Pharmaceutical Chemistry Journal (v.43, #6)

Development of 67Ga-labeled streptokinase by Amir Reza Jalilian; Fatemeh Mirazizi; Habibolah Nazem (287-293).
Radiolabeled streptokinase can be used in the imaging of thrombi in many cardiovascular diseases. Streptokinase was successively labeled with [67Ga]-gallium chloride using cyclic DTPA-dianhydride followed by biodistribution studies in wild-type and thrombosis-induced mice using scarification and SPECT. The radiochemical purity if the tracer was checked using HPLC >95 and RTLC >99% followed by SDS-PAGE to check the protein integrity. The biodistribution studies were performed in normal (up to 167 h) and thrombosis-earing rats (2 h) using scarification and preliminary SPECT studies (up to 2 h). ID/g% and SPECT techniques demonstrated the specific binding of the tracer in the heart and aorta 2 h post-injection. The use of Ga-68 radiosiotope can lead to superior imaging results with respect to the fast accumulation of the tracer and 68Ga half-life (68 min).
Keywords: streptokinase; gallium-67; biodistribution; femoral vein thrombosis; SPECT; ferric chloride-induced thrombosis

Synthesis of new pyrazolo[1,5-a]pyrimidines by D. V. Kryl’skii; A. S. Chuvashlev; A. P. Arzamastsev; A. I. Slivkin (294-296).
A series of condensed heterocycles containing the pyrazolo[1,5-a]pyrimidine moiety were synthesized from 5-amino-3-methyl-4-phenylpyrazole. The spectra of potential biological activity of the synthesized compounds were determined using computer-aided prediction methods, which showed that the most probable properties were corticotropin-releasing hormone antagonism, cyclooxygenase inhibition, and neuroleptic, nootropic, and cardioprotector activity
Keywords: 5-amino-3-methyl-4-phenylpyrazole; heterocyclization; pyrazolo[1,5-a]pyrimidine; synthesis; pyrazolo[1,5-a]quinazolines; potential biological activity; prediction

Synthesis of 2,4,6-triisopropylbenzenesulfonic acid N-azolides and their regulatory effect on cell proliferation, energy expenditure, and apoptosis processes by Z. P. Belousova; I. S. Lipatov; I. A. Potapova; Yu. V. Tezikov; A. V. Bykov; O. V. Maksimova; E. S. Karnaukhova (297-300).
A series of new N-azolides of 2,4,6-triisopropylbenzenesulfonic acid have been synthesized. Their biological activity with respect to the processes of cell proliferation, energy expenditure, and programmed cell death (apoptosis) has been studied. Convincing evidence is obtained for pronounced immunomodulating and cytoprotecting properties of two compounds (N-imidazolide and N-triazolide of 2,4,6-triiospropylbenzenesulfonic acid), which produce a positive influence directed at pathological states, in particular, cell proliferation, cell energy expenditure, and apoptosis.
Keywords: N-imidazolide, N-1,2,4-triazolide, N-benzimidazolide, and N-benzotriazolide of 2,4,6-triisopropylbenzenesulfonic acid; immunomodulating, cytoprotective properties; proliferation; energy expenditure; apoptosis

Synthesis and antimicrobial activity of 1-[4-(1-adamantyl)phenoxy]-3-amino-2-propanol by Yu. V. Korotkii; N. A. Vrynchanu; Yu. N. Maksimov; M. O. Lozinskii (301-304).
Reaction of 1-[4-(1-adamantyl)phenoxy]glycidyl ether with amines leads to the corresponding 1-[4-(1-adamantyl) phenoxy]-3-alkyl(dialkyl)amino-2-propanols. The proposed structures of the synthesized compounds are confirmed by IR and NMR spectroscopy. Substances tested by the serial dilution method exhibited a high level of antimicrobial activity.
Keywords: adamantane; aminopropanols; epoxide; antibacterial activity; antifungal activity

The title compounds VIa – j have been prepared from the lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid I. The lead molecule was converted to hydrazide III via acid chloride II, which on reaction with different substituted aromatic aldehydes a – j afforded Schiff base, and on further structural variation of the Schiff base furnished the final compoundsVIa – j (Scheme I). The synthesized compounds were tested for their antibacterial and antifungal activity (MIC) in vitro against two Gram-positive bacteria, S. aureus and S. pyogenes, and two Gram-negative bacteria E. coli and P. aeruginosa, and fungi C. albicans, A. niger, and A. clavatus, taking gentamycin, ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and griseofulvin as standard drugs. All the synthesized compounds have been established by elemental analysis amd IR and NMR spectral data.
Keywords: antibacterial; antifungal activity; fluoroquinolone; N-methylpiperazine; thiazolidinone

Aseries of 1,3-di(2-substituted 10H-phenothiazin-10-yl)propan-1-one (IVa – p) was synthesized by using the phenothiazine framework through a three-carbon atom chain by condensation of the different chlorides of 3-(10H-phenothiazin-10-y1)propionic acid (IIIa – d) with 2- substituted phenothiazines (Ia – d), and the structures of these compounds were confirmed by IR, 1H NMR, mass, and elemental analysis. The newly synthesized compounds were evaluated for antimicrobial activity.

Synthesis and biological evaluation of some new spiro derivatives of barbituric acid by Shailee Kesharwani; Nitendra K. Sahu; D. V. Kohli (315-319).
A series of spiro-barbiturates has been synthesized using an appropriate synthetic route and characterized by elemental analyses and spectral data. All the synthesized compounds were screened in vivo for their anticonvulsant activity and acute toxicity. All the synthesized compounds were administered at doses of 30, 100, 200, and 300 mg/kg body weight and the anticonvulsant activity was noted at 1 h time intervals after drug administration. All the synthesized compounds were evaluated for the phenobarbitone-induced hypnosis potentiation test. All the synthesized compounds tested showed sedative-hypnotic and anticonvulsant activity, but spiro compounds 2 and 3 were the most potent sedative hypnotic and anticonvulsant agents.

Quantitative determination of flavonoids from the aerial part of greater knapweed (Centaurea scabinosa L.) by M. S. Lar’kina; T. V. Kadyrova; E. V. Ermilova; E. A. Krasnov (320-323).
Quantitative determination of flavonoids from the aerial part of greater knapweed (Centaurea scabiosa L.) has been carried out by differential spectrophotometry in combination with a modified method of forming flavonoid complexes with aluminum chloride in HCl. Depending on the plant collection site, the quantitative content of flavonoids in the aerial part of greater knapweed varied within 1.3 – 2.0% (calculated as rutin). The random error of measurement did not exceed 3% at a confidence probability of 0.95. The systematic error of the proposed metohd did not exceed the error of determination. The accumulation dynamics of flavonoids in the aerial part of greater knapweed during the 2006 vegetative peroid have been tracked for plants growing in Tomsk and Kemerovo regions. The maximum content of flavonoids (1.70 ± 0.04% calculated as rutin) was observed in the stage of full flowering, which is therefore the optimum period for collecting the aerial part of the plants for the maximum yield of flavonoids. The maximum amount of flavonoids was accumulated in leaves (1.96 ± 0.04%), which is somewhat greater than the content of flavonoids in the entire aerial part of greater knapweed (1.70 ± 0.04%).
Keywords: Centaurea scabiosa L.; flavonoids; differential spectrophotometry

Quantitative estimation of flavonoids in the vegetative and reproductive organs of showy tick trefoil (Desmodium canadense) by G. Puodziunene; V. Janulis; L. Ivanauskas; A. Lukosius; Z. Barsteigene; V. Ribokaite (324-327).
Qualitative and quantitative analysis of flavonoids in the vegetative and reproductive organs of showy tick trefoil [Desmodium canadense (L) DC., Fabaceae] herbs (stems, leaves, buds, inflorescences, legumes, and seeds) collected at various stages of vegetation at the Department of Medicinal Herbs of the Kaunas Botanical Garden (Vytautas Magnus University) was performed using HPLC techniques. A total of 15 flavonoids of aglycon and glycoside nature including apigenin, apigenin-7-O-glycoside, luteolin, rutin, vicenin-2, vitexin, isovitexin, vitexin rhamnoside, orientin, homoorientin, quercitrin, quercetin, hyperoside, astragalin, and kaempferol were identified. Among the vegetative organs, the maximum amount of flvaonoids was found in leaves, where the total content of flavonoids was 23,952.2 mg/g in the budding phase and reached a maximum of 25,472.71 mg/g (2.55%) at the ripening phase (1.88 times greater than in herbs at the beginning of flowering). In stems, the maximum amount of flavonoids (2,318.0 mg/g) was accumulated in the budding phase while the minimum (1,910.77 mg/g) was found at the beginning of seed ripening phase. the maximum amount of flavonoids in the reproductive organs was found in inflorescences, where the total content of flavonoids was 8,164.1 mg/g at the budding phase, reached a maximum of 15,226.39 mg/g in the full flowering phase, and then gradually decreased. Legumes at the beginning of ripening contained 8,892.3 mg/g flavonoids while seeds in the fully ripened phase contained only 4,270.1 mg/g (0.43%) flavonoids. Among the individual flavonoids, orientin and homoorientin predominated in all cases. Thus, not only the inflorescences of showy tick trefoil but also leaves can be used as medicinal raw material. The optimum time for collecting leaves for the raw material is from the budding phase until the beginning of fruit ripening.
Keywords: showy tick trefoil (Desmodium canadense); herbs; flavonoids; vegetative organs; reproductive organs; vegetative phase

Results of optimization of the composition and technology of solid gelatin capsules with a dry fucus extract (DFE) containing fucoidan (polysaccharide of fucus algae) are presented. The Box-Wilson method of mathematical planning of experiments was used to determine the optimum conditions of DFE granulation in a mixture with lactose. DFE granules were obtained under the established optimum conditions and their processing properties were determined. The final medicinal preparation in the form of DFE 0.2 g pellets in solid gelatin capsules showed high indices of quality and a high degree of bioavailability in in vivo experiments.
Keywords: fucoidan; lactose; brown seaweed; Fucus vesiculosus; dry extract; mixed granulation; hygroscopicity

Kinetic method for studying the antiradical activity of medicinal plant extracts by V. A. Volkov; N. A. Dorofeeva; P. M. Pakhomov (333-337).
A kinetic method for studying the activity of medicinal plant extracts with respect to the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical is developed. The initial rate of DPPH decay under standard conditions is suggested and theoretically justified as a kinetic parameter to compare the antiradical activity of extracts. A 10- to 150-fold decrease of the DPPH reaction rate with antioxidants (AO) of plant extracts in aqueous EtOH is achieved by adding acids to the reaction medium. The reaction at the optimum acid concentration decreases with increasing acid strength. Using this approach, the influence of organic acids extracted from the plant material on the results can be eliminated by adding stronger acids. The noise level on the kinetic curves and, therefore, in the measurement error, is decreased by smoothing the data using a general equation of the kinetic curve obtained using the Microcal Origin 7.0 and SYSTAT TableCurve 2D 5.01 software. It is found that the extent of DPPH conversion in the interval from 0 to 60% after the first 30 min depends linearly on the initial AO concentration.
Keywords: antiradical activity; antioxidants; 2,2-diphenyl-1-picrylhydrazyl (DPPH)

Antiradical activity of fruit juices in reactions with diphenylpicrylhydrazyl by N. I. Belaya; A. N. Nikolaevskii; T. N. Ivleva; O. G. Sheptura (338-340).
The antiradical activity (ARA) of fresh squeezed juices and those reconstituted from concentrate was examined in reactions with diphenylpicrylhydrazyl (DPPH). Fresh squeezed juices contain a higher amount of phenolic substances and exhibit stronger ARA. The maximum ARA among the studied fruit juices was observed for orange and grapefruit juices. The ability to discolor aqueous EtOH solutions of DPPH can be used as a test for primary quantitative evaluation of the ARA of fruit juices.
Keywords: antiradical activity; diphenylpicrylhydrazyl; phenolic compounds

Polysaccharide complexes with metal cations: structure and application (a review) by O. V. Sibikina; A. A. Iozep; A. V. Moskvin (341-345).
Data available in the scientific research and patent literature on the structure and application of polysaccharide complexes with metal cations are reviewed for the period 1990 – 2005.
Keywords: polysaccharides; complexes with metal ions

Adsorption of some organic compounds on the new natural biologically active substance shunlite by O. Yu. Vasil’eva; G. B. Tikhomirova; A. S. Berlyand (346-349).
The adsorption of phenol, methylene blue, cyanocobalamin, and bovine serum albumin from aqueous solutions (modeling the stomach and duodenum environment) on the new natural biologically active substance shunlite has been studied. The sorption capacity of shunlite for these substances increases in the order bovine serum albumin < phenol < cyanocobalamin < methylene blue. Sorption isotherms are presented. Conclusions about its mechanisms are made.
Keywords: shunlite; toxic organic substances; sorption; Langmuir equation; distribution coefficient; sorption mechanism

Toxicological characterization of new medicinal forms of hiporamin (gel and liniment) by L. V. Krepkova; V. V. Bortnikova; M. A. Dzhavakhyan; T. A. Sokol’skaya (350-351).
New soft medicinal forms (0.5% gel and liniment) of the antiviral phytodrug hiporamin have been developed on the basis of arespol. Experimental toxicological characterization of the new preparations was carried out on Chincilla rabbits by means of eight-week applications onto depilated back skin areas. Both gel and liniment of hiporamin were well tolerated by the animals with no manifestations of general toxicity and local irritant action.
Keywords: hiporamin; gel; liniment; local irritant action

Development and in vitro biopharmaceutical evaluation of a dihydroquercetin microemulsion by M. V. Karlina; O. N. Pozharitskaya; A. N. Shikov (352-354).
Dihydroquercetin (DHQ) is a readily available compound with a broad spectrum of biological activity that makes development of new drug forms based on this compound imperative. In particular, it exhibits capillary-protective, anti-oxidant, and anti-inflammatory effects. Microemulsions are promising systems for delivering drugs and can increase their biological availability and provide their controlled release. A water-in-oil microemulsion containing DHQ (2%), surfactant (Tween 80), cosurfactant (propyleneglycol), an oil phase (Labrafil M 1944 CS), and water was prepared. Physicochemical parameters (particle size, viscosity, refractive index, denisty, and pH) and the in vitro release of DHQ were studied by the paddle-over-disk method in systems modeling local transdermal application and the paddle method in systems modeling oral application. Release rate constants were calculated. The proposed microemulsion ensures uniform prolonged release of the active substance.
Keywords: dihydroquercetin; microemulsion; biopharmaceutical evaluation; bioaccessibility

Ion-exchange sorption of mineral impurities from enzyme-containing solutions by P. A. Yavich; L. I. Churadze; T. A. Rukhadze; M. B. Kakhetelidze; N. D. Gagua; L. I. Zhvaniya (355-356).
The possibility of using ion-exchange techniques for purifying latex enzymes and extracting the excess of mineral compounds has been studied using papaya latex as an example. Mixed bed ion-exchange has been used in an apparatus with KU-2 cation exchanger in the H+-form and EDE-10P anion exchanger in the OHform. Optimum processing parameters (component ratio, particle size, mixing rate, etc.) have been chosen. This allowed the ash content to be reduced to the necessary level. The purified latex enzyme solutions will be used in the technology of Karipazim preparation.
Keywords: enzyme; purification; ion-exchange resins

Optimization of the spectrophotometric method for quantitative determination of ascorbic acid in medicinal forms by E. V. Zykova; O. V. Ostrovskii; V. G. Zaitsev; G. P. Dudchenko (357-359).
A modified method for determination of ascorbic acid is developed. Its metrological characteristics are determined. Two procedures for quantitative determination of ascorbic acid in medicinal forms are compared. The modified method has advantages over the traditional titration method. The modified method can be applied to quantitative determination of ascorbic acid in injectable medicinal forms.
Keywords: modified method for determination of ascorbic acid; substance analysis; medicinal forms; sodium phosphomolybdic acid

Controlled-potential coulometry for the analysis of carboxylic acids by S. G. Abdullina; O. A. Lira; G. K. Ziyatdinova; G. K. Budnikov; N. P. Kodryanu (360-362).
Coulometric titration methods with potentiometric indication of the end-point have been developed for determining benzoic, salicylic, nicotinic, and ascorbic acids in various pharmaceutical dosage forms, liniments, and aqueous alcohol solutions. The relative standard deviation was within 0.01–0.02.
Keywords: carboxylic acids; controlled-potential coulometry; electrogenerated hydroxide ions; pharmaceutical analysis

Differential scanning calorimetry as a screening technique in compatibility studies of acyclovir extended release formulations by F. Barboza; D. D. Vecchia; M. P. Tagliari; M. A. S. Silva; H. K. Stulzer (363-368).
Acyclovir (ACV) has been investigated during the past years, mainly due to its antiviral activity. Assessment of possible incompatibility between an active component and different excipients along with the evaluation of thermal stability are crucial parts of a normal study prior to the final formulation setting of a medicine. Thermal analysis studies were used as important and complementary tools during pre-formulation to determine the compatibility of drug-excipients with the purpose of developing an acyclovir extended release formulation. Fourier transform infrared spectroscopy (FT-IR) and x-ray powder diffraction (XRPD) analyses were also realized. The results showed that ACV only exhibited interaction that could influence the stability of the product in the binary mixtures of ACV/magnesium stearate.
Keywords: acyclovir; compatibility studies; extended release formulations

Development and validation of HPLC method for analysis of some antiretroviral agents in their pharmaceutical dosage forms by Abhinav Garg; Love Kumar Soni; Satish G. Kaskhedikar; Kona S. Srinivas; Loveraj Singh; Kamal K. Gupta; Dhananjay Dwivedi (369-374).
Anew analytical method using reversed-phase high performance liquid chromatography (HPLC) has been developed for analysis of four antiretroviral molecules Lamivudine, Abacavir, Zidovudine, and Efavirenz. The proposed method was validated in accordance with the ICH Q2 (R1) validation guidelines by determining its selectivity, linearity, accuracy, and precision. Based on the results, the method is an effective choice to analyze these drugs in their single and combined pharmaceutical dosage forms.
Keywords: HPLC; analytical method development; HIV; antiretroviral agents