Pharmaceutical Chemistry Journal (v.43, #8)

Individual bioequivalence: concept, research, and variability (a review) by O. V. Reshetko; K. A. Lutsevich (431-435).
Current regulations in all countries do not indicate that one generic drug can be used as a substitute for another, even when the two drugs have been demonstrated to be bioequivalent to the same brand-name drug. The concept of individual bioequivalence, which can provide optimum switching of a patient from one (reference) generic to another without loss of efficacy and safety, is proposed.
Keywords: individual bioequivalence; generic medications; interchangeability of drugs

Sodium 131i-mercaptododecaborate biodistribution in B-16 melanoma in mice by S. N. Koryakin; V. A. Yadrovskaya; A. P. Baranov; E. V. Isaeva; S. E. Ul’yanenko (436-438).
The biodistribution of sodium mercaptododecaborate labeled with radioactive iodine (131I-BSH) in melanoma B-16 and surrounding tissues in mice has been studied for administration by various methods including intraperitoneal, single and double intratumor injection, and introduction under tumor bed. It is shown that a high content of 131I-BSH in the tumor is reached in all cases. The maximum accumulation of the boron compound is observed 1 h after administration. In this case the ratio of radioactivities in melanoma B-16 and surrounding tissues in most animals was greater than 3. A study of 131I-BSH uptake in tumor cells showed that a considerably greater accumulation of the compound is observed 3 and 6 h after intraperitoneal administration in the intercellular space (65.3% and 63.0%, respectively) in comparison to the cellular content (34.7% and 37.0%, respectively). The levels of accumulation become identical in about 12 h after administration. Approximately equal uptake of the boron compound in the intercellular space and tumor cells was observed over the entire period of investigation (0.5–2 h) after a single intratumor administration of 131I-BSH. The results of this study suggest that the intratumor administration of boron compounds is promising for neutron capture therapy, especially in combination with neutron teletherapy.
Keywords: sodium 131I-mercaptododecaborate; murine melanoma B-16; biodistribution

Imidazole derivatives and their antitumor activity (review) by M. A. Iradyan; N. S. Iradyan; F. G. Arsenyan; G. M. Stepanyan (439-443).
Bis(2-chloroethyl)amino derivatives of imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, and imidazolylpeptides are reviewed. Data are presented for active compounds, some of which have passed the preclinical testing stage. Structures under consideration are interesting with respect to both the search for new antitumor drugs and the synthesis of compounds with different biological properties.
Keywords: imidazole; 4(5)-aminoimidazol-5(4)-carboxamide; 4-nitro-5-thioimidazole; benzimidazole; imidazolylpeptides; bis(2-chloroethyl)amino derivatives; antitumor activity

Synthesis and biological activity of substituted 4-aryl-2-methylenehydrazino-4-oxobut-2-enoic acids and their derivatives by N. A. Pulina; V. V. Zalesov; O. A. Bystritskaya; A. E. Rubtsov; N. V. Kutkovaya (444-447).
Aseries of substituted 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids and their anilides and esters were obtained using reactions of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and their amides and esters with benzophenone hydrazone, benzyl monohydrazone, and triphenylphosphazines. The methyl ester of 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-chlorophenyl)-4-oxobut-2-enoic acid was also synthesized by decyclization of 3-(1,2-diphenyl-2-oxoethylidenehydrazino)-5-(4-chlorophenyl)-3H-furan-2-one using methanol. The synthesized compounds exhibit moderate anti-inflammatory, analgesic, and antimicrobial activity.
Keywords: derivatives of 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids; synthesis; biological activity

Synthesis and antimicrobial activity of pyrimidinophanes with two uracil units and bridging nitrogen atoms by V. E. Semenov; A. D. Voloshina; N. V. Kulik; S. Yu. Uraleva; R. Kh. Giniyatullin; A. S. Mikhailov; V. D. Akamsin; Yu. Ya. Efremov; V. S. Reznik (448-453).
A series of pyrimidinophanes containing two uracil units and nitrogen atoms in bridging polymethylene chains –(CH2) n N(Et)(CH2) m – (n, m = 5, 6) have been synthesized. The uracil moieties are represented by 6-methyl-, 5-decyl-6-methyl-, and 5-fluorouracils. Quaternization of the bridging N atom with ethylbromide or n-decylbromide yielded amphiphilic pyrimidinophanes, which were evaluated for their antibacterial and antifungal activity in terms of minimal inhibiting concentration (MIC) against Gram-positive and Gram-negative bacteria and fungi. It has been found that MICs of the amphiphilic pyrimidinophanes decrease with increasing lipophilicity of the alkyl substituents at the bridging N atoms and with increasing polymethylene N(pyr)–N chain length (in some cases MIC against Staphylococcus aureus is below 1 ìg/mL). The MICs increase dramatically upon introduction of lipophilic n-decyl substituents at C(5) atoms of the uracil moiety. The results can be used in the search for new highly effective antimicrobial agents.
Keywords: pyrimidinophanes; uracils; quaternization; antibacterial activity

Influence of the structure of substituted benzodiazepines on their pharmacokinetic properties by A. G. Artemenko; V. E. Kuz’min; E. N. Muratov; P. G. Polishchuk; I. Yu. Borisyuk; N. Ya. Golovenko (454-462).
The influence of the structure of substituted benzodiazepines on their pharmacokinetic properties including the bioavailability, elimination half-life, clearance, and distribution volume in the human organism has been studied. The analysis was performed using the QSAR/QSPR method based on the Simplex representation of molecular structure. Completely adequate models capable of describing quantitatively the structure—pharmacokinetic properties relationship were obtained using the statistical methods of projection onto latent structures and multiple linear regression. Structural factors determining changes in the pharmacokinetic properties of substituted benzodiazepines are established on the basis of the obtained models.
Keywords: benzodiazepines; ADME; bioavailability; pharmacokinetic properties; QSAR/QSPR; Simplex representation

Computer design of trans-stilbene derivatives with pronounced anti-inflammatory activity and low toxicity by V. R. Khairullina; A. D. Mukhametov; A. Ya. Gerchikov; G. G. Garifullina; F. S. Zarudii; L. A. Tyurina (463-467).
Using models developed for predicting the anti-inflammatory activity of nonsteroidal anti-inflammatory drugs (NSAIDs) and their selectivity in inhibiting isomeric forms of cyclooxygenases, the structure of resveratrol has been analyzed for the presence of fragments that influence negatively the anti-inflammatory activity. Based on this analysis, five potential NSAIDs with modified resveratrol structures that possess pronounced anti-inflammatory activity and low toxicity are proposed. These compounds are recommended for synthesis and in vitro and in vivo investigations.
Keywords: SARD-21; resveratrol; cyclooxygenase; inflammation; anti-inflammatory; drugs; trans-stilbenes

Bioavailability of coenzyme Q10 in various pharmaceutical formulations by E. I. Kalenikova; E. A. Gorodetskaya; O. S. Medvedev (468-471).
The bioavailability of coenzyme Q10(CoQ10) in various pharmaceutical formulations (solutions and tablets) containing solubilized CoQ10 in comparison to lipophilic powder of CoQ10 has been studied in rats. It is established that the bioavailability of solubilized CoQ10 in tablets and solution after peroral administration is higher than that of lipophilic CoQ10 powder. The time to reach peak CoQ10 concentrations in plasma was shorter for the solution of the solubilized form. Auxiliary swelling substances in tablets prolong and increase the absorption of CoQ10.
Keywords: coenzyme Q10 ; pharmacokinetics; solubilized substance

Increasing the solubility of an angioprotector by the method of solid dispersions by R. U. Khabriev; V. A. Popkov; V. Yu. Reshetnyak; I. I. Krasnyuk Jr.; O. V. Manakhova (472-476).
The effect of solid dispersions (SDs) on the solubility of parmidin has been studied by comparing the solubility of parmidin, its SDs, and physical mixtures with polyethyleneglycol-1500, polyvinylpyrrolidone-10000, and β-cyclodextrin. It is established that the formulation of SDs increases the solubility and the dissolution rate of parmidin. Data obtained using a complex of physical and chemical methods suggest that improvement of the drug release from SDs is due to the solubilization and the formation of a colloidal-dispersion state of the given substance.
Keywords: solubility; parmidin; solid dispersions; polyethyleneglycol-1500; polyvinylpyrrolidone-10000; β-cyclodextrin

Complex filler based on lactose and microcrystalline cellulose for direct tablet molding by N. N. Zhuikova; O. S. Sablina; E. A. Shtokareva; A. S. Gavrilov (477-479).
The influence of lactose and microcrystalline cellulose on the flowability and moldability of tabletization mixtures and the quality of tablets obtained by direct molding has been studied. The optimum filler composition for direct molding is proposed. The possibility of replacing the wet granulation technology by direct molding is established for five well-known medicinal preparations.
Keywords: lactose; microcrystalline cellulose; direct molding of tablets

GC/MS analysis of aqueous ethanol solutions of drugs. Part 1. Menthol and p-aminobenzoic acid derivatives by A. I. Ermakov; Yu. Yu. Khomyakov; L. P. Soshenko; V. G. Plyushchikov (480-483).
Ajoint GC/MS analysis of aqueous and aqueous-ethanol solutions of some drugs including menthol, validol, benzocaine, novocaine, and menovazin has been performed using a Varian 3900/2100T (USA) instrument equipped with a Varian Factor Four VF-5ms capillary column. The structures of some impurities that were previously based on theoretical considerations are confirmed. Structural-analytical possibilities of the latest modification of the Varian GC/MS system with an ion-trap source are investigated. It is possible to obtain clear mass spectra even for low-intensity and partly overlapping chromatographic peaks using the given device combination. The results can be used for quality control of drugs based on the investigated compounds.
Keywords: drugs; menthol; validol; benzocaine; novocaine; menovazin; GC/MS analysis; impurity chemical structure