finding a substance in nanoparticles reduces its toxicity primarily due to the effect of "passive targeting". The prolonged action of medicinal substances enclosed in nanoparticles is discussed, due to their gradual release. It is noted that the targeted delivery of nanoparticles makes it possible to increase the effectiveness of the drugs by an order of magnitude. It is reported on the drug-delivery technology in the field of oncology and the use of the method of selective delivery of cytostatics to tumor tissues using the receptor-mediated endocytosis. Biological and pharmacological studies based on nanopoporous silicon on the creation of liposomal drugs for the treatment of cancer, cardiological pathologies, tuberculosis are carried out. Data on the work of the scientific and educational center for training specialists in the field of biotechnology and pharmacy are given.

The results of many years of scientific research in the field of physico-chemical biology and its most important direction - lipidology, conducted by the leading scientific school under the leadership of Academician RAS Vitaly I. Shvets, are reported. On the creation of synthetic, biotechnological methods for obtaining lipids, with the possibility of their practical use by designing on this basis effective diagnostic and medicinal products and application in practical medicine. The further development and use of methods of bionanotechnology for the development of modern medicines for directed action on the basis of increasing the effectiveness of classical drugs by their incorporation into nanocontainers is described. It is reported on the development of technologies for obtaining nanoscale forms of drugs, the study of their pharmacological properties and use in medical practice. Information is provided on the preparation of liposomal antitumor, hepatoprotective, anti-tuberculosis, cardiac preparations based on the proposed echnologies, the study of properties and the use for therapeutic purposes. The technologies for obtaining and conducting biological studies of nanoforms based on copolymers of lactic and glycolic acids of antineoplastic, anti-inflammatory, antibacterial and a number of other drugs have been developed: It has been shown that the use of nanosized drugs can lead to a significant increase in the pharmacological effect due to various factors. It was noted that during the construction of the drug for the treatment of Parkinson's disease, the contents of liposomes loaded with dopamine pass through the blood-brain barrier almost 100 times better than individual dopamine molecules. Finding a substance in nanoparticles reduces its toxicity primarily due to the effect of "passive targeting". The prolonged action of medicinal substances enclosed in nanoparticles is discussed, due to their gradual release. It is noted that the targeted delivery of nanoparticles makes it possible to increase the effectiveness of the drugs by an order of magnitude. It is reported on the drug-delivery technology in the field of oncology and the use of the method of selective delivery of cytostatics to tumor tissues using the receptor-mediated endocytosis. Biological and pharmacological studies based on nanopoporous silicon on the creation of liposomal drugs for the treatment of cancer, cardiological pathologies, tuberculosis are carried out. Data on the work of the scientific and educational center for training specialists in the field of biotechnology and pharmacy are given.

There was carried out the therapeutic drug monitoring of antiepileptic drug carbamazepine by use of a bayesian mathematical modeling method in 47 patients with a focal epilepsy. The database of patients pharmacokinetic characteristics concerning carbamazepine was created. According the results of carbamazepine monitoring anticonvulsant dosage regimen was corrected

Abstract: due to the emergence of new technologies in a pharmakokinetics, a pharmacogenetics and analytical chemistry, the medicine comes to qualitatively new stage of development. Therapeutic drug monitoring as the mean of the real time pharmacotherapy efficiency control becomes the basis of rational therapy in modern medicine. In the article various aspects of the therapeutic drug monitoring (TDM) as subsection of clinical pharmacology are discussed. The main indications to carrying out TDM and the main TDM procedures are submitted. Value of TDM for an epileptology is discussed. The special attention is paid to the bioanalytical methods and new methodical approaches (such as non-invasive drug monitoring and equilibrium dialysis) applied in TDM. TDM role as an independent discipline of a medical sciences, with concentration on modern pharmacokinetics computer programs is separately analyzed.

Используя комбинированный метод эмульгирования, получена наноэмульсионная форма антиконвульсанта карбамазепина. Изучена морфология частиц с помощью просвечивающей электронной микроскопии. Установлено, что средний размер частиц составил 96 нм. С помощью ВЭЖХ определена концентрация карбамазепина в полученных образцах, значение которой составило 0.51 мг/мл. В эксперименте на лабораторных животных получены предварительные данные по специфической активности полученной наноэмульсии.

We have used an original chromatography/mass spectrometry technique to study the pharmacokinetics of dipeptide carnosine in C57 Black/6 mice after intraperitoneal administration of the drug at a dose of 1 g/kg. The basic pharmacokinetic characteristics of carnosine were measured the in the blood and brain. The obtained concentration – time curve has a biexponential character. It is shown that the maximum concentration of carnosine in the blood plasma is C max = 1081.75 ± 124.24 μg/mL and it is achieved in a time interval of T max = 0.25 h. We showed that i.p. administration of exogenous carnosine could significantly increase the concentration of that substance in the brain. Tissue availability of dipeptide carnosine for brain tissue is relatively good and constitutes 59% from the total amount of blood carnosine. It was found that the maximum concentration of carnosine in the brain occurs at the sixth hour after i.p. administration when the concentration of drug in the blood is minimal.

We have used an original chromatography/mass spectrometry technique to study the pharmacokinetics of dipeptide carnosine in C57 Black/6 mice after intra-peritoneal administration of the drug at a dose of 1 g/kg. The basic pharmacokinetic characteristics of carnosine were measured the in the blood and brain. The obtained concentration-time curve has a biexponential character. It is shown that the maximum concentration of carnosine in the blood plasma is Cmax = 1081.75 ± 124.24 μg/mL and it is achieved in a time interval of Tmax = 0.25 h. We showed that i.p. administration of exogenous carnosine could significantly increase the concentration of that substance in the brain. Tissue availability of dipeptide carnosine for brain tissue is relatively good and constitutes 59% from the total amount of blood carnosine. It was found that the maximum concentration of carnosine in the brain occurs at the sixth hour after i.p. administration when the concentration of drug in the blood is minimal.