Pharmaceutical Chemistry Journal (v.43, #11)

Molecular-biological problems of drug design and mechanism of drug action by V. V. Lebedev; S. A. Novikov; E. Yu. Rybalkina; T. N. Zabotina (593-596).
Multiple drug resistance (MDR) appears as a result of sharply increased elimination of drugs from a cell into the extracellular space by ATP-dependent transport proteins. At present, no effective inhibitor of transport proteins is available that could be used to overcome MDR. The influence of two hydrophilic hexapeptides, imunofan and biopoetin, on the activity and amount of transport proteins responsible for MDR formation has been investigated using cell lines of human throat cancer (Hep-2), human oral cavity carcinoma (KB8-5), and human prostate cancer (PC-3). The effect of the hexapeptides was evaluated by comparing the Rh 123 expulsion rate and the expression of transport proteins and their genes. It is established that the indicated hydrophilic hexapeptides in very low concentrations (of the order of 10 – 10 M) inhibit the substrate expulsion from a cell into the extracellular space. However, the two hydrophilic hexapeptides modulate MDR by different mechanisms. Imunofan and biopoetin are the first tumor MDR inhibitors showing activity at such low concentrations.
Keywords: multiple drug resistance; hydrophilic hexapeptides; ATP-dependent transport proteins

Butoconazole nitrate pharmacokinetics studied by capillary electrophoresis by S. P. Senchenko; K. S. Checheneva; M. V. Gavrilin; L. S. Ushakova (597-600).
In view of the wide use of butoconazole nitrate in practical gynecology, a method for determining this drug in the blood of experimental animals has been developed based on capillary electrophoresis. Samples were prepared using sedimentation of plasma proteins by acetonitrile. The separation was carried out at 27°C in a quartz capillary (75 μm diameter, 65 cm working length) at 20 kV. The leading electrolyte was a phosphate buffer solution at pH 3.6. Detection was performed by spectrophotometry at 210 nm. The proposed technique was used to study the pharmacokinetics of butoconazole nitrate in rats upon a single intraperitoneal injection at a dose of 80 mg/kg. The kinetic curves of butoconazole nitrate concentration in the blood were constructed and were typical of drug removal with bile.
Keywords: capillary electrophoresis; butoconazole nitrate; pharmacokinetics

Search for new drugs by V. M. Rzheznikov; L. E. Golubovskaya; B. I. Keda; L. P. Sushinina; T. A. Titova; V. N. Tolkachev; Z. S. Smirnova (601-605).
Analogs of 11β-hydroxyestrone and 17α-ethynylestradiol with a cytotoxic bis-(2-chloroethyl)amino-containing substituent were synthesized in two principal steps from the corresponding 11-hydroxysteroids. Introduction of this bulky fragment influences negatively the estrogenic and antitumor activities of the synthesized compounds.
Keywords: chemical synthesis; cytotoxic steroids; antitumor and estrogenic activities; stereochemistry of 11-C-substituents

Synthesis and neurotropic activity of substituted 5-dialkylaminoacetyl-3a,4,5,9b-tetraydro-3H-cyclopenta[c]quinolines by G. F. Krainova; Yu. B. Vikharev; L. V. Anikina; E. V. Sivtseva; V. A. Glushkov (606-609).
A series of substituted 5-dialkylaminoacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines were synthesized by amination of the corresponding 5-chloroacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines. The acute toxicity, analgesic activity, and influence of the obtained compounds on the locomotor and exploratory activity in the open-field test were studied.
Keywords: quinolines; amides; Povarov reaction; analgesic activity; open-field test

Synthesis and antibacterial and antifungal properties of some phosphorus-containing 1,2-dihydroxynaphthalenes by N. R. Khasiyatullina; V. F. Mironov; A. V. Bogdanov; V. V. Zobov; A. D. Voloshina; N. V. Kulik; A. I. Konovalov (610-612).
A series of phosphorus-containing 1,2-dihydroxynaphthalenes have been obtained via the reaction of 1,2-naphthoquinone derivatives with tri(n-butyl)- or triphenylphosphine followed by treatment of the intermediate phosphobetaines with various acids. The antimicrobial activity of the synthesized compounds has been studied and the structure—activity relationship established, which gives grounds for the search for new biologically active compounds in this direction.
Keywords: ortho-quinones; tertiary phosphines; phosphonium salts; antibacterial activity; antifungal activity

Medicinal plants by E. A. Krasnov; V. A. Raldugin; E. Yu. Avdeeva (613-614).
A new quercetin glycoside named filimarin was isolated from honeysweet (Filipendula ulmaria L. Maxim.) by colun chromatography over polyamide and silica gel. Based on chemical and spectral data, the structure of filimarin is identified as quercetin-4′-O-β-D-galactopyranoside. Results of voltammetric measurements showed that filimarin possesses pronounced antioxidant activity that is comparable with that of dihydroquercetin and ascorbic acid.
Keywords: Filipendula ulmaria ; flavonoids; filimarin; antioxidant activity

Drug synthesis methods and manufacturing technology by I. I. Romanovskaya; S. S. Dekina; I. I. Pashkin (615-618).
Alkaline protease from Bacillus subtilis and lysozyme from chicken egg white have been immobilized for the first time in poly(N-vinylpyrrolidone) modified by polysilicic acid sol. Elastic polymeric hydrogels that are insoluble under physiological conditions are obtained and provide potential wound-healing coatings with high retention of lytic and proteolytic activities (80 – 100%) and prolonged action (24 h) and complex preparations with proteolytic and 1.7-fold increased lytic activity. It is established that immobilized alkaline protease and lysozyme are stable under conditions modeling the wound pH level during storage for one year and upon sterilization by γ-irradiation.
Keywords: alkaline protease; lysozyme; immobilization; poly(N-vinylpyrrolidone)

The influence of biologically active indolalkylamines (serotonin and tryptamine), amino acids (tryptophan), and catecholamines (epinephrine and norepinephrine) on the activity of pancreatic lipase has been studied. It is established that the biologically active monoamines inhibit lipid peroxidation and potentiate the lipase activity. Ascheme of relationships between the enzymatic and chemical conversion pathways of natural lipids is presented. The influence of biologically active monoamines on these processes is considered. It is shown that heavy-metal ions contaminating water produce a significant effect on the lipase activity. The proposed method of determination of the lipase activity can be considered as a promising biotest in ecological investigations.
Keywords: pancreatic lipase; monoamines; antioxidants; heavy metals

Solubility of erythromycin from solid dispersions by R. U. Khabriev; V. A. Popkov; V. Yu. Reshetnyak; I. I. Krasnyuk Jr; A. S. Lapshova (625-631).
The effect of solid dispersion (SD) formation on the solubility of the antibiotic erythromycin has been studied using the parent substance of erythromycin and its SDs with polyethyleneglycol (PEG-1500), polyvinylpyrrolidone (PVP-10000), and β-cyclodextrin. It is established that SD formation increases the solubility of the antibiotic by a factor of 1.3 – 1.8; the dissolution rate, 1.5 – 2.0. Results using a complex of physical and chemical methods suggest that the increase in erythromycin release from SDs takes place due to a decrease in the degree of crystallinity and the formation of intermolecular complexes.
Keywords: erythromycin; solid dispersions; effect on solubility

Equivalence of ranitidine generic tablets studied using the in vitro dissolution test by I. E. Smekhova; B. L. Moldaver; Yu. M. Perova (632-636).
The pharmaceutical equivalence of Zantac (reference drug) and 10 domestic and foreign generics of ranitidine hydrochloride as 150-mg coated tablets has been studied using the pharmacopoeic (USP 29) dissolution test. Analyses showed insignificant differences in the excipients entering into the compositions of ranitidine generic tablets registered in Russia. It is established that Zantac and generics of two manufacturers are rapidly soluble (according to the WHO classification). Analysis of the similarity coefficients determined for the dissolution profiles measured in media with different pH values showed the biological nonequivalence of some generics and the reference drug. It is demonstrated that the in vitro dissolution test recommended by WHO can be used for determining the bioequivalence of ranitidine generics.
Keywords: generic drugs; dissolution test; equivalence; tablets; ranitidine hydrochloride

Quantitative hplc determination of antigrippin drug components by S. Yu. Garmonov; I. A. Salakhov (637-640).
An HPLC technique for simultaneous quantitative determination of antigrippin components ascorbic acid, paracetamol, and chlorpheniramine maleate has been developed. Optimum conditions are determined for chromatographic separation on a Symmetry C18 column of the poorly retained impurity 4-aminophenol and ascorbic acid. The proposed method provides high sensitivity and rapid analysis and ensures accurate and reproducible results in the quantitative determination of active components (ascorbic acid, paracetamol, and chlorpheniramine maleate), a controlled toxic impurity (4-aminophenol), and an excipient (sodium saccharinate) in antigrippin effervescent tablets for children and adults.
Keywords: antigrippin; drug components; ascorbic acid; chlorpheniramine maleate; paracetamol

HPLC determination and pharmacokinetics of the new original domestic drug dibufelon® by S. N. Kondratenko; A. K. Starodubtsev; G. A. Belyakova (641-643).
A simple, specific, sensitive, and precise high-performance liquid chromatography (HPLC) assay with UV detection has been developed for quantitative determination of fenozan acid in human blood plasma. Using this method, the pharmacokinetics of the new domestic preparation dibufelon (OOO Consortium-PIK, Russia) were investigated after a single peroral administration of an 800-mg dose in 12 healthy volunteers. It is established that the drug is rapidly absorbed from the GI tract into the systemic blood flow [C max ,178 ± 29 ng/mL; T max, 3.9 ± 0.5 h; AUC 0–∞, 1434 ± 269 (ng ∙ h)/mL; C max/AUC 0–∞, 0.135 ± 0.011 L/h], rather well retained in humans (MRT, 8.6 ± 0.8 h; T 1/2, 5.3 ± 0.8 h), and, despite a rapid total clearance (Cl t ,824 ± 167 L/h), penetrates well into organs and tissues (V Z , 5590 ± 1204 L).
Keywords: fenozan acid; HPLC; plasma; pharmacokinetics