Regression line analysis of the synergistic effect for the combination of trimethoprim-sulphamethoxazole.
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Biomedical subjects
Publications and source records attributed to K Dornbusch.
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All of 41 naturally occurring coagulase-positive methicillin-resistant strains of Staphylococcus aureus isolated in various laboratories were resistant to several antibiotics and were lipase-negative. Most strains produced hemolysins, and 38 strains produced enterotoxin B. Acriflavine treatment of four strains resulted in elimination of resistance to methicillin and mercury; in one strain, resistance to cadmium was also lost. Production of enterotoxin B and beta-hemolysin was eliminated in all four strains and penicillinase production was eliminated in one strain. In transduction experiments, methicillin resistance and enterotoxin B production were transferred together at a frequency of 0.2 x 10(-8) to 1.1 x 10(-8) by use of ultraviolet-induced phage lysates from naturally lysogenic methicillin-resistant strains. Cotransductions of resistance to mercury and cadmium, as well as production of penicillinase and beta-hemolysin, were obtained to some extent. The extrachromosomal character of these determinants and their possible genetic association are discussed.
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A proposed strategy for the rapid screening of the genotoxic activities of allylic compounds is based on structure-activity relationships elaborated by a battery of quick screening tests. The procedure facilitates the selection of appropriate representatives of this class of compound for subsequent testing, so that both expensive and time-consuming assays and the use of animals can be drastically reduced. The studies have yielded several important results. Allylic compounds with suitable leaving groups have been shown to exert direct genotoxic activity. In the metabolic activation of these compounds the formation of epoxides is clearly of minor importance, playing a role only in the case of 2,3-dichloro-1-propene and some of its homologues, whereas all reactive allylic compounds can be activated to genotoxic alpha,beta-unsaturated carbonyl compounds (acrolein). The most significant factors for genotoxicity are the leaving groups and halogen substituents. Alkyl substituents increase the direct genotoxicity while decreasing the indirect activity (via acroleins).
An oral dose of the combination trimethophim/sulphamethoxazole (160 and 800 mg, respectively) gave concentrations of trimethoprim in seminal plasma that were equal to or higher than that in blood plasma 2--4 hours after intake. Trimethoprim was excreted by both the prostate and seminal vesicles. With a trimethoprim resistant strain it was possible to demonstrate in three patients with subclinical prostatitis that the concentrations of sulphamethoxazole two hours after the oral intake were 20, 26, and 74 microgram/ml in the blood plasma, respectively. This study was carried out on patients who had been on treatment for 2--5 days prior to investigation. In view of published reports on the pH of the fluids from the human prostate and seminal vesicles, respectively, and the importance of the hydrogen ion concentrations for the excretion of lipid soluble substances into the prostatic fluid it was unexpected to find similar concentrations of trimethoprim in both the "prostatic" and "vesicular" fluids. Preliminary studies on the pH of these fluids indicated, however, that they were in the same order of magnitude, i.e. 7.5 to 8.0. The multiglandular origin of the human seminal plasma must be considered in all studied concerning the excretion of drugs into the semen. Many problems related to the excretion of drugs, e.g. organ specificity, kinetics, and influence on organ and spermatozoal functions remain to be investigated.
At the present time, comprehensive metabolism studies of 2,3-dichloro-1-propene (2,3-DCP) have not yet been reported. We have investigated the biotransformation of 2,3-DCP using female Wistar rats in order to elucidate the bioactivation mechanisms. 175 mg/kg, 1,3-14C-2,3-DCP in corn oil was administered to a rat. The animal was killed 20 hr later. Approximately 56.7% of the radioactivity was excreted in the urine, 1.6% in the feces, 5.3% was exhaled as unchanged 2,3-DCP, and 0.3% as CO2. 31.3% remained in the organs and the carcass. Three metabolic pathways were established. 1) Conjugation with GSH leading to S-(2-chloro-2-propenyl)mercapturic acid. 2) The P450 induced epoxidation with subsequent rearrangement to highly mutagenic 1,3-dichloroacetone. 1,3-Dichloroacetone was further converted to the dimercapturic acid, 1,3-(2-propanone)-bis-S-(N-acetylcysteine). 3) The hydrolysis to 2-chloroallyl alcohol followed by alcohol dehydrogenase catalyzed formation of highly mutagenic 2-chloroacrolein. The 2-chloroallyl alcohol is excreted directly in the urine and as the glucuronide. 2-Chloroacrolein is further oxidized to 2-chloroacrylic acid which is also excreted in the urine.