Vol 52, No 6 (2018)

The pharmacokinetics of propranolol were studied in healthy volunteers after a single peroral administration at a dose of 80 mg under normal conditions, on the second day of antiorthostatic hypokinesia, and on the first day after termination of the hypokinesia. The maximum propranolol concentration (–6 ∆%), area under the pharmacokinetic curve (–13 ∆%), elimination half-life (–15 ∆%), mean residence time in the body (–17 ∆%), and distribution volume (–8 ∆%) tended to decrease with antiorthostatic hypokinesia whereas the total clearance (+13 ∆%), ratio of maximum concentrations (125 ± 23%), and relative absorption rate of the drug (158 ± 48%) increased.

The bioequivalence of mefebut drug substance and its tablet dosage form was investigated by studying the main pharmacokinetic parameters and calculating the relative bioavailability. The results showed that mefebut circulated for up to 4 h in rabbit blood after peroral administration. The relative bioavailability was 97.4%.

A series of 5-(arylmethylidene)-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-triones were synthesized and tested for antimicrobial activity against Staphylococcus and Streptococcus bacteria strains.

The structure and analgesic activity of 13-(N-aryl(N,N-diethyl)-aminocarbonyl)-9-methyl-11-thioxo-8-oxa-10,12-diazatricyclo[7.3.1.0^2,7]trideca-2,4,6-trienes and their 10-N-phenyl derivatives were studied. The studied compounds were shown to possess analgesic activity with low acute toxicity.

A series of nine molecules of coumarin hydrazone derivatives have been synthesized. The purpose of this study was to investigate the anti-diabetic activity of synthesized coumarin derivatives by inhibition of α-amylase enzyme isolated from Aspergillus niger microbial strain. The experiment was conducted by taking 5, 10, 50, and 100 μg/mL of each compound and acarbose as a positive control. The tests showed that compounds 3f (IC₅₀ = 49.70 μg/mL), 3g (IC₅₀ = 79.20 μg/mL), and 3i (IC₅₀ = 48.80 μg/mL) as well as reference drug (IC₅₀ = 81.70 μg/mL) exhibited inhibition activity against the enzyme. The synthesized compounds may be helpful in controlling the glucose level as α-amylase is one of the causes of increased sugar level in human body.

The Leuckart reaction offers a fast and convenient method for synthesizing various formamides, amines, and large numbers of biologically active compounds and pharmaceuticals. New 5-(N-piperidino)-1-arylpentan-1-ones (1a-f) and 5-(N-piperidino)-1-aryl-1-aminopentanes (2a-f) were synthesized. The properties of starting aminoketones 1a-f for synthesizing arylaminoketones 2a-f under Leuckart reaction conditions and their thermal stability over a broad temperature interval were studied. The optimal conditions for the key synthetic step, i.e., the Leuckart reaction, were determined experimentally.

One of the most active and promising areas of research in this pharmaceutical field is the application of porous structures in solid-state pharmaceuticals, particularly given the large number of existing and emerging therapeutic molecules that are classified as poorly soluble, including approximately 40% of the top 200 oral drugs globally. Porous compacts have been extensively studied for pharmaceutical applications due to their good biocompatibility, biodegradability, and satisfactory solubility at low toxicity. Porous compacts can be filled in hard gelatine capsule shells or processed to form tablets. Porous formulations in the tablet form showed good biocompatibility without causing undesirable side effects in biological systems. The porous particulate drug formulations can be of both types such as immediate or sustained release delivery system. The evolution of porous matrices as potential drug delivery systems continues with ongoing efforts in improving the loading and controlled release of therapeutics, with particular interest in targeted delivery. The mechanism of immediate release from porous tablets can be attributed to quick entry of water into porous matrix which causes rapid disintegration and dissolution of the tablet. The oral bioavailability of poorly water-soluble drugs is enhanced by porous compacts. Porous compacts are also used to enhance the dissolution of relatively insoluble drugs.

Apixaban is a novel anticoagulant drug acting as a direct, selective and reversible inhibitor of coagulation factor Xa. The purpose of this work was to develop and validate a sensitive, stability-indicating LC-MS method for the analysis of apixaban and estimation of production-related substances in the active pharmaceutical ingredient (API) and pharmaceutical dosage forms. The analyses were carried out on a Macherey-Nagel Nucleodur C18 column (250 × 4.6 mm, 5 μm particle size) with a mobile phase containing acetonitrile and water in gradient program at a flow rate of 0.8 mL/min, the column oven temperature 25°C, and the UV detection tuned to 270 nm. Apixaban was subjected to stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation, and found susceptible to acid and base hydrolysis conditions, while it was stable under thermal, photolytic, and oxidative degradation conditions. The degradation products were well resolved from the main peak and its impurities, proving the stability-indicating power of the proposed method. The proposed method was validated as per International Conference on Harmonization (ICH) guidelines. The method is suitable for practical routine analysis and it has been successfully applied to analyze apixaban in eliquis brand preparations. All analytical results were acceptable according to the pharmaceutical requirements.

A series of C-substituted N-phenylacetylglycylprolines were synthesized. Their structure-activity (antihypoxic) relationship was studied in normobaric hypoxia tests at i.p. doses of 0.1 – 1 mg/kg as a function of the C-substitution. The amide and ethyl ester of N-phenylacetylglycyl-L-proline exhibited antihypoxic activity and could cyclize in biological fluids to form cycloprolylglycine that was identical to the endogenous peptide with antihypoxic, neuroprotective, and other types of neuropsychotropic activity. The antihypoxic effect was stereospecific because the D-enantiomers were inactive. These compounds at concentrations of 10^–7 – 10^–5 M also exhibited neuroprotective activity for SH-SY5Y human neuroblastoma cell culture with 6-hydroxydopamine neurotoxicity. The methylamide and analogous free acid of N-phenylacetylglycylproline could not be cyclized into cycloprolylglycine and were inactive. It was concluded that the activity of the substituted glyprolines was associated with their conversion into cycloprolylglycine.

Literature data on the chemical composition and biological activity of Caragana jubata (Pall.)Poir. (Fabaceae, bean), a new potential source of medicinal raw material that is widely used in Russian folk medicine, were reviewed. Preliminary experiments on the composition of biologically active compounds and the pharmacological activity of the aqueous extract of the aerial part of C. jubata were performed by us. An analysis of the literature data and our results led to the conclusion that polyphenolic compounds (flavonoids), primarily mono- and diglycoside derivatives of O-hydroxylated flavonols, were the dominant fraction of biologically active compounds from C. jubata. According to the literature, C. jubata could possess hepatoprotective and antiviral activity. In vitro antioxidant activity of the aqueous extract of the aerial part of C. jubata, anti-inflammatory and wound-healing activity, and a lack of antibacterial activity against several pharmacopeial strains were found in our research. C. jubata could be recommended for further preclinical and clinical trials for efficacy and safety as a potential medicinal plant based on the information analysis and experiments.

Poly(t-butyl methacrylate) (PTBMA) was selected as a doxorubicin carrier for targeted delivery because it can hydrolyze to form water-soluble polymers. A chain-transfer reaction with thioglycolic acid was used. The thioglycolic acid concentration was 1 mass%, at which a polymer with the optimal biocompatibility (molecular mass ~12 kDa, polydispersion index M_w/M_n ≈ 1.5) was obtained. The polymer was chemically modified by a folate vector. The resulting polymer was converted via acid hydrolysis into a water-soluble copolymer. Then, a conjugate of doxorubicin (DOX) with the copolymer of t-butyl methacrylate and methacrylic acid modified by the folate vector on the terminal carboxylates was prepared. The degree of DOX conjugation to the polymer was 62.7 ± 11.8%. DOX was released from the polymer system almost three times faster at pH 4.6 than at pH 7.4. The cytotoxicity of the polymer conjugate was 1.52 μM.

Previously, targeted development of special procedures regulating analytical control methods for darunavir (DRV) dosage forms showed that the use of expensive imported reference standards (RSs) could be avoided. Part I discussed such procedures and their validation results. They were intended for sections Identity; Talc, Silica, and Titania; and Dissolution of the corresponding monographs. Part II continued the examination of procedures not requiring the use of RSs that were proposed for inclusion into sections of the monographs Side Impurities and Quantitative Determination. HPLC in gradient mode was proposed for estimating the contents of side impurities. The lower limit of quantitation of a separate impurity relative to DRV was 0.02%. The relative standard deviation (RSD) of the total impurity content was less than 10%. The DRV concentration in the section Quantitative Determination was proposed to be determined by direct UV spectrophotometry of the analyte in solution (pH ~ 9) using a procedure that required preliminary experimental determination of the specific absorption coefficient (\( {A}_{1\mathrm{cm}}^{1\%} \)) of the wavelength maximum at 267 nm for DRV in aqueous MeOH solutions (pH ~ 9). The experimental \( {A}_{1\mathrm{cm}}^{1\%} \)) = 393.4 cm–1 (RSD < 1% at confidence level á = 0.05). Therefore, \( {A}_{1\mathrm{cm}}^{1\%} \)) was a physicochemical constant. The RSD of results could be reduced to 1% and the analysis time shortened by 2 – 3 times because the preparation of RS solutions and measurements of their optical densities were obviated if \( {A}_{1\mathrm{cm}}^{1\%} \)) was used for quantitative determinations of DRV by direct UV spectrophotometry.