Cefamandole: in vitro and clinical pharmacokinetics.
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Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes Haemophilus influenzae, most strains of Enterobacter, and many strains of indole-positive Proteus and Bacteroides, with a lower minimal inhibitory concentration for Escherichia coli, Klebsiella, etc. Concentrations of drug in the serum after the parenteral injection of cefamandole exceed manyfold the minimal inhibitory concentrations of over 82% of the bacteria studied. Approximately 65 to 85% is excreted in a biologically active form in the urine. This antibiotic offers advantages of antibacterial effectiveness and at the same time retains the safety of penicillin G and cephalothin in animals. (+info)
Metabolism of DL-(+/-)-phenylalanine by Aspergillus niger.
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A fungus capable of degrading DL-phenylalanine was isolated from the soil and identified as Aspergillus niger. It was found to metabolize DL-phenylalanine by a new pathway involving 4-hydroxymandelic acid. D-Amino acid oxidase and L-phenylalanine: 2-oxoglutaric acid aminotransferase initiated the degradation of D- and L-phenylalanine, respectively. Both phenylpyruvate oxidase and phenylpyruvate decarboxylase activities could be demonstrated in the cell-free system. Phenylacetate hydroxylase, which required reduced nicotinamide adenine dinucleotide phosphate, converted phenylacetic acid to 2- and 4-hydroxyphenylacetic acid. Although 4-hydroxyphenylacetate was converted to 4-hydroxymandelate, 2-hydroxyphenylacetate was not utilized until the onset of sporulation. During sporulation, it was converted rapidly into homogentisate and oxidized to ring-cleaved products. 4-Hydroxymandelate was degraded to protocatechuate via 4-hydroxybenzoylformate, 4-hydroxybenzaldehyde, and 4-hydroxybenzoate. (+info)
Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO-K1 cells.
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1. Affinity estimates were obtained for several muscarinic antagonists against carbachol-stimulated [3H]-inositol phosphates accumulation in Chinese hamster ovary (CHO-KI) cells stably expressing either human muscarinic M3 or M5 receptor subtypes. The rationale for these studies was to generate a functional antagonist affinity profile for the M5 receptor subtype and compare this with that of the M3 receptor, in order to identify compounds which discriminate between these two subtypes. 2. The rank order of antagonist apparent affinities (pK(B)) at the muscarinic M5 receptor was atropine (8.7) > or =tolterodine (8.6) = 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 8.6)> darifenacin (7.7) > or =zamifenacin (7.6)>oxybutynin (6.6)= para-fluorohexahydrosiladifenidol (p-F-HHSiD, 6.6)>pirenzepine (6.4) > or = methoctramine (6.3)=himbacine (6.3)>AQ-RA 741 (6.1). 3. Antagonist apparent affinities for both receptor subtypes compare well with published binding affinity estimates. No antagonist displayed greater selectivity for the muscarinic M5 subtype over the M3 subtype, but himbacine, AQ-RA 741, p-F-HHSiD, darifenacin and oxybutynin displayed between 9- and 60 fold greater selectivity for the muscarinic M3 over the M5 subtype. 4. This study highlights the similarity in pharmacological profiles of M3 and M5 receptor subtypes and identifies five antagonists that may represent useful tools for discriminating between these two subtypes. Collectively, these data show that in the absence of a high affinity M5 selective antagonist, affinity data for a large range of antagonists is critical to define operationally the M5 receptor subtype. (+info)
Cefamandole: antimicrobial activity in vitro of a new cephalosporin.
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Cefamandole, a new cephalosporin derivative, was found to have a broad spectrum of activity against a cross-section of both gram-positive and gram-negative bacteria isolated from clinical material. Gram-positive cocci, except for Streptococcus faecalis, were very susceptible. Penicillin G-resistant Staphylococcus aureus also was susceptible to cefamandole. Minimal bactericidal concentrations for gram-positive cocci approximated the minimal inhibitory concentrations. Strains of Haemophilus influenzae were very susceptible to the drug. Most strains of Escherichia coli, Klebsiella sp., and Proteus sp. were inhibited by low concentrations. Increasing resistance occurred with larger inocula. Strains of Pseudomonas sp. were resistant to cefamandole. (+info)
On the interpretation of quantitative structure-function activity relationship data for lactate oxidase.
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The native flavin, FMN, has been removed from the l-lactate oxidase of Aerococcus viridans, and the apoprotein reconstituted with 12 FMN derivatives with various substituents at the flavin 6- and 8-positions. Impressive linear relationships are exhibited between the sum of the Hammett final sigma(para) and final sigma(ortho) parameters and the redox potentials of the free flavins, and between the redox potentials of the free and enzyme-bound flavins. Rapid reaction kinetics studies of the reconstituted enzymes with the substrates l-lactate and l-mandelate show an increase in the reduction rate constant with increasing redox potential, except that, with lactate, a limiting rate constant of approximately 700 s(-1) is obtained with flavins of high potential. Similar breakpoints are found in plots of the rate constants for flavin N5-sulfite adduct formation and for the reaction of the reduced enzymes with molecular oxygen. These results are interpreted in terms of a two-step equilibrium preceding the chemical reaction step, in which the second equilibrium step provides an upper limit to the rate with which the particular substrate or ligand is positioned with the flavin in the correct fashion for the observed chemical reaction to occur. The relationship of rate constants for flavin reduction and N5-sulfite adduct formation with flavin redox potential below the observed breakpoint indicate development of significant negative charge in the transition states of the reactions. In the case of reduction by substrate, the results are consistent either with a hydride transfer mechanism or with the so called "carbanion" mechanism, in which the substrate alpha-proton is abstracted by an enzyme base protected from exchange with solvent. These conclusions are supported by substrate alpha-deuterium isotope effects and by solvent viscosity effects on sulfite binding. (+info)
Differences in the effects of urinary incontinence agents S-oxybutynin and terodiline on cardiac K(+) currents and action potentials.
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1. The cardiac electrophysiological effects of S-oxybutynin, a single-enantiomer drug under evaluation for the management of urinary incontinence, have been investigated and compared with those of terodiline, an incontinence agent withdrawn following reports of QT lengthening and ventricular tachyarrhythmia. Membrane currents were recorded from whole-cell configured guinea-pig and rabbit ventricular myocytes, and action potentials were recorded from guinea-pig and rabbit papillary muscles. 2. L-type Ca(2+) current (I:(Ca,L)), rapidly-activating K(+) current (I:(Kr)) and slowly-activating K(+) current (I:(Ks)) were unaffected by submicromolar S-oxybutynin and inhibited by higher concentrations; IC(50) values were 17.8 microM for I:(Ca,L), 12 microM for I:(Kr), and 41 microM for I:(Ks). Terodiline IC(50) values were somewhat lower for I:(Ca,L) (15.2 microM) and I:(Ks) (30 microM), but 24 fold lower in the case of I:(Kr) (0.5 microM). 3. The durations of action potentials in guinea-pig and rabbit papillary muscles driven at 1 Hz were unaffected or moderately shortened by 0.1 - 100 microM S-oxybutynin, but lengthened by terodiline. Terodiline (< or =10 microM) also depressed maximal upstroke velocity. 4. The action potential plateau shortened by an average of 23% when control rabbit papillary muscles were driven at 0.4 Hz instead of 1 Hz. Plateau shortening was significantly smaller in the presence of drugs (30 microM S-oxybutynin, 3 and 30 microM terodiline), suggesting that they suppress the transient outward current (I:(to)) involved in rate-dependent shortening. In experiments on rabbit ventricular myocytes, 3 and 30 microM S-oxybutynin inhibited I:(to) by 9+/-2% and 35+/-3%, respectively, whereas 3 and 30 microM terodiline inhibited the current by 31+/-3% and 87+/-3%, respectively. 5. The results indicate that S-oxybutynin has relatively weak non-specific effects on cardiac ion channels, and that clinically relevant submicromolar concentrations are unlikely to have terodiline-like proarrhythmic actions on the myocardium. (+info)
Effect of cyclandelate on dementia.
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Cyclandelate, a vasodilator, was administered to 24 patients with dementia. The dementia in these patients was presumed to be due to cerebral ischemia caused by atherosclerosis in cerebral vessels after other possible causes were ruled out. In a double-blind, cross-over study, patients received 200 mg of cyclandelate four times daily for six weeks and a placebo for six weeks. Six psychological tests, which reflect various aspects of higher cortical ability, were used to evaluate the effect of cyclandelate on the dementia. Cyclandelate was found to be no more effective than placebo in improving higher cortical function in these demented patients. (+info)
p-Hydroxyphenylacetic Acid Metabolism in Pseudomonas putida F6.
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Pseudomonas putida F6 was found to metabolize p-hydroxyphenylacetic acid through 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxymandelic acid, and 3,4-dihydroxybenzaldehyde. Cell extracts of P. putida F6 catalyze the NAD(P)H-independent hydroxylation of p-hydroxyphenylacetic acid to 3,4-dihydroxyphenylacetic acid which is further oxidized to 3,4-dihydroxymandelic acid. Oxidation and decarboxylation of the latter yields 3,4-dihydroxybenzaldehyde. A red-brown color accompanies all of the above enzyme activities and is probably due to the polymerization of quinone-like compounds. 3,4-Dihydroxybenzaldehyde is further metabolized through extradiol ring cleavage. (+info)