Pharmaceutical Chemistry Journal (v.46, #4)

Synthesis and pharmacological properties of a new 3-hydroxypyridine derivative by Vic. V. Yasnetsov; S. Ya. Skachilova; L. N. Sernov; T. A. Voronina; V. V. Yasnetsov (199-202).
The new 3-hydroxypyridine derivative 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-L-glutamate (EMOP-AG) was synthesized. It was established that EMOP-AG (10 and 30 mg/kg, single administration) exhibited antihypoxic activity on various models of acute hypoxia (baric hypoxia with hypercapnia and hemic and histotoxic hypoxia) in mice and produced an equal or stronger effect than reference drugs (amtizol, mexidol, and emoxipin). EMOP-AG (10 and 30 mg/kg) had a marked neuroprotective effect on rats with bilateral ligation of common carotid arteries and was more effective in the treatment of neurologic deficiency than amtizol (10 and 30 mg/kg/day), mexidol (90 and 120 mg/kg/day), and emoxipin (120 mg/kg/day). It was also established that EMOP-AG (30 mg/kg) could prevent amnesia in a step-down passive avoidance situation caused by different factors (maximal electroshock, scopolamine, acute baric hypoxia with hypercapnia, and the combined action of extreme factors).
Keywords: new 3-hydroxypyridine derivative; antihypoxic; antiamnestic; and neuroprotective effects

Synthesis and biological activity of synthetic 17α-hydroxyprogesterone derivatives by O. A. Zeinalov; V. V. Yaderets; T. S. Stytsenko; M. A. Petrosyan; V. A. Andryushina (203-206).
Gestagenic and contraceptive (in combination with estrogen) activities of megestrol acetate, proligestone, and two esters of mepregenol acetate (butyrate and hemisuccinate) were studied. The absence of a correlation between the gestagenic and contraceptive activity (CA) of the synthetic derivatives of 17α-hydroxyprogesterone was established. Of two compounds (proligestone and megestrol acetate) showing the maximum (100%) CA (in combination with ethynylestradiol), proligestone was practically devoid of gestagenic activity while megestrol acetate was a highly active gestagen. It was confirmed that the gestagenic activities of injected megestrol acetate and mepregenol acetate tended to exceed their peroral activities. Pure estrogen was found to contribute to the CA of the mepregenol esters.
Keywords: gestagens; contraceptive activity; 17α-hydroxyprogesterone derivatives; proligestone

Antitumor effect of polymetalloacrylates, a new generation of hemostatics by K. A. Abzaeva; M. G. Voronkov; L. V. Zhilitskaya; L. A. Ostrovskaya; M. M. Fomina; N. V. Blyukhterova; V. A. Rykova (207-209).
The antitumor activity of 14 polymetalloacrylates against two models of murine solid tumors (Lewis lung carcinoma and Acatol adenocarcinoma) was studied. The acute toxicity of these compounds was evaluated. It was shown that polymetalloacrylates represented a new class of compounds for oncology with potential antitumor activity and an original mechanism of action. It was found that polyacrylates of the noble metals Ag (argacryl), Au (auracryl), and Pt (platacryl) were the most effective polymetalloacrylates against the tested tumors and could be recommended for further extensive experimental investigation.
Keywords: polymetalloacrylates; grafted animal tumors; antitumor activity

Antihypotensive activity of 2-acetylamino-5,6-dihydro-4H-1,3-thiazine for an endotoxic shock model in rats by M. V. Filimonova; T. P. Trofimova; G. S. Borisova; A. A. Mandrugin (210-212).
The high anti-hypotonic activity of the new NOS inhibitor 2-acetylamino-5,6-dihydro-4H-1,3-thiazine hydro-bromide was demonstrated for an endotoxic shock model in rats.
Keywords: endotoxic shock; anti-hypotonic activity; NO-synthase inhibitors

Computer analysis of the structure – antidepressant activity relationship in series of 1,2,4-triazole and thietane-1,1-dioxide derivatives by I. L. Nikitina; R. A. Gabidullin; E. E. Klen; L. A. Tyurina; E. K. Alekhin; F. A. Khaliullin (213-218).
Characteristic structural signatures of antidepressant agents were determined using the SARD-21 computer-aided modeling system. The influence of these signatures on the antidepressant activity was evaluated. This information was used to develop a mathematical model capable of predicting the antidepressant effectiveness of 1,2,4-triazoles and thietane-1,1-dioxides at a recognition level of 80%. The established structural parameters can be used to design new highly effective antidepressants and to predict a priori antidepressant activity in the 1,2,4-triazole and thietane-1,1-dioxide series.
Keywords: mathematical model; antidepressant activity; 1,2,4-triazoles; thietane dioxide

Composition of water-soluble polysaccharides from Calendula officinalis L. flowers by A. P. Korzh; A. M. Gur’ev; M. V. Belousov; M. S. Yusubov; M. L. Belyanin (219-221).
Water-soluble polysaccharides (WSPS) were isolated from Calendula officinalis flowers using aqueous extraction followed by precipitation with EtOH and dialysis through a semi-permeable membrane. The WSPS were standardized with respect to uronic acid, protein, and nucleic acid content. Total WSPS were separated into five main components (PSC-1, PSC-2, PSC-3, PSC-4, PSC-5) by ion-exchange chromatography over DEAE cellulose. The main components in WSPS from C. officinalis were acidic polysaccharides (rhamnogalactouronan I).
Keywords: Calendula officinalis L.; water-soluble polysaccharides; calendula flowers

The isolation of total ecdysteroids from Silene viridiflora is described. The preparation acts as an effective immunomodulator in normal animals (mice, 18 – 20 g) and in mice with secondary immunodeficiency developed under irradiation, acute toxic hepatitis, and prolonged physical load conditions. The immunomodulating activity of total ecdysteroids from S. viridiflora is comparable with that of the known immunity stimulator T-activin, a preparation of polypeptide nature from cattle thymus.
Keywords: total ecdysteroid preparation; Silene viridiflora ; immunostimulating effect

Chemical constituents of Ficus odorata by P.-W. Tsai; K. A. De Castro-Cruz; C.-C. Shen; C.-T. Chiou; C. Y. Ragasa (225-227).
A dichloromethane extract of the leaves of Ficus odorata (Moreaceae family) contains l-sitosteryl3β-glucopyranoside-6'-O-palmitate (1), squalene (2), lutein (3), α-amyrin acetate (4), lupeol acetate (5), and β-carotene (6). The structure of 1 was elucidated by extensive 1D and 2D NMR spectroscopy. Compound 1 was tested for cytotoxicity using sulforhodamine B assay against the human lung adenocarcinoma epithelial cell line (A549), human stomach adenocarcinoma cell line (AGS), human colon adenocarcinoma (HT29) and human prostate cancer cell line (PC3). It exhibited cytotoxicity against AGS cell line with 60.28% growth inhibition
Keywords: Ficus odorata ; Moreaceae; β-sitosteryl-3β-glucopyranoside-6'-O-palmitate; cytotoxicity

Lyophilization of liposomal drug forms (Review) by O. Yu. Arshinova; E. V. Sanarova; A. V. Lantsova; N. A. Oborotova (228-233).
Lyophilization is a promising approach to ensuring the long-term stability of liposomes. Decades of studies in this field have revealed various cryoprotective mechanisms such as water replacement and formation of a cryoprotector matrix. Much progress has been made in obtaining highly stable liposomes after lyophilization based on optimization of the formulation and process parameters. This paper reviews cryoprotective mechanisms, their parameters affecting the cryoprotective effect, and techniques used most often in the studies. The parameters are discussed with respect to two aspects, namely, formulation factors (choice of the lipid bilayer composition, vesicle size, selection of cryoprotectors, dry mass ratio of cryoprotector to lipid, distribution of cryoprotector on both sides of the lipid bilayer) and processing factors (freezing protocols, drying protocols, etc.).
Keywords: lyophilization; liposomes; cryoprotector; formulation

Development of effective pilot-scale technology for producing N,N-bis-met-histone H1.3 used for lymphoma treatment by D. A. Gusarov; I. V. Sokolova; V. D. Gusarova; E. A. Evteeva; T. V. Vorob’eva; S. A. Kosarev; E. D. Shibanova; D. I. Bairamashvili (234-240).
Much attention is presently devoted to the treatment of lymphoma using monoclonal antibodies. Unfortunately, preparations such as Rituximab (MabThera) are not produced in the Russian Federation and must be imported from abroad. It was shown that H1-type histones with activities similar to that of Rituximab can be used for such therapy. We have developed an pilot-scale technology for the production of recombinant N,N-bis-met-histone H1.3. The activity and purity of the obtained preparation were demonstrated in several tests. The produced amount of active pharmaceutical ingredient was sufficient to start clinical trials in Russia.
Keywords: N,N-bis-met-histone H1.3; lymphoma; chromatography; technology

Effect of polyethyleneglycol on coenzyme Q10 bioavailability from nanosystems in vitro by M. V. Karlina; V. M. Kosman; O. N. Pozharitskaya; A. N. Shikov; V. G. Makarov; J. Heinämäki; J. Yliruusi; R. Hiltunen (241-244).
Coenzyme Q10 (CoQ10) is a natural antioxidant of the oil-soluble benzoquinone group that is involved in electron transport in mitochondria. CoQ10 possesses a broad spectrum of pharmacological activity. However, its insolubility in water and low bioavailability upon peroral administration are significant disadvantages. The present work was aimed at a biopharmaceutical evaluation of nanosystems (NS) with CoQ10 that are suitable for peroral administration and exhibit increased bioavailability in vitro. Solid NS of CoQ10 with polyethyleneglycol (PEG) carriers of various molecular weights (1,500; 6,000; 35,000) were prepared in order to increase the dissolution rate of CoQ10. The NS particle sizes were in the range 48.4 – 200.3 nm. The influences of the PEG molecular weight and the ratio of NS components were evaluated using dispersion analysis. Regression equations describing the effects of these factors on the drug-release and dissolution rates were obtained by processing the results. Response surfaces that adequately described drug dissolution were plotted.
Keywords: coenzyme Q10; nanosystem; bioavailability

Synthesis of the myorelaxant 1,3,5-tris-(2′-diethylbenzylammonioethyl)-1,3,5-triazine-2,4,6-trione tribromide by O. I. Lukashov; N. A. Sokolova; A. V. Morozov; P. V. Kazakov; N. S. Mirzabekova; N. E. Kuz’mina (245-248).
A new commercially applicable method for the synthesis of the myorelaxant 1,3,5-tris-(2′-diethylbenzylammonioethyl)- 1,3,5-triazine-2,4,6-trione tribromide (isocyuronium bromide) is described.
Keywords: myorelaxant; cyanuric chloride; 1,3,5-triazine; 2-diethylaminoethanol

Evaluating the activity of low-molecular-weight heparin in preparations and substances by A. L. Berkovskii; E. V. Sergeeva; A. V. Suvorov; A. A. Kozlov (249-252).
The task of developing effective production of low-molecular-weight heparins (LMH), which are widely used in clinical practice, is timely. The quality assurance system of pharmaceutical preparations under WHO guidance stipulates, in particular, the application of specific and selective quality monitoring of the activity of heparin in preparations and substances. Using a test system based on purified reagents (thrombin, factor Xa, antithrombin III), a technique for the measurement of LMH according to the anti-Xa/anti-IIa chromogenic method recommended by the European Pharmacopoeia has been developed. The proposed technique has been evaluated with respect to the main analytical characteristics. The established accuracy, precision, linearity, and reproducibility allow the validated chromogenic method adapted for the proposed test system to be recommended for introduction into the quality control of LMH production.
Keywords: low-molecular-weight heparin; chromogenic methods; test systems; manufacturing quality control

Aversectin C is an agent included in the composition of antiparasitic fodder granules. The concentration of aversectin C in blood plasma and its residual amounts in organs and tissues of sheep was determined by HPLC. The principal pharmacokinetic parameters of aversectin C were calculated based on these data.
Keywords: aversectin C; antiparasitic fodder granules; residual content of aversectin C in sheep organs and tissues.

Investigations in photostability of dithranol incorporated in solid lipid nanoparticles by M. S. Gambhire; M. R. Bhalekar; B. Shrivastava (256-261).
The purpose of this study was to improve the stability of dithranol, an effective drug for topical treatment of psoriasis. Solid lipid nanoparticles (SLNs) were prepared by pre-emulsion followed by ultrasonication technique to investigate whether the inclusion in the lipid matrix could increase stability of the drug. Physicochemical characterization of the particles by differential scanning calorimetry (DSC) revealed that homogenization followed by ultrasonication is a suitable approach for dithranol-loaded SLN preparation. Preparation of SLNs was based on the previous part of this study. Mass-spectrometric determinations of dithranol and its degradation product were performed. The obtained average particle size was 219 nm; up to 69.88 % of drug was entrapped in the SLNs. The results showed that the inclusion of dithranol in SLNs reduced the rate of drug degradation.
Keywords: Dithranol; photosensitivity; photostabilty; solid lipid nanoparticles (SLNs)