Vol 51, No 5 (2017)

Pharmacokinetic studies of the new bone-seeking radiopharmaceutical (RP) ⁶⁸Ga-labeled N,N,N′,N′-ethylenediaminetetrakis(methylenephosphonic acid) (EDTMP) for PET diagnosis of bone metastases showed that ⁶⁸Ga-EDTMP accumulated rapidly in bone 1 h after i.v. injection, e.g., up to 3.55 ± 0.20%/g in femur, 2.24 ± 0.13%/g in vertebrae, 2.00 ± 0.21%/g in rib, and 1.81 ± 0.10%/g in skull, was cleared rapidly from blood, and had minimal uptake in internal organs and tissues. Most of the activity was excreted through the urinary tract. Knee joints also had significant ⁶⁸Ga-EDTMP accumulations. It was found that the bone concentration of ⁶⁸Ga-EDTMP was significantly greater than that of ⁶⁸GaCl₃ (p < 0.001 – 0.05). The ratios of specific activity in bone to those in organs and tissues (differential accumulation factors, DAFs) were greater than unity at all time points. For example, the maximum femur/blood and femur/muscle ratios were 8.00 ± 1.31 and 43.1 ± 7.4. Thus, ⁶⁸Ga-EDTMP could be considered a potential RP for PET imaging of bone damage.

Molecular aspects of the biological mechanism of action of the synthetic peptide HFRWPGP, including an assessment of the stability to membrane proteolytic enzymes and the determination of several intermolecular interaction parameters of the peptide and rat-brain cytoplasmic membranes. It was hypothesized based on the results that the peptide apparently acts as an allosteric activity modulator for several receptor systems and can after the nature of signal transfer to cells. It was established that heptapeptide HFRWPGP in the presence of cerebellum and hippocampus cytoplasmic membranes was degraded in a manner similar to that of Semax proteolysis (used as a reference peptide) under the same incubation conditions.

The hepatoprotective and choleretic activities of three levopimaric acid derivatives were studied experimentally using a CCl₄-induced acute hepatitis model in rats. It was established that all investigated levopimaric acid derivatives tended to increase bile secretion whereas (5R,9R,13S,18S)-20-isopropyl-5,9-dimethyl-17-{[(4-methylphenyl)sulfonyl]imino}-14-oxopentacyclo[10.6.2.0^{1, 10}.0^{4, 9}.0^{13, 18}]eicosa-15,19-diene-5-carboxylic acid (I) and dimethyl (4bS,8R)-2-isopropyl-3^′-4b,8-trimethyl-2^′,4^′-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthrene-11,5^′-[1,3]thiazolidine]-8,12-dicarboxylate (II) reduced transaminase enzyme levels in blood serum.

Deoxyvasicine thione (III) and mackinazoline thione (6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline-11-thione, IV) were synthesized and condensed with aromatic and heterocyclic aldehydes at the α-methylene [CH₂-3 (III) or CH₂-6 (IV)]. Either 3- and 6-arylidene derivatives (V – XIII) or 6-hydroxymethylaryl derivatives (XIV) were formed depending on the reaction conditions. Formylation of IV synthesized the 6-hydroxymethylidene derivative (XV). 6-Chloro-, -hydroseleno-, and -anilinomethylidenemackinazoline thiones (XVI – XIX) were also synthesized. The antimicrobial activity of the synthesized compounds against S. aureus, E. coli, Bacillus cereus, Candida albicans, and Pseudomonas aeruginosa was studied.

Histone deacetylase (HDAC) is a promising target for cancer treatment. HDAC inhibitors consist of three pharmacophoric features: an aromatic cap group, zinc binding group (ZBG), and a linker chain connecting cap group to ZBG. Herein, we report on (i) substituted isatin moiety as the cap group that recognizes the surface of active enzyme pocket and (ii) thiosemicarbazide moiety incorporated as linker group responsible for connecting the cap group to ZBG (hydroxamic acid). The synthesized compounds were evaluated for their antiproliferative activity and HDAC enzyme inhibition. The binding mode analysis of proposed compounds was evaluated by docking studies. Several analogs were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells, with GI₅₀ values in the micromolar range. One compound (Vd) was found to have greater in vitro antiproliferative activity in comparison to other compounds.

Essential oil (EO) from Artemisia sieversiana Willd. growing in Buryatia was characterized by gas chromatography with mass-spectrometric detection (GC-MS). Chamazulene (36%), which possesses anti-inflammatory and antioxidant properties, was the main constituent. EO-based emulsions with rather narrow particle-size distributions and average sizes û nm were prepared by combining mechanical dispersion and high-pressure homogenization procedures.

Science-based selection of the base-carrier for a combined gel dosage form containing phenylacetic-acid derivatives was studied. One-factor dispersion analysis with repeated observations was used. For this, gels with nine bases were prepared and characterized qualitatively. According to the results, one composition was eliminated from further experiments because of thermal instability. The release of active substances (benzketozone and diclofenac sodium) from the proposed gels was determined by Kruvchinsky equilibrium dialysis. The experiments confirmed that the base-carrier type influences significantly the release of active substances from gel compositions. Dispersion analysis results showed that a carrier based on Carbomer 934P gave the optimum release of active substances.

A series of pinane-type sulfides and sulfoxides were synthesized from (1S)-(–)-β-pinene. Their hemocoagulation activity in vitro on human blood plasma was studied. All tested compounds exhibited antiaggregation and anticoagulation activity. The most water-soluble sulfoxide with a mercaptoacetic acid moiety inhibited spontaneous platelet aggregation and that induced by collagen and arachidonic acid and also reduced the coagulation activity of human blood plasma. The hemocoagulation activity was due to selective inhibition of platelet receptors, decreased yield of thrombocytic microvesicles, and suppression of their activity.

Dry extract of Gentiana algida Pall. displayed immunomodulating activity in experiments on mouse line F1 (CBA × C57B1/6) with experimental azathioprine-induced immunosuppression of the cellular, humoral, and macrophage components of the immune response. It was found that the plant extract reduced the suppressive effect of the cytostatic azathioprine on the antibody response, cell-mediated immune reaction, and macrophage phagocytosis. This resulted in increases as compared with the suppressed levels of the absolute and relative amounts of antibody-forming cells, index of delayed-type hypersensitivity, phagocytic index, and phagocyte number. Dry extract of G. algida was characterized chemically by high contents of iridoids (82.07 mg/g), flavonoids (86.91 mg/g), and triterpenes (23.98 mg/g), which caused the observed immunomodulating activity.

Rational drug use considers the medical, biological, and pharmaceutical factors that ensure high bioavailability and efficacy. On the other hand, the interaction of a drug with in vivo systems is of interest to take into account chronopharmacology, which studies drug action as a function of human biorhythms. According to chronopathology, various pathological processes and disorders, in particular diabetes mellitus (DM), are related to biorhythm disruption. The pathogenesis of DM involves desynchronosis related to not only the disruption of endogenous insulin secretion but also the artificially induced rhythm of conventional insulin therapy. Available data on the influence of carbohydrate metabolism biorhythms on the efficacy of hypoglycemic treatment were summarized. The expediency of studying and developing schedules for administered hypoglycemic drugs was discussed.

Results of experiments on prolonged release of paracetamol from polymer matrix tablets with cross-linked poly(acrylic acid) Carbopol^® Ultrez 21 as the prolonging polymer were reported. The effects of factors such as tableting technology, type of alkaline agent, and ratio of Carbopol^® to alkaline agent on paracetamol release kinetics were studied. It was established that matrices prepared by wet granulation had the best potential for prolonging the release. The ratio of Carbopol^® to alkaline agent and their relative amounts also enabled the drug release rate to be prolonged.

Forced degradation studies of candesartan cilexetil (CCX) and hydrochlorothiazide (HCTZ) were performed by using stressed drugs under acid, alkaline, and neutral hydrolysis; oxidation; photolysis; and thermal degradation conditions. A simple and specific method of high-performance liquid chromatography with UV detection was developed for simultaneous determination of CCX, HCTZ, and their degradation products. Optimum conditions were achieved with a running buffer mixture of acetonitrile and 10 mM phosphate buffer (pH 7.0; 32 : 68, v/v) at a flow rate of 1.0 mL/min using a Zorbax stable-bond cyano (SB CN) column (4.6 × 150 mm, 5 μm), 25°C column temperature, and 254 nm UV detection wavelength. This method was validated for linearity, range, accuracy, precision, and specificity according to International Conference on Harmonization (ICH) guidelines. All figures of merit for method validation are acceptable. The method proved to be stability-indicating because it also analyzed drugs in the presence of their degradation products with a resolution of the critical peak pair at least 1.5 and peak purity values greater than 990. CCX was stable under neutral hydrolysis, photolysis, and thermal degradation conditions but degraded under acid and alkaline hydrolysis and oxidation conditions. HCTZ was stable under oxidation, photolysis, and thermal degradation conditions but degraded under neutral, acid, and alkaline hydrolysis conditions.