Vol 51, No 9 (2017)

The effects of testosterone undecanoate on the functional activity of P-glycoprotein (ABCB1 protein) were studied in male Chinchilla rabbits. Testosterone was given as single intramuscular doses of 12 or 24 mg/kg. The functional activity of P-glycoprotein was determined in terms of the pharmacokinetics of its marker substrate - fexofenadine - on days 7, 14, and 21 after hormone administration. Administration of testosterone at a dose of 12 mg/kg (n = 7) increased the C_max of fexofenadine on days 7 and 14 and AUC_0-t on day 14 and decreased total clearance on day 14. Use of testosterone at a dose of 24 mg/kg (n = 7) led to increases in the C_max of fexofenadine on day 7 and AUC_0-t on days 7, 14, and 21 and decreased total clearance on days 7 and 14. These changes in the pharmacokinetics of fexofenadine provide evidence of decreases in the functional activity of Pgp on the background of testosterone administration. Correlational relationships were found between measures of the pharmacokinetics of fexofenadine and serum testosterone levels.

The purpose of this study was to investigate the effects of cilostazol on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined following oral and intravenous administration of nifedipine (1.5 and 6.0 mg ・ kg^-1) in rats. Cilostazol inhibited CYP3A4 enzyme activity at a 50% inhibitory concentration (IC₅₀) of 4.1 μM. The areas under the plasma concentration–time curve (AUC_0-∞) and the peak concentration (C_max) of nifedipine were significantly increased, respectively, in the presence of cilostazol compared to that in the control. The total body clearance (CL/F) was significantly decreased by cilostazol. Consequently, the absolute bioavailability (AB) of nifedipine with cilostazol was significantly higher than that in the control. The metabolite to parent AUC ratio (MR) in the presence of cilostazol was significantly decreased compared to that in the control. The AUC_0-∞ of intravenous nifedipine was significantly increased with cilostazol compared to that in the control. The increased bioavailability of nifedipine in rats can be mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver by cilostazol. In addition, the reduction of CL/F of nifedipine by cilostazol may also be a factor.

Interaction of 1-dimethylamino-4-diethylaminobutyn-2, 1-dimethylamino-4-piperidinobutyn-2, and 1-dimethylamino-4-morpholinobutyn-2 with the corresponding alkyl esters of monobromo(chloro)acetic acid was used to synthesize novel monoammonium salts. Studies of the antimicrobial activity of the resulting compounds showed that salts containing hydrophobic alkoxycarbonylmethyl radicals had marked antibacterial activity against Gram-positive and Gram-negative microorganisms.

Approaches to creating complexes based on branched oligohexamethyleneguanidine hydrochloride are addressed. Novel combinations of bactericidal agents were obtained, methods for the synthesis of a series of p-aminosalicylic acid derivatives were selected, the solubilities of their complexes with oligohexamethyleneguanidine were determined, and the bactericidal activities of the resulting complexes against Mycobacterium smegmatis were assessed. The minimum inhibitory concentrations of all complexes were in the range 0.1 – 1 μg/ml of culture medium. Thus, these complexes may be useful for creating a bactericidal formulation with powerful and long-lasting biocidal action, highly reproducible properties, and low toxicity.

The efficacy of photon capture therapy (PCT) is to a significant extent determined by the properties of the formulation containing the element efficiently absorbing external X-irradiation and operating as a dose-enhancing agent (DEA). We report here a comparison of the efficacies of bismuth and gadolinium as DEA in PCT technologies with X-irradiation at 110 kV for the treatment of superficial tumors. Bismuth and gadolinium are comparable in that they are available as the same chemical form – a complex with diethylenetriaminepentaacetic acid, for which the physicochemical properties are similar for both elements. Studies were performed on mice with transplanted B16F10 melanoma as a tumor model. Both DEAwere given by the intratumor route at the same dose of 5 mg of DEAper animal. Irradiation was with an x-ray apparatus with a tension of 110 kV using a dose of 20 Gy. The results showed significantly greater antitumor efficacy for PCT with both gadolinium and bismuth than with short-focus radiotherapy. In terms of the log dead cells (lgN), there was an increase in lgN from 0.78 for short-focus irradiation to 2.5 for PCT using gadolinium or bismuth, with identical dose exposure. There were no significant differences in the antitumor efficacies of PCT with bismuth and gadolinium for x-ray irradiation at 110 kV.

Palladium(II) thiocyanate complexes of general formula, [PdL₄](SCN)₂, where L = thiourea (Tu), N-methylthiourea (Metu), N,N-dimethylthiourea (Dmtu), tetramethylthiourea (Tmtu), imidazolidine-2-thione (Imt) and thionicotinamide (Tna) were prepared by the reaction of K₂[PdCl₄] with thioamides followed by the addition of Potassium thiocyanate in 1:2:2 molar ratio. The complexes were characterized by elemental analysis, and spectroscopic techniques (IR, ¹H and ¹³C NMR), and were screened for antibacterial activities against four strains of bacteria {Staphylococcus aureus (ATCC 25923), Bacillus subtilis (DSM 3256), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 10197)}. Some of the compounds exhibited signifiacnt antibacterial activity even higher than the standards showing the potential for their use as potent antibacterial agents. POM analyses reveal that the compounds are slightly toxic. Moreover, they have 8 ~ 12 % drug score, which is an important parameter for a compound possessing the drug properties.

The present article reports on the biogenic synthesis of silver nanoparticles using Ficuspalmata leaf extract. A color change in the reaction mixture of AgNO₃ and leaf extract was the first sign of silver nanoparticles synthesis, further confirmed by UV-VIS spectroscopy. The obtained nanoparticles were characterized by x-ray diffTaction (XRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). XRD revealed crystalline nature of nanoparticles. SEM showed that the synthesized particles were predominantly spherical with an average particle size of 28 – 33 nm. FTIR revealed that organic compounds like flavonoids, alkaloids, and saponins were present in leaf extract and mainly involved in the reduction of Ag⁺¹ to Ag⁰. Antibacterial assays showed that synthesized silver nanoparticles had the power to inhibit the growth of both Gram-positive and Gram-negative bacterial strains. The results indicate that F. palmata leaf extract can be used for the synthesis of silver nanoparticles producing antibacterial effect.

A chain of new vanadium(IV) complexes of Schiff bases, derived from acetohydrazide (HL^1-3) or 4-aminoantipyrine (HL^4-7) have been prepared and physicochemically distinguished using different tools including analytical, spectral, and magnetic techniques. The spectral and analytical data showed that ligands HL^1-3 acted as neutral bidentate ligands, chelated through hydrazono carbonyl and azomethine groups, whereas HL⁴ acted as neutral tetradentate ligand coordinated via pyrazolone carbonyl, NH group, hydrazono carbonyl, and azo (N=N) groups forming binuclear complexes. The HL⁵ and HL⁶ behave as neutral bidentate ligands coordinating through pyrazolone carbonyl and NH groups; in case of ligand HL⁶, in addition to the mentioned mode, C=N and CN groups participated to bind a second VO(II) ion form binuclear complexes. HL⁷ behaves as a monobasic bidentate ligand bonded via deprotonated OH and azomethine groups. All complexes adopt square pyramidal geometry around vanadium ion. Results revealed that the oral management of vanadium complexes significantly reduced the blood glucose level in rats suffered from diabetes. The correction of altered biochemical parameters via treatment with vanadium complexes points the improved glucose balance.

A series of arylsubstituted tetrazolocyclanodihydropyrimidines was prepared and their cytotoxic actions on SPEV-2 cells were studied. The activity of these substances was found to depend on the nature and position of the substitution groups in the benzene ring and the size of the alicycle. The most active compounds were o-chloro(methyl)phenyltetrazolohexahydroquinazolines.

A novel ecdysteroid-containing pharmaceutical substance – Lychnis chalcedonica extract – was developed. The phytoecdysteroid composition of the ethanolic extract was determined. Courses of intragastric administration of Lychnis chalcedonica extract (150 mg/kg) were accompanied by anabolic effects in both trained and untrained animals. The actoprotector properties of the Lychnis chalcedonica extract and improvements in carbohydrate metabolism on exhaustive physical exertion were seen only in trained animals. Lychnis chalcedonica extract is a pharmaceutical substance with potential for use as the basis for developing formulations with actoprotector activity.

A controlled, randomized study using an experimental model of contrast (iopromide)-induced nephropathy (CIN) in normal mongrel rats showed that the combination of treatment by hydration with the nicotinamide adenine dinucleotide (NAD)-containing formulation Nadcin^®, with cytoprotective and antiischemic actions, decreased the plasma creatinine and urea nitrogen levels 72 h after induction of CIN. Aclose correlational relationship (r = 0.78, p < 0.001) was found between the blood endothelin-1 (ET-1) level and O₂^– generation, while there was no relationship between hydrogen peroxide production and the ET-1 level (r = 0.13, p > 0.05) or between the ET-1 level and catalase activity (r = 0.41, p > 0.05). In contrast to monotherapy with hydration, inclusion of Nadcin normalized blood ET-1 and the blood ET-1/creatinine ratio, the blood and renal NAD/NADH and NADP/NADPH redox potentials, and had more marked actions on reversing the overproduction of free radicals and on the antioxidant defense system in the blood and renal tissue. It is suggested that ET-1, the ET-1/creatinine ratio, and the plasma redox potential can be used as early markers for increases in the risk of developing stable impairment of renal function on use of x-ray contract agents.

A comparative dissolution kinetics test was used to study the release (dissolution kinetics) of an original and 10 generic formulations of omeprazole from different manufacturers in a medium simulating the moderately acidic conditions in the stomach typical of the state of medication-induced suppression of acidity; tests were also performed in a model of pathological duodenogastric reflux. HPLC was used to measure omeprazole concentrations in aliquots collected at 4, 10, 15, 20, 30, 45, and 60 min in solution with pH 7.0 ± 0.05 after 2 h of exposure at pH 1.2 ± 0.05 or 4.0 ± 0.05. The duration of action of pathological duodenogastric reflux on the therapeutic formulations of omeprazole was 4 min. Not all the study formulations could be completely recognized as equivalents to the original formulation in the in vitro test conditions.