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J G Christenson

Publications and source records attributed to J G Christenson.

16 recordsLinked to original sources
PubMed1991

Dual-action cephalosporins: cephalosporin 3'-quaternary ammonium quinolones.

When cephalosporins exert their biological activity by reacting with bacterial enzymes, opening of the beta-lactam ring can lead to expulsion of the 3'-substituent. A series of cephalosporins was prepared in which antibacterial quinolones were linked to the 3'-position through a quaternary nitrogen. Like the 3'-ester-linked dual-action cephalosporins reported earlier, these compounds demonstrated a broad spectrum of antibacterial activity derived from cephalosporin-like and quinolone-like components, suggesting a dual mode of action.

Animals↗
PubMed1991

Dual-action cephalosporins: cephalosporin 3'-quinolone carbamates.

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

Animals↗
PubMed1990

Cephalosporin 3'-quinolone esters with a dual mode of action.

According to the generally accepted mechanism by which bacterial enzymes react with cephalosporins, opening of the beta-lactam ring can lead to the expulsion of a 3'-substituent. A series of dual-action cephalosporins was prepared in which antibacterial quinolones were linked to the cephalosporin 3'-position through an ester bond in the expectation that, in addition to exerting their own beta-lactam activity, these cephalosporins would act as prodrugs for the second antibacterial agent. Compared to parent cephalosporins in which the 3'-substituent was acetoxy, the bifunctional cephalosporins exhibited a broadened antibacterial spectrum, suggesting that a dual mode of action may indeed be operative.

Animals↗
PubMed1990

Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals.

Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the beta-lactam moiety and the quinolone moiety. In animals, the ester bond potentially could be hydrolyzed enzymatically or nonenzymatically, to yield the active metabolites desacetylcefotaxime and fleroxacin. The extent to which Ro 23-9424 acts in vivo as a true dual-action cephalosporin, or acts as a combination of active metabolites, is therefore a function of its pharmacokinetic properties. To investigate these properties, Ro 23-9424 was administered as a single intravenous dose of 20 mg/kg of body weight to mice, rats, dogs, and baboons. Timed plasma samples were assayed by an ion-paired high-pressure liquid chromatography method that allowed detection of both intact Ro 23-9424 and fleroxacin. The pharmacokinetic parameters of Ro 23-9424 were similar to published results for cefotaxime, while concentrations of fleroxacin in plasma were low and fairly constant (about 1 to 3 micrograms/ml) in all species, suggesting that excretion of the intact molecule is a major route of elimination for Ro 23-9424, as it is for cefotaxime. For technical reasons, urinary recovery of Ro 23-9424 was not quantitated, but intact Ro 23-9424 was found in high concentrations (greater than 400 micrograms/ml) in mouse urine aspirated directly from the bladder. In all species, low concentrations of free fleroxacin in plasma persisted after the elimination of Ro 23-9424 was complete, but fleroxacin did not accumulate unduly in a 14-day multiple-dose experiment in baboons. Thus, it seems likely that the activity seen in vivo is primarily due to intact Ro 23-9424, although the low levels of free fleroxacin may also have some therapeutic significance.

Animals↗
PubMed1989

Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics.

The recovery of peptidoglycan-synthesizing activity after inhibition by beta-lactam antibiotics was investigated in ether-permeabilized cells of Escherichia coli B. Such cells synthesize sodium dodecyl sulfate-insoluble peptidoglycan when provided with UDP-linked precursors and Mg2+. The ability of beta-lactam antibiotics to inhibit the synthesis of peptidoglycan was correlated with their affinity for penicillin-binding proteins 1A and 1Bs. Penicillin-binding protein 1Bs is thought to be the major peptidoglycan synthetase in E. coli and is a major lethal target for beta-lactam antibiotics. Ether-treated bacteria were preincubated with concentrations of beta-lactams sufficient to completely inhibit peptidoglycan synthesis and then treated with beta-lactamases to inactivate free antibiotic prior to measurement of peptidoglycan synthesis. At 40 min after beta-lactamase treatment, the rate of peptidoglycan synthesis was about 74% of the control rate in cells pretreated with ampicillin, but only 15% of the control in cells pretreated with penicillin G or azlocillin. Reversal of inhibition by several other antibiotics fell between these extremes. When cross-linking of peptidoglycan was measured specifically, reversal of inhibition by ampicillin also occurred more readily than that by penicillin G. Reactivation of peptidoglycan synthesis was not due to de novo synthesis of penicillin-binding proteins since it occurred under conditions that did not allow incorporation of [14C]leucine. We conclude that there is considerable variation in the stability of the inactive acyl enzymes formed between various beta-lactams and penicillin-binding protein 1Bs, with those formed by penicillin G being relatively long-lived.

Anti-Bacterial Agents↗
PubMed1988

Antibacterial properties of (2,3)-alpha- and (2,3)-beta-methylene analogs of penicillin G.

The penam nucleus can assume two conformations; these are designated open and closed. The synthetic (2,3)-alpha- and (2,3)-beta-methylenepenams can be regarded as analogs of the open and closed conformations, respectively. It has been shown that the beta-methylenepenams are essentially inactive, suggesting that the closed conformation of penams is also inactive. In this study, we investigated a series of beta-lactams, all of which contained phenylacetamido side chains: penicillin G, the (2,3)-alpha- and (2,3)-beta-methylenepenams, and the 3-acetoxymethyl- and 3-methylcephalosporins. The alpha-methylenepenam and penicillin G were the most active compounds, while the beta-methylene isomer was only poorly active. Results with permeability mutants suggested that the alpha-methylene compound penetrated the outer membrane somewhat more readily than penicillin G did. The intrinsic potency of the alpha-methylenepenam appeared to be similar to that of penicillin G, on the basis of their affinities for penicillin-binding proteins and their abilities to inhibit peptidoglycan synthesis in ether-permeabilized Escherichia coli, while the beta-methylene analog had very poor intrinsic potency. The alpha-methylene analog was about 10-fold more efficient (Vmax/Km) than penicillin G as a substrate for the cephalosporinases from Enterobacter cloacae and Proteus vulgaris, but it was about 40-fold less efficient with penicillinase from Staphylococcus aureus. These results strongly support the hypothesis that the active conformation of penams is the open conformation and suggest that the position in space of the carboxyl group relative to the beta-lactam carbonyl is an important determinant of cephalosporinlike character, as distinct from penicillinlike character.

Bacteria↗
PubMed1983

Pharmacokinetics of amdinocillin and pivamdinocillin in normal volunteers.

The pharmacokinetic parameters of amdinocillin and pivamdinocillin were studied in 12 normal volunteers. Plasma amdinocillin concentrations were determined by microbiologic assay and urine concentrations by high performance liquid chromatography. Pharmacokinetic parameters were calculated by a two-compartment open model for the intravenous infusion and by a one-compartment model with zero-order absorption for the oral doses. The mean peak serum level after the intravenous infusion of 500 mg was 39 micrograms/ml. At one and a half hours after the oral administration of 250 mg and 500 mg doses, mean peaks were 1.93 and 2.66 micrograms/ml respectively. Half-life was one hour for all doses. Maximal plasma concentration did not increase proportionally with dose. Bioavailability was 45 percent after the 250 mg dose and 38 percent after the 500 mg dose.

Administration, Oral↗
PubMed1982

Correlation of the results of antibiotic synergy and susceptibility testing in vitro with results in experimental mouse infections.

Recent clinical isolates (approximately 150 strains) of the family Enterobacteriaceae were examined by agar diffusion, microdilution, and the Autobac automated system for their responses to beta-lactam antibiotics singly and in combination with amdinocillin (formerly called mecillinam). The ratio of ampicillin, carbenicillin, and cephalothin to amdinocillin was maintained at a 10:1 ratio in most of the evaluations. The same isolates were studied in mice challenged with 100 to 1000 LD50s and treated with graded doses of the antibiotics singly and in combination. Efficacy in vivo was based on the concentration of antibiotic in milligrams per kilograms (mg/kg) required to protect 50% of the animals (PD50). After a single administration of the antibiotics, plasma levels were determined in the critical time period (30 min to 4 hr) during which the acute, overwhelming systemic infections could be controlled by appropriate therapy. Regression curves comparing in vivo and in vitro results were used to establish cut-off points for categorizing bacterial susceptibility in each of the laboratory tests for the single agents and combinations. A high degree of synergism between amdinocillin and the beta-lactam agents was demonstrated in animals (54 to 78% of the strains examined) and to a lesser extent by laboratory methodologies. There was an excellent correlation of in vivo and in vitro responses to ampicillin, carbenicillin, and cephalothin alone and in combination with amdinocillin for those species for which the single antibiotics are generally indicated. The correlations validated the chosen cut-off points. The correlation of in vivo and in vitro responses to the single or combined antibiotics was generally poorer for those species not usually responsive to the single antibiotics. The greatest difficulty in predicting proper in vivo responses, based on the results of in vitro tests, was observed with amdinocillin.

Ampicillin↗
PubMed1981

In vivo activity of ceftriaxone (Ro 13-9904), a new broad-spectrum semisynthetic cephalosporin.

Ceftriaxone (Ro 13-9904) was compared with other newer beta-lactam antibiotics for activity in experimental infections of mice with Enterobacteriaceae, Haemophilus influenzae, Pseudomonas aeruginosa, and gram-positive bacteria. Overall, ceftriaxone was equal or superior to cefotaxime and cefoperazone against systemic infections. All three drugs were highly potent against most organisms but were considerably less active against P. aeruginosa. However, ceftriaxone tended to be more active than the other two agents against 8 of the 10 P. aeruginosa strains tested. Ceftriaxone, cefmenoxime (SCE 1365), and moxalactam were all highly active against systemic infections with 16 strains of Enterobacteriaceae, whereas ceftriaxone was more active against infections with two strains of streptococci. When the drugs were administered at various time intervals before infection, ceftriaxone was superior to cefotaxime, cefmenoxime, and moxalactam. This suggested that ceftriaxone might be eliminated from mice more slowly than the other drugs. In the case of cefotaxime, this was directly confirmed by microbiological assays of plasma samples. In a murine meningitis model induced by Klebsiella pneumoniae or Streptococcus pneumoniae, ceftriaxone was more active than ampicillin or cefotaxime. Ceftriaxone was more active than ampicillin, cefotaxime, piperacillin, cefamandole, or carbenicillin in a pneumococcal, pneumonia model in mice. These studies indicate that ceftriaxone is a potent, broad-spectrum cephalosporin with unusual pharmacokinetic properties.

Animals↗
PubMed1977

Cocaine and benzoylecgonine excretion in humans.

Maximal urinary excretion of unchanged cocaine occurred within 2 h of the intranasal absorption of 1.5 mg/kg body weight of cocaine hydrochloride, and diminished rapidly thereafter. Excretion of benzoylecgonine was maximal 4 to 8 h following administration of the drug and diminished slowly over an interval of several days. Peak cocaine and benzoylecgonine concentrations observed were 24 and 75 microgram/ml, respectively. Benzoylecgonine/cocaine ratios were too varied to allow estimation of cocaine concentrations from benzoylecgonine concentration data or vice versa. Benzoylecgonine concentrations generally exceeded the corresponding cocaine values by a wide margin, but excretion of free cocaine in the absence of benzoylecgonine was observed in one subject. Cocaine was generally detected for only approximately 8 h, and for a maximum of 12 h, whereas benzoylecgonine was generally detected by chromatographic or enzyme immunologic assays for 48 to 72 h. Benzoylecgonine was positively identified in urine by raidoimmunoassay for 96 to 144 h after dosing.

Adult↗
PubMed1972

On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine).

Simultaneous immunological titration of DOPA and 5-hydroxytryptophan decarboxylase activities, from a number of tissues of various species, showed that the two activities were not distinguishable with a monospecific antiserum to hog kidney decarboxylase. Together with previous findings, these data firmly establish the concept that in mammalian tissues the two enzyme activities are associated with a single protein, namely aromatic L-amino acid decarboxylase.

5-Hydroxytryptophan↗
PubMed1971

Decrease in liver aromatic L-amino-acid decarboxylase produced by chronic administration of L-dopa.

L-Dopa, an intermediate in the biosynthesis of catecholamines, is now widely used in the treatment of parkinsonism. A number of clinical observations suggested that L-dopa may induce changes in its own metabolism during the course of therapy. In the present study, it was found that when L-dopa was administered to rats, the activity of liver aromatic L-amino-acid decarboxylase, the enzyme which catalyzes the conversion of dopa to dopamine, was reduced by as much as 50%. There were no corresponding changes in enzyme activity in heart, adrenals, kidneys, and brain. Decarboxylase activity in the liver continued to decrease for at least 5 days after the last dose of L-dopa. The reduction of enzyme activity in the liver occurred when L-dopa was administered either subcutaneously or orally at doses comparable to those used clinically. In vitro and in vivo experiments indicated that this action of L-dopa is not due to some effect on the cofactor, pyridoxal phosphate. Immunological evidence was obtained that enzyme protein is reduced in the same proportion as enzyme activity. By a reduction of decarboxylase activity in liver without any affect on the enzyme in brain, more L-dopa should be made available to the brain for decarboxylation to dopamine. These findings may explain the clinical observations that the therapeutic efficacy of the drug increases with continued administration.

Administration, Oral↗