[Possibilities of effective interaction in the system pharmacovigilance at registration of medicinal undesirable reactions at patients of the senior age groups.]

In recent years, complications of drug therapy are an important medical problem. Data on adverse drug reactions (ADR) in patients of older age groups were analyzed. The object of the study was notification cards for unwanted reactions received from medical organizations of the Irkutsk region for period 2009-2020 years. The Narangio scale was used to assess the causality between ADR and medicines. Of the 1021 ADR notifications in patients over 65 years of age, 2/3 (668) are presented with ADR notifications in women, 353 (34,6%) in men. The presence of background diseases was registered in 915 notifications (89,6%). There were no gender differences except for a higher incidence of chronic obstructive pulmonary disease in men (7,2 and 3,5% respectively, p<0,05) and diabetes mellitus in women (14 and 3,5% respectively, p<0,05). ADRs for antibacterial agents amounted to 31,8%, drugs for the treatment of cardiovascular diseases - 10,5%, cases of therapeutic inefficiency - 5,1%. The ADR data statement was in line with the recommended form of 76%. The most common filling defect was incomplete patient information. The validity of the Narango causation was high. The deadlines for reporting data were observed in 89,1%. For effective interaction in the pharmacovigilance system, it is necessary in each medical organization to constantly inform about the procedure for pharmacovigilance, types of ADRs, the rules for their detection and the timing of data reporting. The work should be supervised by a trained specialist.

Laser induced white emission of diamond.

Laser-induced white emission of diamond was investigated under irradiation with a focused beam of an infrared laser diode. It is a surface-related coherent emission, characterized by an excitation threshold and an exponential dependence on pumping laser power. The mechanism of white emission is discussed in terms of multiphoton ionization of carbon atoms in an irradiated spot. The excitation power dependence of white emission intensity has demonstrated hysteresis loop behavior. This phenomenon could be useful in new broadband laser sources and optical information storage.

Systematic Analysis of Mobile Genetic Elements Mediating ß-Lactamase Gene Amplification in Noncarbapenemase-Producing Carbapenem-Resistant Enterobacterales Bloodstream Infections.

Noncarbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem-resistant Enterobacterales (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole-genome sequencing was used to elucidate carbapenem nonsusceptibility determinants in Enterobacterales bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem nonsusceptible Enterobacterales (CNSE) mechanisms (i.e., isolates with carbapenem intermediate resistance phenotypes or greater) through a combination of phylogenetic analysis, antimicrobial resistance gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%), whereas 25.3% (20/79) were Enterobacterales with intermediate susceptibility to carbapenems (CIE), and 22.8% (18/79) were carbapenemase-producing Enterobacterales (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum ß-lactamase (ESBL) genes (Wilcoxon Test; P-value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6×; n = 17) and K. pneumoniae (median CNV = 3.2×, n = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., ompC/ompF or ompK36/ompK35). Completely resolved CNSE genomes revealed that IS26 and ISEcp1 structures harboring blaCTX-M variants along with other antimicrobial resistance elements were associated with gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE-mediated ß-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS26 translocatable units, or segmental duplication, typically due to ISEcp1 transposition units. Non-CP-CRE strains were the most common cause of CRE bacteremia with carbapenem nonsusceptibility driven by concurrent porin loss and MGE-mediated amplification of blaCTX-M genes. IMPORTANCE Carbapenem-resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing Enterobacterales (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating ß-lactamase gene amplification. By generating complete genomes of 65 carbapenem nonsusceptible Enterobacterales (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.

Efficiency of Measurements of Hepatitis C Virus RNA.

Hepatitis C virus loading was evaluated using modifications of PCR product detection: terminal point fluorescent detection, real time assay, and agarose gel electrophoresis. The advantages and flaws of the real time PCR and electrophoretic detection of amplification products for evaluation of the quantity of virus particle copies are evaluated.

[Isolation and preliminary characterization of carotenoids from pink-pigmented methylotrophs].

An effective method was developed for complete removal of pigments from the cells and solvent mixture for further separation of pigments using thin layer chromatography on silica gel. Carotenoid samples that have been obtained in this way are of good purity for further investigations. Carotenoid pigments of pink-pigmented facultative methylotrophic bacteria Methylobacterium have been characterized. These carotenoids are represented mainly by xanthophylls, particularly hydroxycarotenoids. Strains M. fujisawaense B-3365 and M. mesophilicum B-3352 also have nonpolar carotenes in a small amount. Physico-chemical properties of carotenoids have been studied.

[Biochemical mechanisms of resistance to a new antineoplastic agent amin(cyclopeptidylamin)-S-(-)-malatoplatinum (II) (cycloplatam)]. / Issledovaniia biokhimicheskikh mekhanizmov rezistentnosti k novomu protivoopukholevomu preparatu amin(tsiklopentilamin)-S-(-)-malatoplatine (II) (tsikloplatamu).

The "in vivo" effect of cycloplatam on DNA synthesis in leukemia P388/o (parent strain), P388/c (cycloplatam-resistant strain) and in some organs of tumour-bearing mice, such as spleen, kidney, gastrointestinal mucosa (GI mucosa) and bone marrow, has been studied. Cycloplatam induced a deep and stable inhibition of DNA synthesis in leukemia cells and kidney. DNA synthesis in normal dividing cells (GI mucosa, bone marrow, spleen) was shown to recover more rapidly than in leukemia cells and kidney after cycloplatam treatment. The GSH level was increased tenfold in leukemia P388/c cells in comparison with P388/o. The glutathione peroxidase and glutathione reductase activities were increased twofold in the resistant strain in comparison with the parent strain, while the activity of glutathione-S-transferase showed a 1.5-fold increase. Administration of cycloplatam to tumour-bearing mice caused a marked increase of the GSH level in the both leukemia strains. Alterations in GSH-dependent enzymes following cycloplatam therapy were expressed in a lesser degree. These data indicate that GSH and GSH-dependent enzymes may play an important role in the resistance of P388 leukemia cells to cycloplatam.

New tumoricidal semisynthetic ether phospholipid, plasmanyl-(N-acyl)ethanolamine (PNAE(s)) and enhancement of its tumoricidal activity by calcium ions.

Recently we described a novel, nontoxic, natural ether phospholipid with selective antitumor activity, 1-0-alkyl-2-acyl-sn-glycero-3-phospho-(N-acyl)ethanolamine, i.e., plasmanyl-(N-acyl)ethanolamine (PNAE), isolated from ischemic tissue of chick embryo. The chemical structure of PNAE has been confirmed by partial synthesis. The semisynthetic preparation PNAE(s), 1-0-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine, exhibited tumoricidal activity against human tumor cells T24 and mouse sarcoma cells Mcll as well as in vivo against murine sarcomas S-180 and Mcll. PNAE(s) selectively destroyed tumor cell membranes as has been demonstrated by scanning electron microscopy. The antitumor activity of PNAE(s) in vitro and in vivo was significantly enhanced by Ca2+ ions. These results may be explained by selective damage of tumor cell membranes by PNAE(s), increasing also the tumor cell membrane permeability for exogenous Ca2+ ions and altering the intracellular calcium homeostasis in tumor cells. By increased concentration of Ca2+ in tumor cell cytosol selective damage and lysis of tumor cells was induced. The combined use of parenteral administration of PNAE(s) and peroral doses of calcium gluconate may provide a new approach to enhancement of antitumor activity of PNAE(s) by Ca2+ in a very selective and nontoxic antitumor therapy.

Cycloplatam and oxoplatin--the new antitumor platinum compounds of the second generation.

Cycloplatam, ammine(cyclopentylamino)-S-(-)-malatoplatinum(II), and oxoplatin, cis-dichloro-diammine-trans-dihydroxoplatinum(IV), were first synthesized in the USSR. Their antitumor properties were found at the All-Union Cancer Research Center of the Academy of Medical Sciences of the USSR by the authors of this article. Both new drugs are less toxic than cisplatin and free from nephrotoxicity. Both new compounds exceed cisplatin considerably in their action on plasmacytoma MOPC-406 and in complete cure of mice. Cycloplatam and oxoplatin have no cross-resistance with cisplatin and with the alkylating agent sarcolysin. As to antitumor activity cycloplatam exceeds carboplatin, (cyclobutane-I,I-dicarboxylato)-diammineplatinum(II), oxoplatin--iproplatin, cis-dichloro-bis (isopropylamine)-trans-dihydroxoplatinum(IV). Both drugs have been handed over for preclinical study.

The antitumor activity of oxoplatinum.

A coordination complex cis-dichlorodiamminedihydroxoplatinum (IV) (oxoplatinum) was first synthesized in the USSR by Chugaev and Khlopin in 1927 [3]. Its marked antitumor properties were revealed by one of the authors of this article at the All-Union Cancer Research Center of the Academy of Medical Sciences of the USSR. The paper gives data on the antiblastic and side effects of oxoplatinum and also on the results of pharmacokinetic studies of the drug. Particular attention was paid to the similarity and differences of biological properties of oxoplatinum and cis-dichlorodiammineplatinum(II) (DDP) which has found wide use in oncological practice. It has been established that, on principle, oxoplatinum differs from DDP in action on the body and tumors. The new drug is 10 times less toxic than DDP. Oxoplatinum has a wide spectrum of antineoplastic action resulting in marked inhibition of growth of solid and ascitic forms of transplantable tumors. The drug has a longer duration of antitumor effect after the end of the therapeutic course. An important property of oxoplatinum is its high therapeutic index. The new drug manifests high antitumor activity with different ways of its administration into the body. Oxoplatinum in therapeutic doses does not produce necrotic lesions in the kidneys. The new drug exerted no cross-resistance with DDP and the alkylating antitumor agent sarcolysin. At the present time oxoplatinum is undergoing preclinical investigation.

[Antitumor action of cis-dichlorodiammineplatinum(II) and the effectiveness of a combination with sarcolysine]. / Protivoopukholevoe deistvie tsis-dikhlorodiaminplatiny (II) i éffektivnosti kombinirovaniia s sarkolizinom.

Therapeutic properties of cis-dichlorodiammineplatinum (II) were studied on 12 strains of transplantable tumors and leukemias in mice. The compound is characterized by a wide spectrum of antitumor action. The greatest effect was gained in adenocarcinoma of the lage intestine (strain AKATOL), proventricular cancer (strain PRG) and adenocarcinoma of the mammary gland (strain Ca-755). The terms of survival in mice with leukemia (strain La and L-1210) and ascites hepatoma 22 are increased considerably. In some L-1210 animals the complete cure was noted. Cis-dichlorodiammineplatinum (II) may be effectively combined with sarcolysin. Much greater antitumor effect was obtained on 3 tumor strains (AKATOL, Ca-755 and sarcoma 37) with the combined therapy than with each drug used separately. The histological study of Ca-755 during chemotherapy indicated that immunocompetent cells of the organism play an important role in the mechanism of antitumor action of the platinum complex. This is manifested in the development of intensive lymphohistiocytic reaction around and inside the tumor. A damage to the convoluted tubules of the kidney and intestinal villi is one of the main adverse side-effects of the combination.