Volume 52, Nº 11 (2019)
- Ano: 2019
- Artigos: 14
- URL: https://journals.rcsi.science/0091-150X/issue/view/15291
Molecular-Biological Problems of Drug Design and Mechanism of Drug Action
Chemical Enhancers or Transcutaneous Conductors: Transcutol
Resumo
The concept of enhancers or transcutaneous conductors and their classification and mechanism of action are discussed. Special attention is paid to transcutol, a conductor with pronounced solubilizing and penetrating properties that facilitates the accumulation of locally applied medicines in the skin lipid layer without perturbing its structure. The transcutaneous action effectiveness of chemical enhancers is shown to depend on not only the structure and concentration but also the physicochemical characteristics of the penetrating drugs. Diffusional transport in the stratum corneum and the ability to monitor the occurring processes can be used to optimize the design of drugs for transcutaneous targeted delivery.
Article
Comparative Pharmacokinetics and Biodistribution of Etoposide in a Polymer Dosage Form and as Free Drug Substance
Resumo
A polymer dosage form of etoposide (PFE) was obtained as submicron particles based on the copolymer of lactic and glycolic acids (PLGA). Pharmacokinetics and biodistributions of etoposide in rat blood and organs after a single i.p. injection of the polymeric form and etoposide drug substance at doses of 10 mg/kg (of active ingredient) were compared and showed that absorption and elimination of etoposide from rat organs slowed if the PFE was used. The increases of T1/2 and MRT and decreases of Kel, Cmax/AUC(0 – 48), and Cl were indicative of this. Liver and lungs had the greatest tissue availability (ft) for the PFE. Etoposide accumulation in tumor tissue was studied after a single i.p. injection of PFE and etoposide drug substance at doses of 25 mg/kg to mice with grafted Ca755 murine breast adenocarcinoma. The etoposide distribution coefficient between blood and tumor tissue after 1 and 24 h was greater for the PFE, indicating the accumulation of etoposide in tumor tissue was greater if the PFE was used.
Antitumor Activity and Toxicity of Olivamide Dosage Form, a New Semi-Synthetic Olivomycin a Derivative
Resumo
Methods for selective chemical modification of the antibiotic olivomycin A (OA) were developed at G. F. Gause Institute of New Antibiotics. The compound with the highest activity against various tumor cell lines was selected from a series of OA analogs. The aim of the work was to study the antitumor activity and toxicity of a dosage form of this compound, i.e., olivamide. Antitumor activity was studied in four syngenic grafted murine tumors. Chronic toxicity was assessed in experiments with rats that determined the animal body mass, clinical and biochemical blood analysis, urinalysis, electrocardiography, and structures of internal organs. The preparation exhibited high antitumor activity and displayed dose-dependent nephro- and hepatotoxic properties.
Synthesis and Anti-Inflammatory Activity of Tyrosol and Its Structural Analogs
Resumo
The anti-inflammatory activity of tyrosol and 12 structural analogs including 3 new compounds was determined. Several structure-activity (anti-inflammatory) relationships were found. Adding a tert-butyl substituent to the aromatic ring and increasing the length of the alkyl chain decreased the anti-inflammatory activity. Pronounced antiulcer activity was found for p-tyrosol.
Synthesis, Antimicrobial Properties, and Toxicity of a Nanobiocomposite Based on Ag(0) Particles and Poly(1-Vinyl-1,2,4-Triazole)
Resumo
The synthesis of a water-soluble polymer nanocomposite with Ag(0) particles encapsulated in a poly(1-vinyl-1,2,4-triazole) matrix is reported. The nanocomposite contains isolated spherical Ag(0) particles sized from 2 to 8 nm that are uniformly distributed in the polymer matrix and have a characteristic plasmonic absorption maximum at 412 nm. The new nanocomposite belongs to marginally hazardous category 4. The structural morphology of animal brain tissue is not disturbed after subacute intragastric injection. The bacteriostatic concentration of the nanocomposite varies in the range 0.5 – 32 μg/mL; bactericidal, 1 – 64 μg/mL.
Antiproliferative Evaluation of (E)-3-(3-(Allyloxy)-2-Methoxyphenyl)-1-(2,4,6-Trimethoxyphenyl)Prop-2-En-1-One as a Novel Apoptosis Inducer Against Prostate Cancer PC-3 Cells
Resumo
(E)-3-(3-(Allyloxy)-2-methoxyphenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one displayed potent antiproliferative activity against the PC-3 cell line. For colony assay, it can inhibit the colony formation at a concentration of 10 μM. Morphological changes of PC-3 cells were determined using DAPI (4′,6-diamidino-2-phenylindole) staining and chromatin condensation. Treatment with this compound at 10 μM induced apoptosis from 2.0% to 30.4% compared with control according to flow cytometry analysis. It also induced the downregulation of apoptosis-related markers Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein). However, treatment with NAC (N-acetyl-L-cysteine) almost completely attenuated chalcone-induced cell inhibition and cell apoptosis in PC-3 cells.
Synthesis of New 6-[4-(2-Fluorophenylpiperazine-1-YL)]-3(2H)-Pyridazinone-2-Acethyl-2- (Substitutedbenzal)Hydrazone Derivatives and Evulation of Their Cytotoxic Effects in Liver and Colon Cancer Cell Lines
Resumo
In this study, seven new 3(2H)-pyridazinone derivatives expected to show cytotoxic activity in liver and colon cancer cell lines were synthesized. Their structures were confirmed by the IR, 1H-NMR, 13C-NMR spectra and elementary analyses. Compunds V1-V7 were tested on HEP3B (liver cancer) and HTC116 (colon cancer) cell lines for cytotoxicity by using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium] proliferation assay. Human fibroblast cells were used as safety control in these tests. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(2-chlorobenzal)hydrazone (compound V3 ) was the most active agent with respect to HEP3B and HTC116 cell lines.
Methods of Microbial Identification During Drug Quality Analysis and Applicability Assessment
Resumo
Rapid and correct identification of microorganisms is an essential part of pharmaceutical analysis. Several phenotypic, genotypic, and proteotypic methods, each of which has its own advantages and limitations, are currently used to identify microorganisms. The aim of the present work was to reveal features and validate the operation of a Vitek 2 Compact 30 bacteriological analyzer (bioMerieux, France), which was based on determining the biochemical properties of microorganisms. The applicability of this method was determined using accuracy, precision, and robustness. Correct results were found in 86% of 396 cases. Results obtained under repeatability and intermediate precision conditions showed no differences. Approaches to molecular and genetic identification of microorganisms isolated from preparations in addition to automated biochemical identification were discussed.
Development of a Quantitative Determination Procedure for Polyphenolic Compounds in Medicinal Plant Raw Material and Medicinal Herbal Preparations Using TLC with Stepwise Elution
Resumo
A cost-effective and rapid procedure to identify and quantify polyphenolic biologically active compounds of plant origin (with gallic acid, tannin, and quercetin as examples) using high-performance thin-layer chromatography (HPTLC) was developed. The optimal TLC conditions were chosen experimentally and justified theoretically with quantitative interpretation of the HPTLC data on a PC. The proposed method was tested using medicinal plant raw materials such as nettle leaves, common oak bark, and sea buckthorn fruit. The procedure could be used for quality control of drug substances, single-component and complex preparations, plant materials, biologically active additives, premixes, food items, and cosmetics.
A Novel UV-Spectrophotometric Method for Simultaneous Estimation of Amlodipine and Captopril
Resumo
An UV-spectrophotometric method for simultaneous determination of amlodipine and captopril has been developed and validated. Simultaneous equation method is applied for the quantification of both drugs, which is based upon the measurement of absorbance at two wavelengths, λmax = 236 and 213 nm for amlodipine and captopril, respectively, in 0.1 N HCl solutions. The calibration curves for amlodipine and captopril are linear in concentration ranges of 0.195 – 100 and 0.39 – 100 μg/mL, respectively. Accuracy of the method is 98 and 99% for amlodipine and captopril, respectively. The inter-day precision for amlodipine and captopril in terms of RSD is 10 and 8%, while the intra-day RSD is 6 and 9%, respectively. Sensitivity of the method in term of the limit of detection for amlodipine and captopril is 0.195 and 0.39 μg, respectively. The method gives 98% reproducible results.
DAD Based Stability Indicating RP-UPLC Method for Simultaneous Determination of Olmesartan Medoxomil and Amlodipine Besylate
Resumo
Stability indicating RP-UPLC-DAD method for simultaneous determination of olmesartan medoxomil (OLM) and amlodipine besylate (AML) in tablet dosage forms has been developed. The method was fully validated, showing satisfactory data for all suitability parameters tested. The study of degradation products showed that OLM and ALM are more stable with respect to thermolysis and photolysis than under other stress-induced degradation conditions. The proposed stability indicating method can be applied in pharmaceutical analysis for drug stability monitoring and quality control.
Search for New Drugs
Polyene Macrolide Antibotic Derivatives: Preparation, Overcoming Drug Resistance, and Prospects for Use in Medical Practice (Review)
Resumo
Series of semi-synthetic polyene macrolide antibiotics (PMAs) that were prepared by chemical modification in original research by the authors are reviewed. Chemical modification, in particular phosphorylation, was shown to produce highly efficacious PMAs with low toxicities and extended spectra of biological activity. The prospects of using liposomal and nano-derivatives of these antifungal antibiotics are discussed. Crucial issues related to the resistance of pathogenic fungi and the expanding distribution of invasive mycoses are identified. Semi-synthetic PMAs are shown to be highly effective at preventing and treating invasive mycoses and opportunistic fungal infections occurring in AIDS patients. Special attention is paid to structure—activity relationships for the semi-synthetic PMAs. Possible mechanisms of action of these compounds on pathogenic fungi are discussed. An automated intellectual information system was developed for selecting the optimal conditions for development, synthesis, and application in medical practice of new PMAs.
Drug Synthesis Methods and Manufacturing Technology
Development of a Dosage Form of the New Antitumor Antibiotic Olivamide
Resumo
Methods for selective chemical modification of the antitumor antibiotic olivomycin A(OA) were developed at GINA. The compound olivamide with advantages over starting OA was selected from series of OA analogs. The goal of the present work was to develop a dosage form of the antitumor semi-synthetic antibiotic olivamide that guaranteed the stability and high specific activity of olivamide drug substance and was designed for further comprehensive preclinical studies.