Vol 53, No 7 (2019)

We present here results of studies of the antidiabetic activity of compound GK-2 (bis-(N-monosuccinyl-glutamyl-L-lysine) hexamethylenediamide), an NGF mimetic, in a model of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Two-week prophylactic courses of oral GK-2 did not decrease blood glucose levels in healthy animals but reduces the severity of hyperglycemia and eliminated the insulin resistance effect induced by streptozotocin. Morphological analysis of the pancreas of the animals using monoclonal antibodies to insulin showed that while streptozotocin decreased the number of insulin-producing cells in the pancreas, GK-2 produced a statistically significant reduction in this harmful effect and promoted recovery of pancreatic islet size. A strong correlation was found between the extent of the cytoprotective action as indicated by morphometric measures and the strength of the hypoglycemic effect.

Medicines with the F₃C-O group can increase the lipophilicity of an aromatic ring system and protect it from oxidative attacks. We have synthesized 3,5-bis(2-trifluomethoxybenzylidene)-4-piperidone (4a), an EF24 analog with ortho trifluoromethoxy group, via aldol condensation reaction and evaluated its cytotoxicity by MTT assay. Owning to the ortho-trifluoromethoxy group, compound 4a exhibited excellent cytotoxicity against A549 cells. Mechanistic investigation indicated that 4a could induce oxidative stress, including the generation of reactive oxygen species (ROS), imbalance of redox buffering system, lipid peroxidation, and collapse of mitochondrial membrane potential, and finally leading to cell apoptosis. These data indicated that the introduction of the ortho-trifluoromethoxy group into curcumin analogs may be an effective strategy to enhance the anti-cancer ROS based activity.

S-carboxyalkyl derivatives of 2-thiouracil were synthesized and their pharmacological activity was studied. Several of the compounds were characterized by antiglycation activity. These compounds had no effect on PPAR or glucokinase activity and had weak activity in cleaving protein crosslinks.

Taking into account the high efficacy of 2-arylpropionic acid derivatives among NSAIDs and based on their SARs, we have evaluated the anti-inflammatory, antinociceptive, and antiaggregant activity and ulcerogenic properties of a new synthesized non-protein amino acid (NPAA) derivative S(-)-2-amino-2-methyl-3-phenylpropanoic acid (NPAA-36). A new method of NPAA-36 synthesis was developed and experiments were carried out, which showed that this compound injected in a dose of 10 mg/kg (i.p.) inhibited xylene-induced ear oedema by about 31.1%, which proved its anti-inflammatory properties. The antinociceptive activity of NPAA-36 was assessed in tail-flick test by the ability to increase the tail cut-off latency by 36.78% within 60 min after injection at the same dose. Investigation of the ulcerogenic properties of NPAA-36 demonstrated that it exhibited lower gastrointestinal toxicity than a well-known arylpropionic acid derivative NSAID. Results of in vitro experiments showed the antiplatelet activity registered not in all (only in 41.2%) cases, which might imply lower bleeding. The obtained data indicate that the new NPAAderivative can be a potential basis for the development of new anti-inflammatory drugs with weak side effects.

Arelevant task in the technology of cosmetic and pharmaceutical substances is that of protecting the skin from the harmful influences of ultraviolet light - sunburn, photodermatoses, skin cancerogenesis, and light-induced aging. Gels containing N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 (xymedone) and amphiphilic components, i.e., nonionic surface-active substances (surfactants), were developed and studied. Aspectrophotometric method was used to study the selective absorption of xymedone in the UV range. Overall, the structural- mechanical characteristics of gels and assessment of the effects of surfactant on xymedone release processes were used to select the optimum composition for effective protection against light by gels. Studies in models of ultraviolet erythema in albino guinea pigs and volunteers receiving prophylactic applications showed that xymedone-containing gel had photoprotective effects. The presence of a hydroxyethylated higher fatty alcohol in the gel composition with xymedone increased its photoprotective activity.

Experiments on cell cultures addressed the antiviral properties of 2-anilino-4,6-di-tert-butylphenol and N-(3,5-di-tert-2-hydroxyphenyl)acetamide, both of which are o-aminophenol derivatives, and 3,4-dihydroxy-benzoic acid against herpes simplex virus and in experimental cutaneous herpes in white mice. Assessment of the data obtained here indicates that all three study compounds were significantly less active than acyclovir in cell cultures. In experiments on laboratory animals, the efficacy of ointment containing N-(3,5-di-tert-2-hydroxyphenyl) acetamide was comparable with that of acyclovir ointment, while ointments containing 2-anilino-4,6-di-tert-butylphenol and 3,4-dihydroxybenzoic acid were less active.

This study was aimed at developing a new, technically simple method for the preparation of a once-daily sustained release matrix formulations, which would enable reproducible release of the active ingredient. Thermoplastic granulation is a new technique in pharmaceutical formulation. Coated particles of an active pharmaceutical ingredient (API) in sustained release matrix are prepared by thermoplastic granulation technique via heating (50 – 75°C) in fluid-bed dryer (FBD) granulator. The FBD creates ideal conditions for the most intense heat and mass transfer by spraying melted liquids onto the granular API. A variety of innovative processes such as granulation, agglomeration, coating and microencapsulation can be realized. Melted mixture of cetyl alcohol, glyceryl monostearate, and polyethylene glycol 4000 (PEG 4000) was used for fluid-bed coating. The present article deals with assessing the influence of rheological properties and hydrophile-lipophile balance (HLB) parameter of thermoplastic granules on the mechanism of drug delivery from sustained release matrix in solid dosage forms. The drug release kinetics model is affected by rheology, HLB of cetyl alcohol, and physicochemical properties of API granules.

A new group of compounds – 1-(methoxybenzyl)-4-[2-((methoxybenzyl)amino)ethyl]piperazin-2,3-diones was synthesized. As compared with previously studied linear methoxyphenyltriazaalkanes, the structure of the triazaalkane linker was found to influence the cardiotropic actions of the corresponding compounds. The most effective among the new group was 1-(2,4-dimethoxybenzyl)-4{2-[2,4-dimethoxybenzyl)amino]ethyl}piperazin-2,3-dione, which had significant antiarrhythmic activity at a dose of 2 mg/kg in a calcium chloride arrhythmia model, along with activity at the level of a tendency in models of aconitin arrythmia and reperfusion ventricular fibrillation.

A bisresorcinol, (8′Z)-3,5-dihydroxy-1-[16′-(3″,5″-dihydroxyphenyl)-8′-hexadecen-1′-yl]benzene (I), was isolated as an abundant constituent from the Vietnamese medicinal plant Heliciopsis terminalis (Kurz) Sleumer (Proteaceae). The antioxidant, hepatoprotective, and anti-inflammatory activities of compound I were tested in correlation with the use of H. terminalis as a hepatoprotective drug by ethnic people in Vietnam. Bisresorcinol I showed weak scavenging activity against DPPH radical at an EC₅₀ value of 156.9 mg/mL. At a concentration of 100 mg/mL, compound I inhibited 19,78% of MDAproduction as one of the biomarkers for lipid peroxidation. Bisresorcinol I protected HepG2 cells against harmful CCl₄. The hepatoprotective ability was observed at a concentration of 100 mg/mL with up to 44.42% cells alive, which was significantly higher than that in the control treated with CCl₄ (29.93 %). The NO scavenging activity of I was determined in RAW 264.7 cells with an IC₅₀ value of 71.15 mg/mL. Bisresorcinol I exhibited its anti-inflammatory activity through modulation of proinflammatory cytokines IL-6 and TNF-α as well as anti-inflammatory IL-10 in RAW264.7 cells.

The relaxivities of aqueous solutions of the manganese complexes Mn-CDTA, Mn-DTPA, and Mn-EDTA were compared with that of the gadolinium complex Gd-DTPA. Relaxivities R1 and R2 of Mn-CDTA solutions were slightly greater than those of Gd-DTPA. The lowest relaxivities were seen for Mn-DTPA, while Mn-EDTA occupied an intermediate position between Mc-CTDA and Mn-DTPA.

An algorithm for assessing the possibility of joining two datasets obtained by different operators for attestation of standard samples of biological medicinal substances (SS BMS) is proposed. These studies tested the uniformity of the results obtained by different operators during attestation of industrial standard samples of the specific activity of an oral poliomyelitis vaccine, i.e., divalent live attenuated types 1 and 3 “BiVak polio” vaccine, using the Mann-Whitney and Z statistics for independent sets run manually using a formula, with subsequent interpretation of the results. Results from calculation of the Mann-Whitney test in Statistica software (version 10) are presented.

Second-generation antipsychotic substances, as compared with first-generation antipsychotics, are more effective in relation to psychotic symptoms and have significantly lower potential for developing extrapyramidal impairments such as parkinsonism and late dyskinesia. However, use of these agents is associated with significant weight gain in patients. Advances in the pharmacogenetics of antipsychotic-induced weight gain are analyzed here.