Pharmaceutical Chemistry Journal (v.49, #11)

Multi-Day Monitoring of Ubidecarenone Level in Rat Plasma and Tissues After a Single Intravenous Injection by E. I. Kalenikova; E. A. Gorodetskaya; O. G. Tokareva; M. A. Belousova; O. Yu. Kulyak; M. M. Artem’eva; O. S. Medvedev (719-723).
The pharmacokinetics of ubidecarenone (CoQ10) in rat plasma and the kinetics of its organ levels were studied for the first time for 8-16 d after a single i.v. injection at a dose of 30 mg/kg. The pharmacokinetics followed a classical two-compartment curve. The main pharmacokinetic parameters for plasma (C 0, AUC 0→∞, K α, K el, t 1/2α, t 1/2el, Cl T, V d) and several organs (C max, T max, AUC 0→t , f tiss) were calculated. The results proved that CoQ10 injected i.v. rapidly attained and maintained for a long time high levels in plasma, myocardium, brain, liver, and kidneys. This was potentially important for treating acute ischemic states.
Keywords: ubidecarenone; pharmacokinetics; acute ischemic states

M-Dinitroaromatic Moiety as a Fragment of Biologically Active Compounds by V. B. Piskov; V. P. Chernyshev; S. D. Karakotov (724-734).
Data on the biological activities of compounds containing m-dinitroaromatic (m-DAr) moieties were presented and led to the conclusion that including this moiety in the structures of new biologically active compounds was promising. It was established that one nitro group in m-DAr could be replaced by trifluoromethyl without losing the biological activity of the obtained analogs.
Keywords: m-dinitroaromatic moiety; biologically active compounds

1-Substituted 2-Benzylaminobenzimidazoles with Phenyl Methoxyls: Synthesis, Computer Prediction, and Pharmacological Activity by O. N. Zhukovskaya; V. A. Anisimova; A. A. Spasov; P. M. Vasil’ev; V. A. Kosolapov; A. F. Kucheryavenko; N. A. Gurova; L. V. Naumenko; V. A. Kuznetsova; D. V. Sorotskii; O. A. Solov’eva; E. V. Reznikov; V. V. Gurova; V. S. Sirotenko (735-742).
Condensation of 1-substituted 2-aminobenzimidazoles with aromatic aldehydes produced the corresponding azomethines, reduction of which by sodium borohydride afforded 1-substituted 2-benzylaminobenzimidazoles. The Microcosm information technology (IT) tool was used to assess in silico the potential for antiarrhythmic, antiaggregant, antioxidant, hemorheologic, and antiglycating activity in this series of compounds. Pharmacological screening identified which of the synthesized compounds were active. It was shown that the computer predictions correlated with the experimental data.
Keywords: 1-substituted 2-benzylaminobenzimidazoles; synthesis; Microcosm IT tool; in silico search; antiarrhythmic, antiaggregant, antioxidant, hemorheologic, and antiglycating activity; experimental study

Influence of N,N′-Substituted Piperazines on Cytolysis by O. S. Veselkina; I. L. Solovtsova; N. N. Petrishchev; L. V. Galebskaya; M. E. Borovitov; D. I. Nilov; M. A. Solov’eva; E. A. Vorob’ev; K. S. Len’shina (743-748).
The hemolytic activity of N,N′-substituted piperazines and their influence on the hemolytic process initiated by radiation (red LED, 653 nm) in the presence of radachlorin (RADA-FARMA, Russia) photosensitizer and on complement-dependent hemolysis were studied. All compounds did not cause human RBC lysis in the studied concentration range (0.15 – 3.0 mM) although dose-dependent inhibition of photo-induced hemolysis that manifested as an increase of the 50% lysis time was observed. The piperazine derivatives did not substantially influence RBC lysis by the activated complement. Therefore, the antihemolytic effect of the N,N’-substituted piperazines was due to their antioxidant activity.
Keywords: N,N′-substituted piperazines; photo-induced hemolysis; photosensitizer; antioxidants; complement system

A synthetic method for 2,4-dimethoxyphenylbiguanide, which was selected using the Prediction of Activity Spectra of Substances (PASS) computer program, was developed. The influence of this novel biguanidine derivative on the content of reduced glutathione and the activities of glutathione peroxidase, glutathione reductase, and glutathione transferase in the heart and blood serum of rats with experimental rheumatoid arthritis was estimated. The studied parameters changed toward the control values after the test compound was injected into animals with the pathology, which could be explained by manifestation of its cardioprotective and antioxidant activities. The obtained data could be used to develop new methods for prevention and treatment of this pathological condition.
Keywords: 2,4-dimethoxyphenylbiguanide; rheumatoid arthritis; rats; reduced glutathione; glutathione peroxidase; glutathione reductase; glutathione transferase

Antidiabetic and Antilipidemic Effects of Some Polar and Nonpolar Extracts of Securigera Securidaca Flowers by Abbas Ahmadi; Mohsen Khalili; Shideh Margedari; Babak Nahri-Niknafs (753-759).
Medicinal plants are widely used for pharmacological agents. These herbs are very rich sources of bioactive compounds. Securigera securidaca is reputed in folk medicine as antidiabetic and antilipidemic drug. In this research, the effect of solvent’s polarity in bioactive extract of this plant was evaluated by GC/MS analysis. Then, hypoglycemic and hypolipidemic activities of different extracts were studied in diabetic rats and compared to glibenclamide.The results showed that carbon tetrachloride extract of this plant has the best and significant activity for reducing of glucose and lipid levels compared to other extracts because of higher content of sterols and fatty acids.
Keywords: antidiabetic and antilipidemic drugs; Securigera securidaca ; solvent’s polarity; bioactive compounds

Modern Technologies for Synthesizing Drug Substances: Toward Highly Efficient Drug Production by I. A. Narkevich; I. N. Tarasov; Z. M. Golant; A. V. Alekhin (760-764).
Implementation of new technologies for synthesizing drug substances, e.g., continuous-flow microreactor synthesis of active drug substances (ADS) and asymmetric synthesis of intermediates and ADS using enzymes created by gene engineering methods, is highly significant for localizing ADS production in Russia. The possibility of using the existing Russian scientific infrastructure for rapid implementation of domestic production of a new ADS portfolio with the least operating losses, maximum economic efficiency, and high competitiveness was demonstrated.
Keywords: pharmaceuticals; active drug substances; microreactor ADS synthesis; asymmetric synthesis of intermediates and ADS; localized ADS production in Russia

This review considered international approaches to assessment of the content of genotoxic impurities (residual solvents and various inorganic and organic impurities) in drugs. Foreign and domestic regulations defining requirements for the classification, control, and toxicological risk assessment of potential genotoxic impurities in drug substances and drugs were compared. The use of highly sensitive and specific analytical methods for detecting genotoxic impurities in drugs was justified. The need to improve the domestic regulatory framework on the control of elemental genotoxic impurities (heavy metals) and to prepare guidelines on the assessment of potentially genotoxic organic impurities in drugs was demonstrated.
Keywords: genotoxic impurities; drugs; threshold of toxicological concern (TTC)

The urgency to satisfy pharmaceutical regulatory requirements, including drug quality risk management, prompted the application of risk assessment methodology during the pharmaceutical development (PD) stage of an actual drug production process to be studied. Risk assessment results for the industrial process in combination with information regarding risks to the final product that were obtained during the PD allowed an objective opinion about the influence of the product properties and process parameters on critical drug quality parameters during its mass production to be formulated.
Keywords: risk; quality risk management; pharmaceutical development; process; risk assessment; risk analysis; risk assessment methods; FMEA

Modern Approaches to the Development of Reference Standards for Quality Assessment of Drug Substances by V. A. Merkulov; E. I. Sakanyan; V. I. Klimov; T. B. Shemeryankina; V. A. Yashkir; A. V. Barmin (776-778).
Reference standards, including pharmacopoeial reference standards, are widely used for quality assessment of drug substances. Leading global pharmacopoeias contain monographs regulating the requirements for the classification, attestation, and use of reference standards. The drug standardization system in the Russian Federation, which includes drug substances, requires revision for the creation and attestation of national reference standards, including pharmacopoeial ones.
Keywords: reference standards; pharmacopoeial reference standards; drug substances; pharmacopoeial monograph; regulation

Arrhenius Kinetics As a Bioactivity Assessment Criterion for Drug Substances and Excipients by O. V. Levitskaya; A. V. Syroeshkin; T. V. Pleteneva (779-781).
Arrhenius kinetic principles, in particular, E a values, were used to assess the biological activity of drug substances in aqueous solutions with different D/H ratios. The obtained activation energies indicated that deuterium-depleted solutions had lower toxicity and biological activity.
Keywords: drug substances; excipients; activation energy

The present study was aimed to optimize the conditions of Codonopsis pilosula desulfurization using orthogonal experiment analysis with four independent variables including desulfurization temperature, time, ultrasonic power, and ratio of ethanol to raw material. Aspects of the antibacterial activity of polysaccharides extracted from sulfur-fumigated C. pilosula and after desulfurization by the agar-well diffusion method against Escherichia coli have also been studied. The results showed that the optimum extraction conditions were as follows: desulfurization temperature, 45°C; desulfurization time, 50 min; ultrasonic power, 700 W; and ethanol to raw material ratio, 10 : 1. Under these conditions, the desulfurization rate was 55.4%. The antibacterial activity of polysaccharides extracted from desulfurized C. pilosula was higher than that of polysaccharides extracted from sulfur-fumigated herbs, with the MIC values of 35 and 70 mg/mL, respectively.
Keywords: desulfurization; antibacterial activity; polysaccharides; Codonopsis pilosula

RP-HPLC Method Development and Validation for Simultaneous Determination of Esomeprazole and Diclofenac Sodium in Pharmaceutical Dosage Forms by Farah Khan; Irshad Ahmad; Muhammad Akhtar; Heena Abdul Rauf; Hamza Altaf; Muhammad Munawar Hayat (788-794).
A new RP-HPLC method was developed and validated for simultaneous determination of esomeprazole (ESO) and diclofenac sodium (DIC) in pharmaceutical dosage forms. BDS Hypersil C18 column (250 × 4.6 mm, 5 μm) and mobile phase consisting of methanol and 50 mM phosphate buffer (35:65) were used in this analysis. The flow rate was adjusted at 1.0 mL/min and detection was performed at 213 nm wavelength for both esomeprazole and diclofenac sodium. Etoposide (ETO) was used as internal standard giving a retention time of 4.13 min. The method was linear in a range of 25 – 1000 ng/mL and 15.5 – 500 ng/mL for ESO and DIC, respectively. The method has good linearity (r 2 = 0.999) with the intra-day and inter-day variability less than 3% for both drugs. The limits of detection were 15 and 10.5 ng/mL, while the limits of quantification were 25 and 15.5 ng/mL for ESO and DIC, respectively. The proposed method demonstrates good robustness, resisting to small deliberate changes in pH and flow rate of mobile phase. The developed method was successfully applied for determining drug concentrations in spiked human plasma, injection, capsule and tablet dosage forms, where it exhibited good performance and reproducibility.
Keywords: Diclofenac sodium; Esomeprazole; Pharmaceutical dosage form, RP-HPLC