Pharmaceutical Chemistry Journal (v.51, #11)

Preclinical Study of the Pharmacokinetics of a New Intravenous Dosage Form of Ubiquinol by E. I. Kalenikova; E. A. Gorodetskaya; O. Y. Kulyak; L. P. Kozaeva; V. G. Makarov; O. N. Pozharitskaya; A. N. Shikov; O. S. Medvedev (949-953).
The pharmacokinetics of ubiquinol in a new dosage form for intravenous injection were studied for the first time. Biexponential kinetic curves were found using HPLC with electrochemical detection in 48-h experiments in rats. The main pharmacokinetic parameters, i.e., area under the kinetic curves, elimination half-life, and total clearance, were calculated. The pharmacokinetics were nonlinear in the studied dose range (5, 10, and 20 mg/kg) with a higher dose corresponding to lower clearance. Multiple administrations increased the clearance, which implied extensive uptake of the drug into organ tissues that was required to manifest the protective effects of ubiquinol. Gradual oxidation of ubiquinol in blood plasma indicated that it was involved in endogenous redox processes.
Keywords: ubiquinol; ubiquinone; pharmacokinetics; intravenous administration; redox status

The pharmacokinetics, bioequivalence, and safety of Femorix® (Valenta Pharm Co., Russia) and Aubagio® (SanofiWinthrop Industrie, France) film-coated tablets (14 mg) were compared in a double-blind randomized investigation in parallel groups of healthy volunteers. The bioavailabilities of Femorix® film-coated tablets (14 mg, Valenta Pharm Co., Russia) were 96.18% [87.92 – 105.22%] for ln(Cmax) and 96.24% [88.67 – 104.44%] for ln(AUC0–72) of those for Aubagio® film-coated tablets (14 mg, Sanofi Winthrop Industrie, France), which fell in the commonly accepted range (80 – 125%) for proving the bioequivalence of the tested products.
Keywords: teriflunomide; bioequivalence; pharmacokinetics; AUC ; C max ; T max ; T 1/2

The present study is aimed at evaluating the anti-elastase and anti-collagenase activity and determining the active constituents of Excoecaria agallocha L. plant extracts. Ethanol extracts of E. agallocha exhibit highest extraction yield (23%) and greater total content of phenolic compounds and flavonoids as compared to other extracts. At a concentration of 80 μg/mL, the ethanol extract produced more significant (p < 0.01) inhibition of elastase (82.7%) and collagenase (76.12%) activity and acted as a non-competitive inhibitor. Fourteen flavonoids were identified in the active ethanol extract. Further studies will provide direct way to the development of elastase and collagenase inhibitors from E. agallocha.
Keywords: elastase; flavonoids; HPLC-UV-MS; mangrove; rutoside

The Effects of Cimetidine, N-Acetylcysteine, and Taurine on Thioridazine Metabolic Activation and Induction of Oxidative Stress in Isolated Rat Hepatocytes by Aziz Eftekhari; Elham Ahmadian; Yadollah Azarmi; Alireza Parvizpur; Javad Khalili Fard; Mohammad Ali Eghbal (965-969).
Thioridazine (TZ) is used commonly in the treatment of schizophrenia. However, its clinical use has been associated with liver toxicity. Therefore, we examined the cytotoxic effect of TZ on freshly isolated rat hepatocytes to evaluate the role of TZ pathogenesis in hepatotoxicity. In addition, the effect of N-acetylcysteine (NAC), taurine, and cimetidine on this toxicity was investigated. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), cellular glutathione (GSH) content, and mitochondrial depolarization were assessed as toxicity markers. Results showed that TZ caused an increase in ROS formation as well as LPO and GSH depletion. Moreover, mitochondrion seems to be targets of TZ-induced toxicity. The severe hepatotoxicity of TZ in enzyme-induced rats suggests the potential role of reactive intermediates. The present study proposes the protective effect of NAC and/or taurine against TZ-induced cellular injury, probably through their radical scavenging properties and effects on mitochondria.
Keywords: thioridazine; hepatotoxicity; formation of reactive oxygen species; oxidative stress

L-Arginine – Cellulose-Acetate-Sulfate Complex and its Influence on Endothelial Dysfunction in Rats by E. A. Shakhno; T. A. Savitskaya; D. D. Grinshpan; T. G. Pokrovskaya; V. I. Yakushev; M. V. Pokrovskii (970-974).
The composition of a complex of L-arginine with cellulose acetate sulfate as the sodium salt was established. Its structure was characterized using computer simulation and spectroscopic methods. The Langmuir equation was shown to be applicable for describing adsorption isotherms of the complex on activated carbons of various origins. Amino acids were released from the immobilized complex predominantly in alkaline solution. The complex with 70-200 mg/kg of L-arginine exhibited pronounced cardioprotective activity and possessed antihypertensive and endothelioprotective action.
Keywords: L-arginine; cellulose acetate sulfate; activated carbon; immobilized complex; L-NAME; endothelial dysfunction

Synthesis, Docking, and Anticoagulant Activity of New Factor-Xa Inhibitors in a Series of Pyrrolo[3,2,1-ij]Quinoline-1,2-Diones by S. M. Medvedeva; A. Yu. Potapov; I. V. Gribkova; E. V. Katkova; V. B. Sulimov; Kh. S. Shikhaliev (975-979).
New factor-Xa inhibitors in a series of pyrrolo[3,2,1-ij]quinoline-1,2-diones substituted by condensation at the β-carbonyl with rhodanine, arylamines, and H-tryptamines were synthesized, characterized, and studied by molecular docking. Promising factor-Xa inhibitors with inhibitory constants in the micromolar concentration range (IC50 = 0.7 – 40 μM) were discovered.
Keywords: pyrrolo[3,2,1-ij]quinolin-2-ones; derivatives; condensation; molecular docking; factor-Xa inhibitors; anticoagulants

Experimental Antioxidant Activity of a β-Cyclodextrin – Histochrome Complex by M. M. Bikbov; N. A. Nikitin; V. K. Surkova; R. R. Farkhutdinov; L. M. Khalilov; A. R. Tulyabaev; A. F. Nikitina; S. A. Fedoreev; N. P. Mishchenko (980-984).
A2:1 β-cyclodextrin – histochrome complex was synthesized based on a comparison with experimental studies of histochrome and showed antioxidant activity prolonged to 16 d as compared with 6 d for histochrome in tests of the duration of the in vitro antioxidant effect. PMR measurements proved that a β-cyclodextrin – histochrome complex formed. Computer modeling of the β-cyclodextrin–histochrome complex showed that the head-to-tail complex corresponded to the energy minimum.
Keywords: histochrome; emoxypine; β-cyclodextrin; antioxidant activity

Peptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) are known as antifungal and antibacterial agents. However, FMDP peptides bind to the blood serum proteins in an irreversible way thereby losing their biological activity. In the present work, one of the most potent FMDP peptides, LysNvaFMDP, was immobilized on iron-oxide(II/III) magnetic nanoparticles (MNPs) in order to obtain a potentially more resistant form of this compound capable of binding to proteins. The obtained nanostructures were characterised using FT-IR and DLS techniques. Then, the degree of binding of the immobilized FMDP agent to albumin from bovine pancreas and to the proteins from human blood serum was tested using UV-VIS spectrophotometric method in comparison to the unbound form of this peptide. Microbial growth inhibition tests were also carried out. The form of LysNvaFMDP immobilized on MNPs turned out to have lower affinity to the proteins in comparison to the unbound form and, as a result, it showed a higher antimicrobial activity against Lactobacillus acidophilus ATCC 4356 strain. The immobilized form of FMDP agent is significantly protected from binding to albumin and other blood serum proteins and thus retains its antimicrobial activity. It is possible that such a form of this agent will reach clinics.
Keywords: FMDP peptides; antimicrobial agents; magnetic nanoparticles; albumin; blood serum proteins

Synthesis of Analogs of Trans-Fagaramide and Their Cytotoxic Activity by Melissa Barrera Tomas; Tze Chieh Shiao; Phuong Trang Nguyen; Steve Bourgault; René Roy (995-1004).
A series of 30 compounds were synthetized inspired by active trans-fagaramide structure skeleton. On this synthetic platform, 18 compounds were achieved via Knoevenagel condensation using maleic acid and piperonal, followed by peptide coupling with various amines, giving an average yield of 54%. Subsequently, nine compounds were obtained by palladium-mediated Heck coupling with an average yield of 79%. In addition, cytotoxic activity was evaluated against cardiomyoblast H9c2, breast adenocarcinoma MCF7, hepatocellular carcinoma HepG2, and glioblastoma U-87 cells. The results revealed two aryl halogen-substituted compounds moderately active against H9c2 and MCF7 with IC50 values > 50 μM. One functionalized coumarin showed inhibitory activity against H9c2 (IC50 > 50 μM). In contrast, p-aminophenyl-β-monosubstituted trans-fagaramide was found to inhibit MCF7 (IC50 > 50 μM) without showing toxicity against H9c2 cells.
Keywords: trans-fagaramide; Knoevenagel condensation; peptide coupling; palladium-mediated Heck coupling; cytotoxic activity

Synthesis, Characterization, Pharmacokinetics and Evaluation of Cytotoxicity for Docetaxel-Oleate Conjugate Targeting MCF-7 Breast Cancer Cells by Neela M. Bhatia; Pragati K. Kulkarni; Snehal S. Ashtekar; Deepak V. Mahuli; Manish S. Bhatia (1005-1013).
The present work envisages synthesis of an ester conjugate of anticancer drug docetaxel with oleoyl chloride, with the aim to selectively target the breast cancer cells MCF-7 so as to minimize non-specific hemolytic side effects. The synthesized docetaxel-oleate conjugate was characterized and confirmed by physicochemical and spectral methods. Solubility and partition coefficient determination indicated increased solubility and lipophilicity, while protein binding studies revealed low protein binding capacity of the conjugated drug. Subsequently, the conjugate was evaluated for its in vitro cytotoxicity, drug release, and hemolysis effects. The results indicated a lesser RBC lysis at a more significant anticancer activity of the parent drug and a selective diffusion at pH of cancer cells (compared to the pH of normal cells), thereby increasing specificity and decreasing adverse effects. In addition, an analytical HPLC method was developed for hydrolytic study of the conjugated drug. The proposed method showed good separation of the target compounds with high accuracy and precision. Hydrolysis study indicated a minimum hydrolysis of the conjugate at various pH that simulated gastric and intestinal fluids. Thus, the synthesized conjugate proves to be a useful prodrug in reducing systemic toxicity of docetaxel as well as selectively targeting cancerous cells.
Keywords: Synthesis; docetaxel-oleate conjugate; prodrug; targeted drug delivery; breast cancer

Biologically Active Compounds in Aqueous Extracts of Caragana jubata (Pall.) Poir. by P. A. Kakorin; I. B. Perova; E. D. Rybakova; K. I. Éller; G. V. Ramenskaya; L. A. Pavlova; Yu. O. Teselkin (1014-1020).
Polyphenolic compounds (flavonoids) of lyophilized aqueous extracts from Caragana jubata (Pall.) Poir. raw material from 2010 and 2015 were studied using modern HPLC-DAD-MS. Primarily mono- and diglycosides of O-hydroxylated (myricetin, quercetin, kaempferol) and O-methylated flavonols (isorhamnetin, laricitrin, syringetin) were identified. Long-term storage of dried raw material under standard conditions had little effect on the quantitative content of polyphenolic compounds. Acute toxicity studies of C. jubata extract showed no toxicity.
Keywords: Caragana jubata (Pall.) Poir.; HPLC-DAD-MS; flavonoids; acute toxicity

Interchangeability Issues with Glaucoma Medicines Using Latanoprost as an Example by N. D. Bunyatyan; O. V. Filippova; B. K. Romanov; A. B. Prokof’ev (1021-1024).
The possible interchangeability of eye drops was analyzed using glaucoma medicines containing latanoprost as examples. It was shown that the reference and generic drugs could be identical with respect to composition of active ingredients when manufactured from the same pharmaceutical substance but could differ in the excipient composition, in particular, have a different buffer and osmolality that could produce differences in their clinical effects. An analysis of the literature showed that the therapeutic efficacy and safety could vary for pharmaceutically equivalent drugs. The lack of therapeutic equivalence on the background of pharmaceutical equivalence could be caused by the use of different packaging and different dosing systems. Therefore, results from clinical trials must be compared to confirm the interchangeability of eye drops.
Keywords: generic drugs; interchangeability; glaucoma; eye drops; latanoprost; excipients

Additive Manufacturing Technologies for Pharmaceutics by I. A. Narkevich; E. V. Flisyuk; O. A. Terent’eva; A. A. Semin (1025-1029).
Three-dimensional (3D) printing methods used to manufacture drug delivery systems, including inkjet printing, fused deposition modeling, and tablet production from powered substances, are reviewed. Various dosage forms prepared using 3D printing technologies over the past 10 years are summarized.
Keywords: 3D printing; dosage form; personalized medicine; additive manufacturing

Analytical Control of Darunavir Tablet Dosage Forms. Part I. by M. S. Goizman; A. A. Korlyukov; K. Yu. Suponitskii; N. L. Shimanovskii; T. E. Popova; A. O. Popova; O. N. Glotova; O. A. Zotova; G. B. Tikhomirova (1030-1036).
Purposeful development of special methods to be included into pharmacopoeial monographs on the quality of darunavir (DRV) preparations is shown to allow the use of expensive imported standard samples (SSs) for drug analysis to be avoided. Part I of the present work describes these methods and their validation. UV spectrophotometry is proposed in the “Authenticity” section for detecting DRV by the coincidence of extrema in the spectrum of an aqueous MeOH extract (pH 9) with well-known peaks in the spectrum of deprotonated DRV at 230 nm (minimum) and 267 nm (maximum). This section also requires GC analysis for solvated EtOH, the presence of which indicates that DRV ethanolate was used as the active pharmaceutical ingredient (API) and the absence of which, that non-solvated amorphous DRV was used. The significant increase in the accuracy of the quantitative determination and the sharp reduction in its duration allow the use of SSs to be avoided. For this reason, the “Dissolution” section proposes determining the DRV concentration in the dissolution medium (pH 3) by spectrophotometry using a method that requires experimental determination of the specific absorption coefficient A1cm1% $$ left({A}_{1mathrm{cm}}^{1%} ight) $$ of DRV solutions in this medium at the maximum (267 nm). The established value A1cm1% $$ left({A}_{1mathrm{cm}}^{1%} ight. $$ = (393.4 ± 2) cm–1 was a physicochemical constant with a relative standard deviation RSD < 1% at confidence level α = 0.05.
Keywords: monograph; darunavir (DRV); DRV ethanolate; amorphous DRV; standard sample (SS); GC; impurities; specific absorption coefficient A 1 cm 1 % $$ left(left({A}_{1mathrm{cm}}^{1%} ight. ight) $$ ; active pharmaceutical ingredient (API); UV spectrophotometry; validation

Validation of a Quantitative Determination Method for Ormustine in a Lyophilized Dosage Form by N. D. Bunyatyan; L. L. Nikolaeva; Yu. V. Olefir; E. V. Sanarova; N. A. Oborotova; A. B. Prokof’ev; E. V. Ignat’eva; I. V. Yartseva; I. D. Gulyakin (1037-1040).
Validation results for a spectrophotometric quantitative determination method for ormustine in a lyophilized dosage form are presented. The method is shown to be suitable for quantitative determination of ormustine with respect to parameters such as specificity, linearity, accuracy, repeatability, and intermediate precision.
Keywords: validation; spectrophotometry; ormustine

Standardization of the Method for Determining Hemagglutinin Content in Human Immunoglobulin Preparations in Russia by O. G. Kornilova; A. V. Nechaev; I. V. Borisevich; É. Yu. Kudasheva (1041-1044).
Documentation for standardization of the method for determining hemagglutinins (HAs) in human immunoglobulin preparations used in Russia is presented. The proposed general pharmacopoeial monograph “Determination of anti-A and anti-B hemagglutinins in medicinal preparations of human immunoglobulin” allows quality control of human immunoglobulin preparations for HAcontent using indirect hemagglutination under standard conditions. The positive and negative components of the domestic standard sample (SS) of HAs contain 1:32 anti-A and 1:16 anti-B, respectively; less than 1:2 anti-A and -B; and 1:64 components of the HA content limit. Introduction of the SS for contents of anti-A and anti-B HAs into pharmacopoeial practice would ensure that results obtained in various ranges are accurate and enable the quantitative contents of the corresponding HAs in human immunoglobulin preparations to be determined.
Keywords: hemagglutination method; anti-A and anti-B hemagglutinins; standard sample; human immunoglobulins; attestation

Applicability of an Alternative Method for Sterility Testing of Medicinal Preparations by M. V. Roshchina; O. V. Gunar; N. G. Sakhno (1045-1048).
The aim of the present work was to examine the applicability of an alternative method for detecting CO2 using an automated BacT/ALERT 3D colorimetric microbiological detection system and analytical parameters for sterility testing of medicinal preparations (MPs) that were selected, justified, and harmonized with leading global pharmacopoeias. The tests used microorganisms and samples of 38 MPs and compared the results with defined criteria for pharmaceutical microbiology. The experimental results showed that the alternative method did not cause discrepancies and was suitable for MPsterility testing. However, the lack of regulations for validation standard procedures in the RF currently limits replacing routine methods by alternative ones.
Keywords: medicinal preparations; sterility testing; alternative microbiological method; method suitability