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Biomedical subjects

D T Chu

Publications and source records attributed to D T Chu.

At least 73 records · Page 4Linked to original sources
PubMed1987

Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones.

The in vitro and in vivo properties of a new 1-difluorophenyl-6-fluoroquinolone, temafloxacin hydrochloride (A-62254), were compared with those of difloxacin and ciprofloxacin. Temafloxacin hydrochloride was as active as ciprofloxacin and difloxacin against staphylococci and as active as ciprofloxacin and 2 twofold dilutions more active than difloxacin against streptococci. Against gram-negative enteric bacteria and Pseudomonas aeruginosa, temafloxacin hydrochloride was 2 twofold dilutions more active than difloxacin but 2 to 4 twofold dilutions less active than ciprofloxacin. The MICs of temafloxacin hydrochloride and difloxacin were increased by 2 to 5 twofold dilutions in urine at pH 6.5 compared with 4 to 5 twofold-dilution increases in the MICs of ciprofloxacin. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were increased by 1 to 3 twofold dilutions in serum. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were the same or within 1 to 2 twofold dilutions at pHs 6.5, 7.2, and 8.0. When administered orally in mouse protection tests, temafloxacin hydrochloride was as active as difloxacin and 5 to 10 times more active than ciprofloxacin against infections with Staphylococcus aureus and streptococci. Against infections with gram-negative enteric bacteria and P. aeruginosa, temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin. Temafloxacin hydrochloride was three times less active than difloxacin but was five times more active than ciprofloxacin against infections with Salmonella typhimurium. Temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin against P. aeruginosa and Proteus mirabilis pyelonephritis in mice. The peak serum concentration and serum half-life of temafloxacin hydrochloride in mice were approximately one-half and one-sixth, respectively, that of difloxacin after oral administration. The peak serum concentration of temafloxacin hydrochloride in mice after oral administration was six times higher than that of ciprofloxacin, and the serum half-life was equal to that of ciprofloxacin.

Animals↗
PubMed1987

The inhibition of phosphoenolpyruvate carboxykinase (guanosine triphosphate) gene expression by insulin is not mediated by protein kinase C.

The role protein kinase C plays in the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin and phorbol esters was studied in H4IIE hepatoma cells (ATCC CRL 1548). The combined effects of phorbol 12-myristate 13-acetate (PMA) and insulin on the suppression of mRNA coding for PEPCK (mRNAPEPCK) synthesis were additive. A potent inhibitor of both cyclic nucleotide-dependent protein kinases and protein kinase C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, inhibited the cAMP and PMA-mediated regulation of mRNAPEPCK synthesis, but did not affect the action of insulin. Desensitization of the protein kinase C pathway by exposure to PMA for 16 h abolished the subsequent action of the phorbol ester, but did not affect insulin- or cAMP-mediated regulation of PEPCK gene expression. We conclude that insulin suppresses PEPCK gene expression independently from the protein kinase C-mediated pathway used by phorbol esters.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1987

Regulation of phosphoenolpyruvate carboxykinase gene transcription in H4IIE hepatoma cells: evidence for a primary role of the catalytic subunit of 3',5'-cyclic adenosine monophosphate-dependent protein kinase.

The purpose of these studies was to determine whether the catalytic subunit of cAMP-dependent protein kinase is involved in the regulation of P-enolpyruvate carboxykinase (PEPCK) gene transcription. Cyclic AMP analog pairs that preferentially stimulate either type I or type II protein kinase in a synergistic manner were used to compare regulation of mRNAPEPCK synthesis in H4IIE rat hepatoma cells with protein kinase activation in vitro. Type II protein kinase is predominant in H4IIE cells and analog pairs directed toward this isozyme resulted in a synergistic increase of mRNAPEPCK that was due to a corresponding enhancement of PEPCK gene transcription. When compared to a single analog the addition of a type II-directed analog pair reduced the total analog concentration required for maximal induction of transcription by about 30-fold. H4IIE cells have a small amount of type I kinase; pairs specific for this form of the enzyme were also effective, but to a lesser extent than those for the type II kinase. (Rp)-cAMPS, a cyclic nucleotide-dependent protein kinase antagonist, inhibited the agonist-induced increase of mRNAPEPCK in a concentration-dependent manner. The results indicate that the activation of PEPCK gene transcription by cAMP in H4IIE cells is mediated by cAMP-dependent protein kinase. Although the type II isozyme is primarily responsible, type I is also effective. These isozymes have identical catalytic subunits, hence this component presumably mediates the cAMP effect.

Animals↗
PubMed1986

The effect of phorbol esters and diacylglycerol on expression of the phosphoenolpyruvate carboxykinase (GTP) gene in rat hepatoma H4IIE cells.

The effect of the tumor promoter phorbol 12-myristate 13-acetate (PMA) on expression of the P-enolpyruvate carboxykinase gene was studied in rat hepatoma H4IIE cells. Like insulin, PMA provokes a concentration and time-dependent decrease of mRNA coding for that enzyme that is due to an inhibition of P-enolpyruvate carboxykinase gene transcription. This effect of PMA is rapid, reversible, specific for phorbol esters known to be active in other systems, and it does not require on-going protein synthesis. PMA overrides the stimulatory effects cAMP and glucocorticoid analogs have on the transcription of this gene. A synthetic diacylglycerol, sn-1,2-dioctanoylglycerol, also inhibits P-enolpyruvate carboxykinase gene transcription. These effects of PMA and synthetic diacylglycerol are specific, since neither affected total mRNA synthesis. We conclude that diacylglycerol and phorbol esters, specific stimulators of protein kinase C, inhibit the transcription of P-enolpyruvate carboxykinase gene in H4IIE cells. The findings support the hypothesis that diacylglycerols generated in the plasma membrane can act as an intracellular signal that regulates specific gene expression.

Animals↗
PubMed1986

The cytoskeleton of neurites after microtubule depolymerization.

We previously reported a positive correlation between the number of cold-stable microtubules (MTs) remaining after cold treatment of cat sympathetic nerve and the extent to which the original uniform polarity orientation of axonal MTs was recapitulated after rewarming (J cell biol 99 (1984) 1289). We interpreted these data to indicate that cold-stable fragments, part of larger, generally labile MTs, could act as seeds to organize MT assembly in axons. We report here a direct investigation of the form of cold-stable MTs in neurites of PC-12 cells using two-dimensional reconstruction of serial thin sections. Our data provides strong support for our previous interpretation. The number of MTs in cold-treated neurites was 2-3 times as great while the total length of polymer was approximately half that in control neurites. The average length of MTs in cold-treated neurites was 7-10 times lower than in control neurites. We observed that treatments that depolymerize axonal microtubules cause a marked increase in the number of membranous elements within the axoplasm. This may, however, be a non-specific result of an insult to the axon, since such changes have also been observed in severed, regenerating nerve fibres. We observed that neuroblastoma neurites respond to MT-depolymerization stimuli by developing lateral filopodia similar to those observed in chick dorsal root ganglion cells. Ultrastructural observation of detergent-lysed, whole mounted neuroblastoma (Neuro 2A) cells indicated that the cytoskeleton remaining after MT depolymerization splayed out perpendicular to the long axis of the neurite. That is, we were able to observe many more cytoskeletal 'ends' after MT depolymerization. The concomitant production of filopodia and the splaying of the cytoskeleton after MT depolymerization supports the hypothesis put forward by Wessels et al. (Exp cell res 117 (1978) 335) that the presence or absence of cytoskeletal ends regulates which region of the cell surface is involved in motile behaviour.

Animals↗
PubMed1986

Synthesis and biological activity of benzothiazolo[3,2-a]quinolone antibacterial agents.

A new class of heterocyclic compounds with potent antibacterial activity, namely, 2-substituted amino-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3, 2-a]quinoline-6-carboxylic acids, is described. The compounds are conformationally restricted analogues of 7-substituted amino-6-fluoro-1-aryl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acids. Compounds 7 and 10, having a 4-methylpiperazinyl and a piperazinyl substitution at the 2-position, respectively, possess in vitro antibacterial activities comparable to norfloxacin (15). Compound 8, which has a 4-acetylpiperazinyl substitution at the 2-position, is active against Gram-positive organisms and nearly inactive against Gram-negative organisms. An efficient and short synthesis of this novel heterocyclic system via an intramolecular nucleophilic displacement cyclization reaction is reported.

Acinetobacter↗
PubMed1986

Chiral DNA gyrase inhibitors. 1. Synthesis and antimicrobial activity of the enantiomers of 6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid.

New quinolone antimicrobial agents (racemic, (1'S,2'R)- and (1'R,2'S)-6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)- 1, 4-dihydro-4-oxoquinoline-3-carboxylic acids) were synthesized, and their in vitro antimicrobial potencies and spectra were determined. As compared to their conceptual parents, these agents retained a considerable amount of the antimicrobial potency and spectra of ciprofloxacin and of 6-fluoro-1-phenyl-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxy lic acid against Gram-positives. Gram-negatives were considerably less sensitive. The (-)-(1'S,2'R) analogue was the more potent of the enantiomers, but the degree of chiral discrimination by most bacteria was only 4-fold. The 4-fold chiral discrimination was observed also using purified DNA gyrase obtained from Micrococcus luteus, whereas the two enantiomers were essentially equiactive against the enzyme derived from Escherichia coli. These results confirm that there is a substantial degree of bulk tolerance available at N-1 of quinolone antimicrobial agents and suggest that electronic factors controlled by substitution at that site are of considerable importance. On the other hand, chiral recognition brought about by attachment of optically active groups to the N-1 position in these derivatives is relatively small.

Anti-Bacterial Agents↗
PubMed1986

Synthesis and structure-activity relationships of new arylfluoronaphthyridine antibacterial agents.

Novel arylfluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared and their antibacterial activity evaluated. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. The in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or o,p-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(2,4-Difluorophenyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (38) was found to possess excellent in vitro potency and in vivo efficacy.

Anti-Bacterial Agents↗
PubMed1986

In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria.

The MICs of difloxacin (A-56619), A-56620 and ofloxacin were similar or within one to two-fold dilutions against a variety of anaerobic bacteria. Ciprofloxacin was slightly less active (two- to four-fold dilutions) than difloxacin, A-56620 and ofloxacin. Norfloxacin was less active than the other fluoroquinolones tested against anaerobic bacteria. The MICs of norfloxacin, A-56620, ciprofloxacin and ofloxacin against most anaerobes, except the Gram-positive cocci, were lower at pH 8.1 than at pH 6.6. MICs of the fluoroquinolones against anaerobic cocci were the same at pH 6.6, 7.3 and 8.1. Norfloxacin and ciprofloxacin were most affected by the acidic pH. Ofloxacin and A-56620 were affected to a lesser extent by an acidic pH than norfloxacin and ciprofloxacin. The potency of difloxacin was similar at the three pHs tested. A subcutaneous anaerobic infection model in mice was used to determine the in-vivo efficacy of the new fluoroquinolones against Bacteroides fragilis. Difloxacin was the most potent compound in this test.

Anti-Bacterial Agents↗
PubMed1986

In vitro evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones.

The in vitro antibacterial potencies of A-56619 and A-56620, two new aryl-fluoroquinolones, were compared with the potency of norfloxacin against a broad spectrum of organisms. Cefotaxime, aztreonam, piperacillin, imipenem, penicillin, and gentamicin were also tested for reference purposes. The MICs required to inhibit at least 90% of the strains tested ranged from 0.25 to 4 micrograms/ml for A-56619 and from 0.06 to 0.5 microgram/ml for A-56620 for members of the Enterobacteriaceae. A-56619 was generally twofold less potent and A-56620 was twofold more potent than norfloxacin against most aerobic gram-negative bacilli, including members of the Enterobacteriaceae and Pseudomonas aeruginosa. Against indole-positive Proteus, Morganella, Providencia rettgeri, and Serratia strains, A-56619 was at least 8- to 16-fold less potent than norfloxacin. A-56619 and A-56620 were four- to eightfold more potent than norfloxacin against Staphylococcus aureus and equally potent to fourfold more potent against Streptococcus species, Haemophilus influenzae, and Neisseria gonorrhoeae. The MICs of A-56619 and A-56620 were only slightly affected by increased inoculum size or by the addition of various cations at physiologic concentrations. A-56619 was three- to fivefold less active at pH 8.0 than at pH 6.5 or 7.2. A-56620 was twofold less active at pH 6.5 than at pH 8.0 or 7.2 against members of the Enterobacteriaceae and Pseudomonas aeruginosa; similar pH variations did not affect A-56620 activity against gram-positive cocci. The potencies of A-56619, A-56620, and norfloxacin were less in urine than in Mueller-Hinton broth; however, this effect was more pronounced with norfloxacin. Human serum at a concentration of 50% caused a 4- to 64- fold decrease in the potency of A-56619 and an average 4-fold decrease in the potency of A-56620, compared with no effect on the potency of norfloxacin. A-56619, A-56620, and norfloxacin were bactericidal and, at four times the MIC, reduced the viable cell counts of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by approximately 99.9% within 2 h. A-56619, A-56620, and norfloxacin showed no significant synergistic activity and no antagonism when they were aminoglycoside or beta-lactam antimicrobial agents.

Anti-Infective Agents↗
PubMed1986

In vivo evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones.

A-56619 and A-56620 are two new aryl-fluoroquinolones which are as potent as or more potent than norfloxacin when administered orally and subcutaneously in mouse protection tests against Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. A-56619 and A-56620 were more potent than norfloxacin when administered orally against Escherichia coli, Proteus mirabilis, Serratia marcescens, and Pseudomonas aeruginosa. A-56620 was as potent or two- to threefold more potent than norfloxacin when administered subcutaneously against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Infection with Salmonella typhimurium was more effectively treated with A-56619 (50% effective dose [ED50], 1.4 mg/kg per day) than with norfloxacin (ED50, 62.8 mg/kg per day). E. coli or Pseudomonas pyelonephritis in mice was more effectively treated with A-56619 or A-56620 than with norfloxacin. After oral treatment, the ED50s of A-56619 and A-56620 were less than 12.5 mg/kg per day against E. coli and 62.9 and 38 mg/kg per day against P. aeruginosa pyelonephritis, respectively. Norfloxacin was ineffective at 200 mg/kg per day against E. coli or P. aeruginosa pyelonephritis. A-56619 and A-56620 were also more potent than norfloxacin in treatment of mixed bacterial pyelonephritis caused by E. coli and Streptococcus faecalis. A-56619 was at least 30 times more potent than norfloxacin and A-56620 was 4 to 11 times more potent than norfloxacin when administered against Klebsiella pneumonia in mice. A-56619 and A-56620 were at least 2 to 10 times more potent than norfloxacin against Staphylococcus aureus infections in immunosuppressed mice. A-56619 was equally potent in all in vivo tests when administered orally or subcutaneously, whereas A-56620 was similar to norfloxacin in being more potent when administered subcutaneously. The peak serum levels after subcutaneous and oral administration of A-56619 and A-56620 were higher than that of norfloxacin. The serum hal-lives of A-56619 and A-56620 after subcutaneous and oral administration were longer than the serum half-life of norfloxacin.

Animals↗
PubMed1986

[Monoclonal immunoglobulin in patients with malignant lymphoma].

This paper presents the results of monoclonal immunoglobulin (Ig) determination in 202 patients with malignant lymphoma, 51 with Hodgkin's disease (HD) and 151 with non-Hodgkin's lymphoma (NHL) including 4 patients with mycosis fungoides and 1 with pleomorphic T-cell lymphomas studied from Aug. 1980 to July. 1982. No monoclonal Ig was detected in 4 patients with mycosis fungoides, 51 with HD and 204 normal controls. In the rest 146 patients with NHL, 13 had monoclonal Ig (9%). The types and quantities of monoclonal Ig are discussed. We consider that the presence of monoclonal Ig may be one of the important characteristics of NHL.

Adolescent↗
PubMed1985

Effects of altered thyroid status on beta-adrenergic actions on skeletal muscle glycogen metabolism.

The effects of hypothyroidism on glycogen metabolism in rat skeletal muscle were studied using the perfused rat hindlimb preparation. Three weeks after propylthiouracil treatment, serum thyroxine was undetectable and muscle glycogen and Glc-6-P were decreased. Basal and epinephrine-stimulated phosphorylase a and phosphorylase b kinase activities were also significantly reduced, as were epinephrine-stimulated cAMP accumulation and cAMP-dependent protein kinase activity. Conversely, basal and epinephrine-stimulated glycogen synthase I activities were significantly higher while the Ka of the enzyme for Glc-6-P was lower in hypothyroid animals. Propylthiouracil-treated rats also had increased phosphoprotein phosphatase activities towards phosphorylase and glycogen synthase and decreased activity of phosphatase inhibitor 1. beta-Adrenergic receptor binding and basal and epinephrine-stimulated adenylate cyclase activities were reduced in muscle particulate fractions from hypothyroid rats. Administration of triiodothyronine to rats for 3 days after 3 weeks of propylthiouracil treatment restored the altered metabolic parameters to normal. It is proposed that the decreased beta-adrenergic responsiveness of the enzymes of glycogen metabolism in hypothyroid rat skeletal muscle is due to increased activity of phosphoprotein phosphatases and to reduced beta-adrenergic receptors and adenylate cyclase activity.

Animals↗
PubMed1985

Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents.

A series of novel arylfluoroquinolones has been prepared. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. Structure-activity relationship (SAR) studies indicate that the in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or p-hydroxyphenyl and the 7-substituent is either 1-piperazinyl, 4-methyl-1-piperazinyl, or 3-amino-1-pyrrolidinyl. The electronic and spatial properties of the 1-substituent, as well as the steric bulk, play important roles in the antimicrobial potency in this class of antibacterials. As a result of this study, compounds 45 and 41 were found to possess excellent in vitro potency and in vivo efficacy.

Acinetobacter↗
PubMed1982

Modulation by adrenalectomy and fasting of insulin effects in perfused hindlimb muscle.

Perfused hindlimb muscle from fed adrenalectomized rats accumulated more 2-deoxyglucose at submaximal concentrations of insulin in comparison to muscle from fed normal rats. However, in the fasted state, insulin-stimulated 2-deoxyglucose uptake was largely inhibited by adrenalectomy. Basal 2-deoxyglucose uptake did not differ between fed and fasted normal or adrenalectomized rats. The changes in insulin effects caused by adrenalectomy were due to altered hexose transport as shown by measurements of 3-O-methylglucose uptake and of intracellular free and phosphorylated 2-deoxyglucose. Muscles of fasted normal and fed or fasted adrenalectomized rats showed higher basal glycogen synthase --glucose-6-P/+glucose-6-P activity ratios than those of fed normal rats probably because of decreased glycogen content. However, muscles from fed or fasted adrenalectomized rats did not show any alterations in insulin effects on the activity ratio and half-maximal activation constant (A0.5) for glucose-6-P of glycogen synthase. Because of the dissociation of the effects of insulin on hexose transport and glycogen synthase in muscle of fasted adrenalectomized rats, it is concluded that the impairment in insulin-stimulated hexose transport in these animals is due to a defect lying beyond the interaction of insulin with its receptor.

3-O-Methylglucose↗
PubMed1981

Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle.

The effect of epinephrine on basal and insulin-stimulated glucose uptake in perfused hindlimbs of fed rats was studied. Insulin increased glucose uptake in a dose-dependent manner from a basal value of 1.5+/-0.3 up to a maximum value of 5.3+/-0.9 mumol/min per 100 g with 6 nM (1 m U/ml). Epinephrine at 10 nM and 0.1 muM also increased glucose uptake to 2.6+/-0.1 and 3.1+/-0.1 mumol/min per 100 g, respectively. These same concentrations of epinephrine, however, suppressed the insulin-stimulated glucose uptake to 3.2+/-0.3 mumol/min per 100 g. Both the stimulatory and inhibitory effects of epinephrine on glucose uptake were completely reversed by propranolol, but were not significantly altered by phentolamine. Uptake of 3-O-methylglucose and 2-deoxyglucose into thigh muscles of the perfused hindlimbs was stimulated fivefold by insulin, but was unaffected by epinephrine. Epinephrine also did not inhibit the stimulation of uptake by insulin. Epinephrine decreased the phosphorylation of 2-deoxyglucose, however, and caused the intracellular accumulation of free glucose. These last two effects were more prominent in the presence of insulin. Whereas epinephrine caused large rises in glucose-6-P and fructose-6-P, insulin did not alter the concentration of these metabolites either in the absence or presence of epinephrine.THESE DATA INDICATE THAT: (a) epinephrine has a stimulatory effect on glucose uptake by perfused rat hindlimbs that does not appear to be exerted on skeletal muscle; (b) epinephrine does not affect hexose transport in skeletal muscle; (c) epinephrine inhibits insulin-stimulated glucose uptake in skeletal muscle by inhibiting glucose phosphorylation. It is hypothesized that the inhibition of glucose phosphorylation is due to the stimulation of glycogenolysis, which leads to the accumulation of hexose phosphates, which inhibit hexokinase.

Adrenergic alpha-Antagonists↗