Pharmaceutical Chemistry Journal (v.45, #8)

Pharmacokinetics of a new radiopharmaceutical based on alubmin microspheres and palladium-103 and modified by heat and radiation by V. M. Petriev; V. K. Shiryaev; V. G. Skvortsov; L. A. Smakhtin; O. Yu. Kochnov; O. A. Smoryzanova (449-453).
The pharmacokinetics of albumin microspheres (AMS) labeled with 103Pd (103Pd-AMS) were studied in healthy mice after intramuscular injections. It was established that increasing the denaturation temperature of albumin from 136 to 200°C reduced the rate of 103Pd elimination from muscle tissue. This effect can be explained by a decrease in the rate of 103Pd-AMS proteolysis due to more extensive protein denaturation. Preliminary gamma irradiation (60Co) of AMS prepared at 200°C produced a more significant deceleration of these processes. Increasing the irradiation dose from 0.1 to 1.0 MGy delayed AMS proteolysis and elimination of 103Pd from the protein matrix as a result of an increasing degree of ASM cross-linking. The rate of 103Pd elimination from muscle tissue was more rapid than that from tumor. This can be explained by faster AMS biodegradation in muscle tissue compared with tumor tissue.
Keywords: albumin microspheres; palladium-103

Synthesis and hemolytic activity of cyclopentane and hydrindane 2-acetyl-1,3-diones by O. P. Shestak; V. L. Novikov; E. A. Martyyas; M. M. Anisimov (454-457).
A series of 16 cyclopentane and hydrindane 2-acetyl-1,3-diones were synthesized. The hemolytic properties of these compounds were studied on erythrocytes of white mongrel mice at various pH values. Bifosin (bifonazole), saponin (Fluka, BioChemika, Germany), and triton X-100 were used as reference preparations. It was found that 2-acetylcyclopent-4-ene-1,3-dione (III), 2-acetyl-4-chlorocyclopent-4-ene-1,3-dione (VI), 2-acetyl-4-bromocyclopent-4-ene-1,3-dione (VII), and 2-acetyl-4,5-dichlorocyclopent-4-ene-1,3-dione (IX) exhibited rather strong (as compared to bifosin and saponin) hemolytic action on erythrocytes. The effect was more pronounced at pH 7.4 (ED50 = 0.42 – 4.9 μg/mL) than at pH 6.0 (ED50 = 6.5 – 39.9 μg/mL). It was also established that triketones I, XI, and XV exhibited selective hemolytic effects at pH 6.0. However, the level of their activity was not sufficiently high (ED50 = 55.6 – 72.6 μg/mL). Some of the studied compounds are of interest as potential cytotoxic and antitumor agents.
Keywords: 2-acetylcyclopent-4-ene-1,3-diones; hydrindane 2-acetyl-1,3-diones; erythrocytes; hemolysis; pH-dependent hemolytic effect

Synthesis and phagocytosis-stimulating activity of harmine and glaucine N-oxides by G. K. Mukusheva; Zh. S. Nurmaganbetov; N. M. Ismagulova; O. A. Ponamareva; E. V. Burdel’naya; A. Zh. Turmukhambetov; A. V. Kazantsev; S. M. Adekenov (458-460).
The N-oxides of harmine and glaucine were obtained. The influence of the produced compounds on the phagocytosis-stimulating activity of human blood monocytes in vitro was studied. It was established that harmine and glaucine N-oxides have pronounced phagocytosis-stimulating properties.
Keywords: alkaloids; glaucine; harmine; N-oxides; phagocytosis-stimulating activity

Synthesis and biological properties of 2-(4-chlorophenyl)-3-morpholin-4-yl-(4-alkoxyphenyl)alkanol hydrochlorides by O. A. Papoyan; N. K. Gasparyan; R. G. Paronikyan; A. A. Tatevosyan; D. A. Avakimyan; G. A. Panosyan; G. A. Gevorgyan (461-465).
New 2-(4-chlorophenyl)-3-morpholin-4-yl-1-(4-alkoxyphenyl)propan-1-ones were synthesized via aminomethylation of 2-(4-chlorophenyl)-1-(4-alkoxyphenyl)ethanones. Reduction of the former by lithium aluminum hydride produced 2-(4-chlorophenyl)-3-morpholin-4-yl-1-(4-alkoxyphenyl)propan-1-ols. Reaction of them with Grignard reagents gave 2-(4-chlorophenyl)-1-morpholin-4-yl-3-(4-alkoxyphenyl)alkan-3-ols. The synthesized compounds exhibited pronounced anticonvulsive and some peripheral n-cholinolytic activities while showing no antibacterial activity.
Keywords: aminomethylation; 3-morpholinopropan-1-ones; Grignard reagents; 3-morpholinoalkan-1-ols; 1-morpholinoalkan-3-ols; anticonvulsive; peripheral n-cholinolytic properties; antibacterial activity

A series of new spiro-condensed indoles have been synthesized and the relationship between their chemical structure and biological activity has been established. Reduction of the oxo group in previously synthesized hydrochlorides of 2′-oxyindolin(5′-bromoindolin)-3?-spiro-1-(1,2,3,4-tetrahydro-β-carboline and 3-methyl-β-carboline followed by treatment with an ether solution of HCl leads to the dihydrochlorides of indolin-(5′-bromoindolin)-3′-spiro-1-(1,2,3,4-tetrahydro-β-carboline and 3-methyl-β-carboline.
Keywords: spiro-condensed indoles; dihydrochlorides of indolin(5′-bromoindolin)-3′-sprio-1-(1,2,3,4-tetrahydro)-β-carboline and 3-methyl-β-carboline; synthesis; anticonvulsant activity

Local anesthetic activity of new amidoxime derivatives by L. A. Kayukova; K. D. Praliev; A. L. Akhelova; U. S. Kemel’bekov; G. M. Pichkhadze; G. S. Mukhamedzhanova; D. M. Kadyrova; S. R. Nasyrova (468-471).
Three series of amidoxime derivatives including nitrous derivatives of α-chloro-α-isonitrosoacetone and hydrochlorides of O-aroyl-β-aminopropioamidoximes and 3-[β-(piperidin-1-yl)]ethyl-5-aryl-1,2,4-oxadiazoles were tested for conduction, infiltration, and terminal anesthesia. There are four interesting “hit” compounds, i.e., the hydrochloride of O-m-chlorophenyl-β-(benzimidazol-1-yl)propioamidoxime (VII), the hydrochloride of O-p-nitrophenyl-β-(benzimidazol-1-yl)propioamidoxime (VIII), 3-[β-(piperidin-1-yl)]ethyl-5-p-tolyl-1,2,4-oxadiazole (IX), and 3-[β-(piperidin-1-yl)]ethyl-5-m-chlorophenyl-1,2,4-oxadiazole (X), which exhibit higher activity than the reference drugs (trimecaine, lidocaine, novocaine, kazcaine). As a whole, all tested compounds were active in conduction and infiltration anesthesia (at the level of the reference drugs) and did not show activity in terminal anesthesia. Compounds VIIX are of interest for further testing under condition and infiltration anesthesia conditions.
Keywords: nitrous derivatives of α-chloro-α-isonitrosoacetone; hydrochlorides of O-aroyl-β-aminopropioamidoximes; 3-[β-(piperidin-1-yl)]ethyl-5-aryl-1,2,4-oxadiazoles; conduction; infiltration; terminal anesthesia

Synthesis and pharmacological activity of 2-arylaminonicotinic acid β-(3-carboxypropionyl)hydrazides by M. E. Kon’shin; B. Ya. Syropyatov; A. L. Efremov; T. F. Odegova; V. V. Novikova; M. I. Vakhrin (472-473).
A series of 2-arylaminonicotinic acid β-(3-carboxypropionyl)hydrazides were synthesized by the reaction of 2-arylaminonicotinic acids with succinic anhydride. All of the synthesized compounds possess weak antimicrobial properties. Three compounds exhibit an anticoagulant effect.
Keywords: 2-arylaminonicotinic acid β-(3-carboxypropionyl)hydrazides; synthesis; pharmacological activity

Synthesis and antimicrobial activity of 2,6-dimethyl-3,5-dialkoxycarbonyl-4-phenyl- 1,4-dihydropyridines by V. L. Gein; M. I. Kazantseva; A. A. Kurbatova; E. V. Voronina (474-475).
Reaction of acetoacetic esters, aromatic aldehydes, and ammonia formed under Hantzsch conditions 2,6-dimethyl-3,5-dialkoxycarbonyl-1,4-dihydropyridines. The structures of the products were established using mass, IR, and PMR spectra. It was found that all synthesized compounds exhibited moderate antimicrobial activity.
Keywords: Hantzsch synthesis; 2,6-dimethyl-3,5-dialkoxycarbonyl-4-phenyl-1,4-dihydropyridines; antimicrobial activity

Rauwolfia vomitoria (RV) Afzel (Apocynaceae) is a medicinal plant used in traditional medicinal practice for the treatment of hypertension. This research is devoted to phytochemical constituents, in particular, some specific alkaloids present in the RV root extract. The phytochemical evaluation revealed the presence of alkaloids, tannins, saponins, and flavonoids in this extract. The antioxidant activity of the RV root extract was also evaluated in a series of in vitro assays involving free radicals. The extract exhibited significant hydrogen peroxide scavenging effect relative to ascorbic acid (p < 0.05, IC50 = 98 μg/ml), nitric oxide scavenging effect (50.37 ± 0.4% after 150 min), and metal chelating activity (89.08 ± 2.62%). In addition, it exhibited significant ferric reducing power relative to ascorbic acid (p < 0.05). The total content of phenolic substances was 233.3 ± 2.9 mg/g. The extract was also studied for its inhibitory capacity on lipid peroxidation as a possible mechanism of its aphrodisiac effect, by measuring thiobarbituric acid reactive substances in various male-cow tissues incubated in a 5% solution of the RV root extract, distilled water, and antioxidant vitamins C and E upon keeping the samples frozen for 35 days. Tissues incubated in the test solution had lower levels of malondialdehyde (MDA) compared to those in the samples incubated in distilled water. Results obtained from this study indicate that the RV root extract can be a potential source of natural antioxidants.
Keywords: Antioxidant; malondialdehyde (MDA); lipid peroxidation (LPO)

Specific features of drug encapsulation in liposomes (A review) by E. V. Tazina; K. V. Kostin; N. A. Oborotova (481-490).
Liposomes are hollow particles, the internal space of which is bounded by a lipid membrane. Liposomes are promising drug delivery systems for organs and tissues because of their colloidal properties, controlled size, surface characteristics, membrane action, and biocompatibility. Liposomal drugs have found wide use in the diagnosis and chemotherapy of cancer, vaccinology, ophthalmology, pulmonology, and the treatment of other pathologies. This review describes the methods of encapsulation of biologically active compounds with various physicochemical properties in liposomes, which is very important for the production of liposomal drugs.
Keywords: liposomes; weak amphiphilic bases; weak amphiphilic acids; pH gradient; ammonium sulfate; ionophores; transition-metal ions; calcium acetate

Biopharmaceutical assessment of a polycomplex matrix system based on carbomer 940 and Eudragit® EPO for colon-specific drug delivery by R. I. Mustafin; T. V. Kabanova; I. I. Semina; A. V. Bukhovets; V. R. Garipova; E. V. Shilovskaya; Sh. F. Nasibullin; A. Yu. Sitenkov; R. R. Kazakova; V. A. Kemenova (491-494).
The biopharmaceutical properties of a new drug carrier based on an interpolyelectrolyte complex (IPEC) between Carbomer 940 and Eudragit® EPO have been studied in the form of a polycomplex matrix system (PMS) intended to be a potential carrier for peroral drug delivery systems. The release profiles of diclofenac sodium from the proposed PMS and Voltaren® retard in model gastroitestial tract medium belong to the intestine-soluble and sustained-release types, respectively. Evaluation of the pharmacokinetic parameters of the PMS revealed a close in vitro/in vivo correlation. The proposed PMS, in contrast to the parent drug, provides targeted drug delivery to the colon region and is comparable with Voltaren® retard with respect to the bioavailability and the main pharmacokinetic parameters.
Keywords: interpolyelectrolyte complex; Carbomer 940; Eudragit® EPO; polycomplex matrix system (PMS); Voltaren® retard; in vitro/in vivo correlation

Amino-acid composition and nootropic properties of polynoophyt by I. G. Nikolaeva; L. D. Dymsheeva; S. M. Nikolaev; G. G. Nikolaeva (495-498).
The nootropic activity of the complex plant preparation polynoophyt (polynoofyt) has been established in animal experiments. The amino-acid composition of the phytopreparation has been studied. A total of 19 amino acids including seven essential ones was identified. The most significant concentrations were found for aspargic acid, asparagine, glutamic acid, glutamine, proline, cystine, methionine, leucine, γ-aminobutyric acid, alanine, and arginine.
Keywords: polynoophyt; nootropic activity; amino-acid composition

Pharmaceutical analysis and standardization of gimantan parenteral dosage form by M. S. Sergeeva; L. N. Grushevskaya; B. M. Pyatin; N. I. Avdyunina; L. M. Gaevaya; V. S. Klumova; M. E. Dudenkova; K. V. Alekseev; E. A. Litvin (499-502).
The objective of this investigation was to develop methods for the pharmaceutical analysis of a parenteral dosage form of gimantan, a new anti-Parkinson’s drug. The physicochemical properties of gimantan solution for injection have been investigated. Methods for the determination of the impurity content and the quantitative drug assay were developed based on thin-layer chromatography (TLC) and gas chromatography (GC), respectively. The drug was identified using TLC and GC simultaneously with the purity evaluation and quantitative determination of gimantan. The stability during storage has been studied. The quality standards for gimantan parenteral dosage form have been developed.
Keywords: gimantan; parenteral dosage form; pharmaceutical analysis; standardization; thin-layer chromatography; gas chromatography

Formulation optimization and in vivo evaluation of mucoadhesive xyloglucan microspheres by M. R. Bhalekar; K. P. Patil; S. J. Kshirsagar; S. Mohapatra (503-508).
Mucoadhesive microspheres of the novel polymer, xyloglucan, have been formulated and their performance characteristics have been systematically evaluated in vitro and in vivo. The mucoadhesive microspheres were obtained by incorporating glipizide as model drug in xyloglucan as a mucoadhesive polymer and sodium alginate as a gel-forming polymer by the orifice-ionic gelation method. A32 factorial design was employed to study the effect of independent variables, xyloglucan concentration (X 1 ) and calcium chloride (CaCl2) concentration (X 2 ), on the dependent variables including drug entrapment efficiency, release time (t 80), and percentage mucoadhesion in 1h. The best batch exhibited high drug entrapment efficiency (92.98%) and percentage mucoadhesion (78% after 1h). The drug release was also controlled for more than 8 hours. In vivo testing of the mucoadhesive microspheres revealed significant hypoglycemic effect of glipizide.
Keywords: In vivo study; ionic gelation method; mucoadhesive microspheres; xyloglucan; 32 factorial design

Determination of desmopressin by HPLC–MS by C. T. Nguyen; A. A. Karlitskaya; K. S. Davydova; V. G. Kukes (509-511).
Desmopressin is used for preventing and stopping hemorrhage of various etiologies and is included in the list of most essential drugs. Quantative determination of desmopressin in blood plasma using gas chromatography—mass spectrometry (HPLC/MS) is discussed. A method for the isolation of desmopressin from plasma samples and quantitative determination of desmopressin is described. The percent extraction of the drug from blood plasma has been estimated and the influence of the biological matrix has been assessed. The work has been carried out using a Thermo Finnigan HPLC/MS instrument equipped with an external ion-source based on electrospray ionization.
Keywords: desmopressin; hemophilia; von Willebrand disease; clinical trials; blood plasma; calibration; chromatography—mass spectrometry