Vol 52, No 4 (2018)

Three structurally different peptide agonists of opioid receptors, i.e., gludalan, deltolei, and dalargin, were synthesized and assessed for infarction-limiting effects in rats with coronary occlusion (45 min) and reperfusion (2 h). The opioid peptides dalargin and gludalan (0.1 mg/kg) and deltolei (0.03, 0.1, and 0.2 mg/kg) were injected 5 min before reperfusion. It was found that gludalan and deltolei at a dose of 0.1 mg/kg decreased the ratio of infarction size to the area at risk (IS/AAR) whereas dalargin did not affect the IS. The infarction-limiting effect of deltolei disappeared if the peptide dose was decreased (0.03 mg/kg) or increased (0.2 mg/kg). The opioid receptor antagonists naltrexone (5 mg/kg) or naloxone methiodide (5 mg/kg), which does not penetrate the blood—brain barrier, eliminated the infarction-limiting effect of gludalan.

Compound T1059 (1-cyclohexanecarbonyl-2-ethylisothiourea hydrobromide) was found to be water soluble, moderately toxic (i.p. LD₁₆ and LD₅₀ of 274 and 380 mg/kg), and capable of competitively inhibiting nitric-oxide synthase (NOS) activity with significant selectivity toward inducible and endothelial isoforms (IC₅₀ for nNOS, iNOS, and eNOS of 60.3, 1.8, and 3.2 μM, respectively). T1059 was rapidly absorbed after a single i.p. injection (dose range 10 – 30 mg/kg) and distributed in tissues, causing pronounced suppression of endogenous NO production. T1059 at a dose of 10 mg/kg in normotensive anesthetized Wistar rats produced long-term vasoconstriction. The observed changes in vascular tone did not influence inotropic heart function but were accompanied by weak bradycardia.

2-Substituted 5-aryltetrazoles containing alkyl and aminoalkyl fragments were synthesized using alkylation and Mannich reactions. The tuberculostatic activity of the synthesized compounds against strain M. tuberculosis H37Rv was studied. Pronounced tuberculostatic activity (MIC ≤ 1.5 ìg/mL) was found for tetrazoles containing N(2) dimethyl- and diethylaminoethyl fragments.

Salts of N-decylpyridinium with various inorganic anions were prepared. Their structures and compositions were confirmed using IR spectroscopy and elemental analysis. Their antimicrobial activity against several strains of Gram-positive and Gram-negative bacteria and yeast-like fungi was studied. All tested compounds possessed a broad spectrum of antibacterial activity. The antimicrobial activity increased if chloride was replaced by the investigated inorganic anions.

Turmeric (Curcuma spp.) are rhizomatous perennial herbs with broad spectrum of pharmacological actions. There are more than 80 species of turmeric and 70 varieties/strains of Curcuma longa, which may have different chemical properties and biological activities. Hence, we compared the major active components (curcuminoides) and antifungal activity of three Curcuma longa strains (Ryudai gold (RD), Okinawa ukon, and BK2), C. xanthorrhiza, C. aromatica, C. amada, and C. zedoaria against Fusarium solani sensu lato (FSSL). The content of curcuminoides was determined by HPLC and the antifungal activity was measured by the diameter of colonies grown on Petri dish, microscopic observation, and CLSI microdilution methods. The BK2 turmeric contained highest concentration of curcumin, demethoxycurcumin, and bisdemethoxycurcumin followed by RD, C. xanthorrhiza, Okinawa ukon, and C. aromatica. These compounds were not detected in C. amada and C. zedoaria. All turmeric species inhibited fungal growth in a concentration-dependent manner. The order of IC₅₀ against FSSL was RD (78 to 92 μg/ml) > BK2 (89 to 101 μg/ml) > C. xanthorrhiza (98 to 114 μg/ml) > C. aromatica (183 to 204 μg/ml) > C. amada (183 to 206 μg/ml) > Okinawa ukon (191 to 216 μg/ml) > C. zedoaria (354 to 385 μg/ml). The results showed a correlation between the antifungal activity and curcuminiods contents of turmeric. Curcumin itself showed marked antifungal activity against FSSL (IC₅₀ = 23 to 25 μg/ml) followed by demethoxycurcumin (IC₅₀ = 25 to 27 μg/ml), while the antifungal activity of bisdemethoxycurcumin was extremely low (IC₅₀ = 216 to 238 μg/ml). However, C. amada and C. zedoaria had no curcuminoids but showed antifungal effects which indicated that other compounds could also inhibit the growth of FSSL. The obtained results demonstrated that turmeric species C. longa (strains Ryudai gold and BK2) and C. xanthorrhiza had higher content of curcuminoids and showed excellent antifungal activity against FSSL.

Eucommia ulmoides leaves were phytochemically and biologically studied for their antioxidant properties. Two new geniposides (ulmoside C and ulmoside D) and one known compound (10-O-acetylgeniposidic acid) were isolated from E. ulmoides. Evaluation of their free-radical scavenging activity with respect to DPPH, ABTS, and superoxide anions showed that ulmosides C and D possess outstanding properties with IC50 values of 6.5 ± 0.20 and 7.5 ± 0.01 μM (DPPH), 2.1 ± 0.007 and 3.5 ± 0.31 μM (ABTS), and 8.1 μ0.17 and 10 ± 0.09 μM (superoxide anion), respectively.

The aim of this work was to evaluate the antioxidant capacity of some increasing polarity soluble fractions of hydroalcoholic extract of the leaves of Algerian Lamiaceae Calamintha baborensis Batt., including hexanoic (Hex), chloroformic (Chlor), ethyl acetate (EtOAc) and n-butanolic (n-BuOH) and four subfractions (A, B, C, D) resulting from fractionation on a polyamide column. The EtOAc and n-BuOH extracts of the plant gave the highest values of antioxidant power by different methods: ABTS, percentage inhibition of 68.9/81.7%; DPPH, 27.6/80.99%; ORAC/FRAP, 37.28/28.47 and 21.73/19.52 μM/mL, respectively; IC50 values, 23 and 53.5 ppm. In addition, they were evaluated for their total phenolic content. The antibacterial activity of extracts showed good results with hexanoic and chloroformic fractions against E. coli (19 mm and 19.2 mm diameter of inhibition zone and MIC values about 43 and 43.4 μg/mL, respectively.) Apolar fractions from the leaves of C. Baborensis Batt. were analyzed by gas chromatography–mass spectrometry (GC–MS). The main components of the essential oil of C baborensis Batt. are eugenol (27.04%) and 3-methoxy acetophenone (26.4%).

An HPLC-MS/MS method for determination of rivaroxaban in human blood serum was developed. Sample preparation included protein precipitation by MeOH followed by centrifugation and dilution with deionized H₂O. The developed procedure had simple sample preparation, a short analysis time, and a wide analytical range (1.00 to 1,000.00 ng/mL). The procedure was convenient for routine bioanalytical studies, in particular, for therapeutic drug monitoring.

The potential of using juices to produce medicinal preparations is demonstrated. The current market conditions for medicinal preparations prepared from juices of fresh medicinal plant raw material are characterized. The urgency to develop draft General Pharmacopoeial Monographs “Juices” and “Determination of juice content in fresh medicinal plant raw material” is emphasized. Quality indicators characteristic of the “Juice” dosage form are formulated. Four methods for determining the juice content in fresh medicinal plant raw material used to produce juice are proposed and include two methods for determining juice in raw material for allopathic medicines and two methods applicable to production of homeopathic matrix tinctures.

Technology development for solid dosage forms with a solid dispersion of diclofenac is a crucial problem in pharmaceutical science and practice. The goal of the work was science-based and experimental technology development for tablets containing a solid dispersion of diclofenac with improved biopharmaceutical indicators as an equivalent to the substance. The obtained granulates and tablets had indicators that met the corresponding standards of the Russian SP XIIIth Ed. Almost 100% of the diclofenac was released from the developed tablets. This was 1.3 times greater than from commercial tablets. The recommended shelf life under these conditions is two years. The proposed technology could not only increase the bioavailability of the slightly soluble non-salt form of diclofenac but also facilitate further development of new medicinal preparations with improved bioavailability.

Results from experiments conducted for the parameter Residual Organic Solvents during the course of developing a draft regulation for the drug substance of the innovative pharmacological agent thrombaptanib are reported. The structure of the compound is given. Its pharmacological action is described. A list of potential residual organic solvents was compiled by analyzing the synthetic scheme and manufacturing technology. A separate part of the work describes in detail a developed GC-MS procedure for determining residual organic solvents. Validation results of the procedure for Specificity, Linearity, Accuracy, Precision, and Reproducibility are presented. The validation protocol for the procedure at the time of the studies followed domestic guides for validation that were written based on existing international documents because there was no existing GPM for validation in the current edition of the SP RF. A test sample of thrombaptanib was analyzed using the developed procedure for Residual Organic Solvents. The developed procedure was included in the Residual Organic Solvents section of the draft regulation.