Vol 51, No 8 (2017)

7,10-Dimethyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexane]-4(6H)-one was synthesized from ethyl 4′-amino-5′,8′-dimethyl-1′H-spiro[cyclohexane-1,2′-naphthalene]-3′-carboxylate and reacted with various alkyl(benzyl)halides to afford a new series of benzo[h]quinazolines containing methyl substituents on the benzene ring. The anti-monoamine-oxidase and anticonvulsant activities of the benzo[h]quinazolines were studied.

Acylation of ortho-toluidine hydrochloride by chloroacetylchloride followed by amination by morpholine in the presence of an excess of Et₃N produced morpholinoacetic acid ortho-toluidide and its salicylate salt. The acute toxicity and anti-arrhythmic and antifibrillatory activities of these compounds were studied. The biological activities indicated that these compounds were promising for further studies and evaluation of their potential for implementation into medical practice.

Tetrahydropyrido[2,1-b ][1,3,5]thiadiazine derivatives were investigated for anti-inflammatory activity as compared with that of diclofenac sodium using the formalin-induced paw edema model in albino rats. Compounds with anti-inflammatory activity 1.5 – 3.5 times more potent than that of diclofenac sodium were discovered.

2-(Aryl(thiophen-2-yl)methyl)succinic acids (4a – 4d), 3-(aryl(thiophen-2-yl)methyl)dihydrofuran-2,5-diones (5a – 5d), 7-aryl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acids (6a – 6d), and ethyl 7-aryl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylates (7a – 7d) were synthesized via Stobbe condensation of aryl(thiophen-2-yl)methanones and diethyl succinate. The newly synthesized compounds (5a – 5d, 6a – 6d, and 7a - 7d) were screened in vitro for their antimicrobial and antioxidant properties. Compounds 5b, 6d, and 7d exhibited promising antifungal and antibacterial activity against various microorganisms tested. Compounds 7d and 7b showed remarkable DPPH radical scavenging abilities.

Spinasterol (1) and spinasteryl acetate (2) from the leaves of Ardisia pyramidalis (Cav.) Pers. (Myrsinaceae) were tested on duck chorioallantoic membrane (CAM) vascularity assay. The petechial to severe hemorrhaging, hyperemia, and the formation of ghost vessels were observed in CAMs treated with compounds 1 and 2. Both sterols have effectively suppressed blood vessel branching and inter-capillary elongation. High degree of vonWillebrand factor expression was observed in these CAMs treated with 1 and 2. This is further confirmed by the absence of the epithelial membrane antigen in all samples tested, suggesting that the main mechanism of angio-suppression is related to the action of von Willebrand factor which modulates other angiogenic factors. Spinasterol was found to be most effective in reducing the branch point formation and inter capillary distance with very minimal incidence of mortality, thus suggesting its potential as a source of phytopharmaceuticals.

A method for obtaining trypsin-based biocatalysts immobilized on VION KN-1 and VION AN-1 ion-exchange fiber matrices was developed. The physical, chemical, and kinetic properties of the obtained heterogeneous materials were investigated. The materials with immobilized trypsin that were proposed by us functioned better in the most alkaline region than already existing materials (literature data), allowing expansion of their sphere of use in medicine and cosmetics.

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.

Issues related to regulation of the quality of compounded medicinal preparations by the State Pharmacopoeia of the Russian Federation are considered. Topical questions of the development and implementation of both general clauses and particular monographs related to compounded pharmaceuticals in national pharmacopoeial science and practice are discussed.

Decoctions of herbal mixtures I (including 30% Filipendula ulmaria meadowsweet grass, 10% bilberry shoots, and 60% Bergenia crassifolia green leaves) and II (60% meadowsweet grass, 10% bilberry shoots, and 30% bergenia green leaves) exhibited antioxidant activity. Biologically active substances of herbal mixture I exhibited predominantly catalytic decomposition of hydrogen peroxide formed during electroreduction of oxygen. Active substances of herbal mixture II interacted with oxygen radicals generated as a result of oxygen electroreduction on the electrode surface (EC mechanism) and were more effective than both dihydroquercetin and ascorbic acid. Herbal mixtures I and II normalized the content of thiobarbiturate-reactive products in brain homogenates under conditions of hypoxia-activated lipid peroxidation. In addition, herbal mixture II reduced the concentration of antiradical antioxidants in the lipid extracts. The antioxidant properties were inherent to a greater extent in mixture II dominated by meadowsweet grass, which contained the most complete sum of biologically active phenolic substances (simple phenols, flavonoids, hydroxycoumarins, phenolcarboxylic acids, mainly hydrolyzable tannins), amino acids, and macro- and microelements.

The bioavailability and pharmacokinetic parameters of film-coated Teraligen Retard (TR 20, 40, and 60 mg at doses of 20, 40, and 60 mg, respectively) and immediate-release film-coated Teraligen Valenta tablets (TV 5 mg at a dose of 20 mg) were compared using double blind randomized placebo-controlled investigations involving a single administration to healthy volunteers. The relative bioavailability (ratio of geometric mean 90% CI values) of TR 20, 40, and 60 mg tablets amounted to 80.95% (62.65 – 104.74%), 214.33% (165.64 – 277.34%), and 394.77% (305.08 – 510.83%) for 20, 40, and 60 mg tablets, respectively. An analysis of the dose–concentration relationship gave a linearity coefficient of 0.1902 ng/(mL·mg) for C_max index and 4.6087 (h·ng)/(mL·mg) for AUC_0-t. The results showed that the pharmacokinetic parameters could be considered linearly dose-dependent in the studied range (20 – 60 mg). The delay of drug release from film-coated TR 20, 40 and 60 mg tablets was evaluated by comparing the mean retention time (MRT) of the drug in vivo. The MRT values of TR 20, 40, and 60 mg tablets were 144.18, 157.40, and 156.30%, respectively, and exceeded the MRT of the drug from immediate-release TV tablets. The results led to the conclusion that TR 20, 40, and 60 mg tablets exhibited a prolonged drug-release profile (as compared to that of TV 5 mg tablets) and were characterized by predictable dose-dependent bioavailability.

It was found that oligo(hexamethylene guanidine) (OHMG) reacted very slowly with unactivated high-molecular-mass alkyl halides (dodecyl chloride), possibly due to steric hindrance and the low nucleophilicity of the guanidine moiety. Therefore, this alkyl halide could not be used to modify OHMG under conventional conditions. Ethylation of OHMG was much more facile. However, the substitution in the derivatives was broadly scattered (under ordinary conditions and reagent ratios). It was shown simultaneously that the antibacterial activity of the alkylated derivatives was less than that of the starting OHMG hydrochloride. Benzyl chloride reacted readily with OHMG to produce derivatives with the desired degree of substitution. It was found that benzyl derivatives with 0.2 degree of substitution were more active against mycobacteria than the starting hydrochloride with the activity gradually diminishing if the degree of substitution was increased further. The increased activity may have been related to the optimum increase of OHMG hydrophobicity and/or steric structure. The rather high antibacterial activities of the benzyl derivatives against Mycobacterium smegmatis strain ATCC 607 made them promising for further development and studies of the properties of alkylated OHMG derivatives to discover more active derivatives, including against M. smegmatis. The most obvious candidates could become the methylcarboxy-substituted OHMG derivatives.

Reference standards (RSs) are necessary to standardize medicinal products, including biological drugs, and are key factors of their efficacy and safety. Experience in certification of biological RSs and an analysis of foreign and national guidelines concerning the certification procedure for biological RSs were used as a basis to propose an improved order of attestation for RSs used for quality control of biological drugs. The general statistical approaches for assessing the test results obtained during the determination of the certified characteristics of the biological RSs and their uncertainties are described.