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Biomedical subjects

R G Micetich

Publications and source records attributed to R G Micetich.

At least 37 records · Page 2Linked to original sources
PubMed1997

SYN-1012: a new beta-lactamase inhibitor of penem skeleton.

A new beta-lactamase inhibitor, SYN-1012, with a penem skeleton was synthesized and its biological activity compared with clavulanic acid, sulbactam, tazobactam and BRL-42715. The beta-lactamase inhibitory activity of SYN-1012 was comparable to BRL-42715. Clavulanate and penam sulphones (sulbactam and tazobactam) were more active against TEM-1 and OXA-1, but were less active against TEM-3 and cephalosporinase (Case) than SYN-1012. In combination with piperacillin, SYN-1012 exhibited comparable or slightly lower synergistic effects than BRL-42715 against all the Gram-positive and Gram-negative isolates tested with only exception of Pseudomonas aeruginosa. The separate combinations of SYN-1012 and BRL-42715 with ceftazidime and cefotaxime provided comparable results against Gram-negatives, but not against Gram-positive isolates. Tazobactam was inferior to SYN-1012 in all cases. In comparison to tazobactam, SYN-1012 and BRL-42715 were relatively unstable in human and mouse plasma, and in mouse liver and kidney homogenates. Serum level of SYN-1012 and BRL-42715 after an intravenous administration of 20 mg/kg in rabbit was undetectable after 1 hour.

Animals↗
PubMed1997

The effects of macrolide and quinolone antibiotics in methicillin-resistant Staphylococcus aureus biofilm growth.

Recent studies demonstrate that 14-membered macrolides increase permeability and destruction of Pseudomonas biofilms. The effect of a macrolide antibiotic, erythromycin, on methicillin-resistant Staphylococcus aureus (MRSA) biofilm on Silastic catheter materials in comparison with two different quinolone antibiotics, sparfloxacin (SPFX) and a new quinolone, SYN 1193, was examined. Two different MRSA strains were grown in biofilm, using Mueller-Hinton broth with and without the addition of 10% pooled normal human serum (PNHS), in a modified Robbins device, at 37 degrees C for 24, 48, and 72 hours. Two different clinical MRSA strains were used and minimum bactericidal concentration (MBC) were determined at the time intervals mentioned. Three different dosages of each antibiotic were tested: 5.0, 20.0, and 50.0 micrograms/mL. In addition, a constant dosage of SPFX and SYN 1193, in combination with varying dosages of erythromycin, was tested under similar experimental conditions. SYN 1193 demonstrated the highest MBC in comparison to SPFX; addition of PNHS did not alter the effect of SYN 1193. However, erythromycin alone and in combination with SPFX and SYN 1193 had no effect on MBC. We conclude that (1) macrolide antibiotic erythromycin has poor MRSA biofilm permeability and killing in comparison to SPFX and SYN 1193, and (2) SYN 1193 had the highest MBC to MRSA biofilm.

Anti-Bacterial Agents↗
PubMed1996

Cytotoxic quinolines (part 1). Azolylalkyloxy quinolines and 1-azolylalkyl-4(1H)-quinolones.

A series of 4-azolylalkyloxyquinolines and 1-azolylalkyl-4(1H)-quinolones has been synthesized and evaluated for cytotoxicity against various cancer cell lines. 1-Phenyl-1,2,3-triazole and 1-methylpyrazole were found to be the most effective azoles. The length of the alkyl chain was critical, with 8 to 10 carbon atoms being optimal. Several of the compounds were found to be very cytotoxic in vitro towards various cancer cells. Compounds 9o, 10k, and 10r were evaluated in vivo, but were ineffective and exhibited acute general toxicity at higher dosages.

Animals↗
PubMed1996

Cytotoxic quinolines (part 2). Azolylalkylamino and-thio quinolines.

A series of azolylalkylaminoquinolines and azolylalkylthioquinolines was synthesized and evaluated for cytotoxicity against various cancer cell lines. Structure-activity relationships previously established for azolylalkyloxyquinolines were generally found to apply for the present compounds. The azolylalkylaminoquinolines were found to be more cytotoxic than the corresponding thio compounds. Oxidation of 11a to sulfones 12 and 13 resulted in a reduction of cytotoxicity. Several of the compounds were found to be very cytotoxic in vitro towards different cancer cell lines. Compound 7d, the most cytotoxic in vitro against the P388 cell line in this series, was ineffective in vivo and exhibited significant general toxicity at higher dosages.

Aminoquinolines↗
PubMed1996

Cytotoxic quinolines (Part 3). Synthesis of 1-azolylalkyl-4(1H)-quinolones as cytotoxic agents.

A series of 1-azolylalkyl-4(1H)-quinolones has been synthesized and evaluated for cytotoxic activity both in vitro and in vivo. The effects on cytotoxicity of varying substitution on the quinoline moiety was investigated. The insertion of a 5-amino group proved to be the most effective modification, resulting in a several-fold increase in cytotoxicity in vitro. Previously reported results indicated that the activity of this class of compounds may involve topoisomerase inhibition, but investigation of the current compounds has ruled out this possibility. One compound, 13, showed in vitro cytotoxicity notably superior to Adriamycin, however it demonstrated only slight or no in vivo efficacy depending on the model used.

Animals↗
PubMed1995

Sensitive high-performance liquid chromatographic assay for norfloxacin utilizing fluorescence detection.

A rapid, sensitive and reproducible reversed-phase high-performance liquid chromatographic assay was developed for the determination of norfloxacin. Following protein precipitation with 10% trichloroacetic acid, norfloxacin and the internal standard enoxacin were extracted from plasma with chloroform, dried and reconstituted in the mobile phase. The chromatographic separation of norfloxacin and the internal standard enoxacin was achieved on a C8 column with fluorescence detection set at 280 and 418 nm for excitation and emission, respectively. The peaks with a resolution factor greater than 1.5 were free from interferences. Excellent linearity (r2 > or = 0.998) was observed over the concentration range 0.025-5.0 micrograms/ml in plasma. The inter-assay variability was 13.6% or less at all concentrations examined. The suitability of the assay for pharmacokinetic studies was determined by measuring norfloxacin concentration in rat plasma after administration of a single intravenous 10 mg/kg dose.

Animals↗
PubMed1995

Chemical modification of tazobactam. Synthesis of 2 beta-[(4-substituted)-1,2,3-triazol-1-yl]methyl penicillanic acid sulfone derivatives.

A series of 2 beta-[(4-substituted)-1,2,3-triazol-1-yl] methyl penicillanic acid sulfones was synthesized as beta-lactamase inhibitors. Many of these compounds showed good in vitro inhibitory activity against penicillinase, cefotaximase and plasmid-mediated class III TEM enzymes, but exhibited weaker cephalosporinase inhibition. One member in this series--2 beta-[(4-pyridiniummethyl)-1,2,3-triazol- 1-yl]-6,6-dihydropenicillanate 1,1-dioxide (12a), when tested in combination with piperacillin, showed excellent synergistic activity against microorganisms producing plasmid-mediated enzymes, but had insufficient activity against microorganisms producing chromosomally mediated class I enzymes.

Ampicillin↗
PubMed1995

Synthesis of podophyllotoxin congeners as potential DNA topoisomerase II inhibitors.

We have synthesized a number of new podophyllotoxin congeners in which the A-ring is opened and the C-ring is aromatic. These are based on the chemically modified structures of the naturally occurring podophyllum lignan, diphyllin. These have been synthesized by employing the Michael Initiated Ring Closure methodology. These lignans exhibited considerable DNA topoisomerase II inhibition and were devoid of topoisomerase I inhibition; they did not exhibit very significant activities in the in vitro human tumour cell lines assay. The results obtained provide insights into the structure-activity relationships and the design of chemically modified podophyllotoxin congeners useful in cancer chemotherapy.

Animals↗
PubMed1994

Potentiation of ricin A immunotoxin by monoclonal antibody targeted monensin containing small unilamellar vesicles.

The carboxylic ionophore monensin could be successfully entrapped in small unilamellar vesicles made by the extruder method. Monensin liposomes of size range 100-150 nm were more potent in potentiating ricin A immunotoxin activity in vitro as compared to monensin liposomes of diameter 500 nm or more. These liposomes were further successfully linked to tumor specific monoclonal antibodies with full retention of immunoreactivity. Monoclonal antibody targeted monensin liposomes were 100 times more potent than monensin liposomes in potentiating the activity of ricin A immunotoxins against various tumor cell lines in vitro.

Antibodies, Monoclonal↗
PubMed1994

Synthesis and beta-lactamase inhibitory activity of 6-[(1-heteroarylthioethyl-1,2,3-triazol-4-yl)-methylene]penam sulfones.

The synthesis of beta-lactamase inhibitory activity of a series of sodium 6-[(1-heteroarylthioethyl-1,2,3-triazol-4-yl)methylene]pe nicillanate, 1,1-dioxides are described. Their activity was compared with tazobactam and sulbactam. The Z-isomers were more active than the E-isomers. The in vitro activity of the Z-isomers of the phenylthiadiazole derivatives (13a and 15a) was better than sulbactam against the tested beta-lactamases and comparable to tazobactam especially against TEM-2 and cephalosporinase. But their synergistic activity with five antibiotics was inferior to tazobactam.

Drug Synergism↗
PubMed1991

Metabolism of antidepressants: urinary metabolites of trimipramine in the rat.

1. Studies on the metabolism of the tricyclic antidepressant trimipramine (TMP) in the rat are described. 2. Twenty metabolites of TMP were isolated from rat urine after enzymatic hydrolysis and their structures were determined by a gas chromatographic-mass spectrometric (GC-MS) method. 3. Twelve TMP metabolites were the result of alicyclic (C10 or C11) oxidation in addition to the other metabolic pathways.

Animals↗
PubMed1991

Antibacterial activity and penicillin-binding protein affinity of new cephalosporin derivatives in Staphylococcus aureus and Escherichia coli.

A series of C3-substituted cephalosporins with different levels of oxidation was synthesized and the activities of eight compounds, including affinity for penicillin-binding proteins (PBPs), in Staphylococcus aureus and Escherichia coli were studied. The more hydrophobic cephalosporins, with a thiophene moiety at the C7 position, were more active than C7-methoxyiminoaminothiazole derivatives against S. aureus H (beta-lactam-susceptible), and compounds with a thioether function at C3 were more active than those with a sulphonyl function at this position. In contrast, the most active compounds against E. coli were hydrophilic, zwitterionic C7-methoxyimino-aminothiazole C3-thioether cephalosporins. The physicochemical properties of the most active compounds were in accord with those predicted for rapid outer membrane penetration. However, among the thiophene cephalosporins the dianionic sulphonyl compounds were more active than the monoanionic thioether derivatives. There was a reasonably good correlation between MICs and PBP affinities for S. aureus H. The compounds had most affinity for PBP 1 and least for PBP 4. The two most potent compounds had high affinities for PBPs 1, 2 and 3. The compounds had low affinities for the beta-lactam-insensitive PBP 2a of methicillin-resistant S. aureus strain DU4916-K7. The novel cephalosporins had the highest affinities for PBPs 1a/1b and 3 of E. coli DCO. The major morphological response of E. coli to the compounds was cell elongation.

Bacterial Proteins↗
PubMed1991

Structural characterization of the urinary metabolites of iprindole in rat.

1. The in vivo metabolism of iprindole in rat is described. Each rat received a single dose of iprindole (10 mg/kg) and urine was collected for 48 h. 2. Fourteen metabolites of iprindole were isolated from rat urine after enzymic hydrolysis and their structures were determined by a computerized g.l.c.-mass spectrometric technique, before and after appropriate chemical derivatization. 3. Three concurrent metabolic pathways have been identified for iprindole in rat; aromatic ring hydroxylation is a minor pathway. 4. This is the first reported comprehensive study on the in vivo metabolism of iprindole in rat.

Animals↗
PubMed1990

The metabolism of trimipramine in the rat.

Studies on the metabolism of the tricyclic antidepressant trimipramine, 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, in the rat are described. Many metabolites of trimipramine (TMP) were isolated from rat urine after enzymatic hydrolysis and their structures were identified by a gas chromatographic/mass spectrometric method, before and after appropriate chemical derivatization. Besides unchanged TMP, 20 metabolites were characterized (underivatized, and after acetylation), of which 12 had undergone alicyclic (C10 or C11) oxidation. This is a hitherto unreported metabolic pathway for TMP in the rat.

Animals↗