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Biomedical subjects

V A Ray

Publications and source records attributed to V A Ray.

17 recordsLinked to original sources
PubMed1993

Preclinical toxicology studies with azithromycin: genetic toxicology evaluation.

Azithromycin was subjected to a series of three in vitro and one in vivo genetic toxicology assays for the detection of drug-associated gene or chromosomal effects. In the Ames Salmonella typhimurium tester strains TA1535, TA1537, TA98 and TA100, the presence of azithromycin was not associated with any increase in the number of his- revertants. Urine from mice dosed with up to 200 mg/kg of azithromycin also had no effect on the number of revertants in these same strains suggesting the absence of mutagenic excretory products following oral exposure. When tested up to the cytotoxic level of 240 micrograms/ml, azithromycin caused no increase in the mutant frequency at the thymidine kinase locus of L5178Y/TK cells. Both the mammalian and microbial gene mutation assays included the presence of rat-liver postmitochondrial (S9) fraction for the detection of mutagenic biotransformation products. Mitogen-stimulated human lymphocytes cultured in the presence of 2.5-7.5 micrograms/ml azithromycin for 24 h or 30.0-40.0 micrograms/ml azithromycin for 3 h in the presence of rat S9 had chromosomal aberration frequencies that were no different than negative control cells even though slight to moderate mitotic suppression was associated with these concentrations. In vivo assessment of this compound was completed in male and female mice with a single oral dose of 200 mg/kg followed by sacrifice at 6, 24 or 48 h later and metaphase analysis of bone marrow for chromosomal aberrations. No statistically significant elevations of chromosomally aberrant cells were found. We conclude that azithromycin does not cause gene mutations in microbial or mammalian cells, or chromosomal aberrations in cultured human lymphocytes or in mouse bone marrow in vivo.

Animals↗
PubMed1987

An approach to identifying specialized batteries of bioassays for specific classes of chemicals: class analysis using mutagenicity and carcinogenicity relationships and phylogenetic concordance and discordance patterns. 1. Composition and analysis of the overall data base. A report of phase II of the U.S. Environmental Protection Agency Gene-Tox Program.

This report of the Gene-Tox Assessment Panel is a compilation of data that documents the chemical testing efforts in genetic toxicology through mid-1979. It thus provides an historical perspective of the major efforts in this field and the utility of test models. The total number of chemicals tested in assays reflects chemical availability, commercial interest in specific structural types, the ease or difficulty in assay performance, as well as methodological development resulting from testing experience. Other factors that have been important in assay selection and utility are the perceptions of relevance to hazard evaluation of chemicals and the role that genetic factors may have in other disease states as well as in heritable defects. The phylogenetic diversity of test systems attests to the tremendous effort that has been applied to the testing and evaluation of the effect chemicals can have on genetic structure. The data also illustrate the fact that certain chemicals have an intrinsic capability to alter the genetic structure of cells of diverse biological origin in an heritable manner, whereas others do not. Any attempt to summarize and analyze a data base of this magnitude is a formidable task that would be almost impossible without a computer capability. A computerized system of analysis has been developed at the Environmental Mutagen Information Center (EMIC) that makes it possible to examine the performance of any particular assay in any of 30 chemical classes and to make comparisons with all the other assays individually or in designated groupings. Components of this system include: A distribution of the 2622 chemicals into 30 chemical classes with results of testing in each class. A tabulation of assay results showing the total numbers of chemicals tested, with their definitive and nondefinitive results. A subdivision of assays and results of testing into four major groups: gene mutation, chromosomal aberrations, other genotoxic effects, and in vitro cell transformation assays. These major groups are further subdivided into phylogenetic categories and type of assay. A system of analysis of results utilizing mutagenicity and carcinogenicity comparisons and phylogenetic concordance and discordance. The major utility and/or benefit of this compilation will be derived from a chemical class by chemical class comparative analysis of individual assay performance. Obviously, the data base will serve as a resource for safety evaluation of chemicals through structural correlations and biological end point analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1980

Point mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells. II. Test validation and interpretation.

The L5178Y Mouse Lymphoma TK assay was studied extensively to determine if this mammalian cell assay for gene mutations at the thymidine kinase (TK) locus could provide valid, interpretable determinations of mutagenic potential, and whether this information is of value in the safety evaluation of chemicals. We first determined that test-derived TFTR mutants were phenotypically stable, possessing little or no thymidine kinase activity as measured by labeled thymidine uptake, but demonstrating 100% cross resistance to bromodeoxyuridine. Common solvent vehicles such as acetone, dimethylsulfoxide and ethanol were shown to produce little cytotoxicity and no mutagenic activity when present at 1% levels. Out of a total of 10 noncarcinogens tested, all were negative when results were analyzed by a 2-sample loge t test on control and treated mutant count means. Of the 13 putative animal carcinogens tested, 10 were positive, 2 were negative (auramine O and sodium phenobarbital), and 1 showed sporadic activity (hydrazine sulfate) in the TK assay on the basis of test-derived t statistics. 2 compounds, 1,2-epoxybutane and ICR 191, which have been described as Ames positive non-carcinogens, were also positive in the TK assay. Although this sampling of a total of 29 compounds is insufficient for precise estimations of expected false-positive or false-negative frequencies, these data indicate the TK assay can be expected to detect a majority of carcinogens as mutagens including some missed by more established point-mutation assays.

Animals↗
PubMed1980

An evaluation of the Escherichia coli WP2 and WP2 uvrA reverse mutation assay.

The methodology and status of the Escherichia coli WP2 reverse mutation system as it applies to chemical screening were reviewed using the available published literature. 163 documents were reviewed by the Working Group. These included abstracts, research articles, review articles and publicly available contract and grant final reports. From this group, 115 documents were rejected for critical evaluation by the Working Group. 48 documents were reviewed and the test results summarized. The general conclusion of the Working Group was the the E. coli WP2 reverse mutation system is a valuable tool for mutagenesis research, but that there is no evidence from a review of the literature that this assay will contribute significantly to the results obtainable from careful application of the Ames Salmonella assay. Another review of the role of this system in general screening may be warranted after more research and development with the plasmid-containing WP2 derivatives.

DNA Repair↗
PubMed1979

Point mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells. I. Application to genetic toxicological testing.

We have systematically evaluated the mouse lymphoma TK+/- leads to TK-/- mutagenesis assay to determine if this somatic-cell test system would be a useful addition to the routine screening battery already used in our laboratory for the detection of chemical mutagens. During these investigations we observed that, with certain modifications of the basic assay, mutagenicity data could be obtained in as little as 9 days once the relative cytotoxic properties of the test substance were known. By improving the culturing conditions, we were able to reduce the serum requirements by as much as 50--75% without appreciably altering either cell viability or the recovery of chemically-induced mutants. Phenotypic stability of test-derived trifluorothymidine resistant (TFTR) mutants was confirmed by demonstrating cross-resistance to bromodeoxyuridine and concomitant sensitivity to methotrexate (THMG) in TFTR cells grown for 20 generations under non-selective conditions. While reduced growth rates resulting from temporary cell-division delay in treated cells is probably not a contributing factor to the observed mutation frequencies, only TFTR colonies which formed large distinct colonies in the presence of trifluorothymidine were clearly phenotypically stable mutants when spontaneous mutants were isolated and verified. When a non-mutagen, a weak mutagen, and a well-established mutagen were compared at equitoxic doses under these modified conditions, clear quantitative differences were seen in the respective mutation frequencies induced by these 3 types of agents. With these technical modifications, we feel this assay is both reliable and amenable to the screening of diverse chemical compounds for point-mutational activity in a mammalian cell.

Animals↗
PubMed1975

A comparative study on the genetic effects of hycanthone and oxamniquine.

Oxamniquine (UK-4271; 6-hydroxymethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetrahydroquinoline) is a new schistosomicidal agent currently undergoing clinical investigation in South America. Essentially a complete cure rate against Brazilian Schistosoma mansoni has been seen in adults with a single im dose of 7.5 mg/kg or a single oral dose of 15 mg/kg. These regimens were tolerated without significant toxicity. To assess its mutagenic potential, oxamniquine was examined in a battery of genetic tests designed to detect mutations at the gene and chromosome levels. For comparative purposes, hycanthone, a schistosomicide with extensively studied mutagenic properties, was evaluated in a similar series of tests. Point mutations were measured in a series of histidineless auxotrophs of Salmonella typhimurium in direct plate and host-mediated assays. Gross chromosomal aberrations were assessed in human leucocyte cultures and in bone marrow preparations from drug-treated mice. Effects on germ cells were tested in the dominant-lethal assay. Hycanthone showed significant mutagenic activity in the direct bacterial tests and the in vivo and in vitro cytogenetic assays. No response was detected in the host-mediated or dominant-lethal assays. On the other hand, oxamniquine produced no drug-related mutagenic effects in the cytogenetic, host-mediated, or dominant-lethal tests at doses up to 150 mg/kg administered parenterally. Oxamniquine produced a weak response in the frameshift mutant, TA1538, of Salmonella typhimurium in direct plate tests with and without liver microsomal enzymes. However, this response was achieved only by using a concentration of compound which was several orders of magnitude higher than that required to produce a similar response to hycanthone.

Animals↗
PubMed1975

DD-carboxypeptidase and peptidoglycan transpeptidase from Pseudomonas aeruginosa.

Peptidoglycan transpeptidase and dd-carboxypeptidase have been detected in isolated membranes of Pseudomonas aeruginosa. Cephalosporins and penicillins fail to inhibit the transpeptidase at concentrations as high as 100 mug/ml. dd-Carboxypeptidase, on the other hand, is sensitive to inhibition by beta-lactam antibiotics. The presence of dimethyl sulfoxide in the reaction mixture results in a twofold stimulation of peptidoglycan formation, whereas dd-carboxypeptidase is inhibited approximately 30%. Maximum stimulation of transpeptidase occurs in the presence of both dimethyl sulfoxide and a beta-lactum antibiotic. This is in sharp contrast to the transpeptidase from Escherichia coli, which is sensitive to inhibition by penicillins and cephalosporins.

Acyltransferases↗
PubMed1972

Carbenicillin indanyl sodium, an orally active derivative of carbenicillin.

Carbenicillin indanyl sodium, an orally active derivative of carbenicillin, is active against a broad spectrum of bacterial species. Although the ester has in vitro antimicrobial activity per se when evaluated in Brain Heart Infusion broth, the in vivo antibacterial activity seen in mice and rats reflects primarily the efficient hydrolysis of the ester to carbenicillin. With an acute systemic infection in mice as a test system, orally administered carbenicillin indanyl sodium protected mice against lethal infections produced by Escherichia coli, Salmonella choleraesuis, Pasteurella multocida, Proteus vulgaris, Staphylococcus aureus, and Streptococcus pyogenes. The dose that protected 50% of the animals against each of these infections was comparable to that of parenteral carbenicillin. Against experimental urinary-tract disease in rats produced by E. coli, P. vulgaris, and Pseudomonas aeruginosa, it was again observed that carbenicillin indanyl sodium provided activity comparable to that of parenterally administered carbenicillin.

Animals↗
PubMed1972

Correlation between the binding of beta-lactam antibiotics to Staphylococcus aureus and their physical-chemical properties.

The rate of (14)C-benzylpenicillin (penicillin G) binding to Staphylococcus aureus Oxford cells increased with increasing hydrogen ion concentration. The extent of inhibition of (14)C-penicillin G binding caused by a competing (12)C-beta-lactam antibiotic is a function of hydrogen ion concentration and can be correlated both with net charge of a competing (12)C-molecule and net charge of the S. aureus cell at a given pH. The ability of a beta-lactam antibiotic to compete for (14)C-penicillin G-binding sites can generally be correlated with its hydrophobic nature. It is proposed that, although semisynthetic cephalosporins are chemically less reactive than penicillins, they are superior to benzylpenicillin in their ability to permeate the outer surface of the Staphylococcus cell wall and irreversibly bind to reactive sites.

Anti-Bacterial Agents↗