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Biomedical subjects

G H Miller

Publications and source records attributed to G H Miller.

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

A new tetracycline antibiotic from a Dactylosporangium species. Fermentation, isolation and structure elucidation.

An actinomycete identified as a Dactylosporangium sp. produces a new tetracycline, 4a-hydroxy-8-methoxychlortetracycline (Sch 34164). The addition of magnesium ions to complex fermentation media increased the antibiotic titers. Sch 34164 was isolated by solvent extraction and Sephadex G-25 column chromatography. The novel structure was proposed based on spectroscopic analysis. The shift of C-4a (35 to 77 ppm) and C-8 (140 to 163 ppm) in the 13C NMR as compared to chlortetracycline was indicative of the novel hydroxyl and methoxy substituents, respectively.

Actinomycetales↗
PubMed1987

Direct selection of a specifically blocked mutant of Actinomadura brunnea. Isolation of a third 8-methoxy substituted chlortetracycline.

Actinomadura brunnea produces 2'-N-methyl-8-methoxychlortetracycline. A derivative of this strain has been isolated that is specifically blocked in methylation of the 2'-amino position. This isolate was detected by screening approximately 30,000 colonies of a mutagenized population of Actinomadura brunnea using a direct soft agar overlay with an Escherichia coli indicator. The antibiotic produced by the blocked mutant has been identified as 8-methoxychlortetracycline (Sch 36969) based upon its biological activity, relative mobility on TLC and HPLC, and spectroscopic data.

Chemical Phenomena↗
PubMed1987

In vitro and in vivo characterization of novel 8-methoxy derivatives of chlortetracycline.

The in vitro activities of three new 8-methoxychlortetracyclines, Sch 36969, 33256 and 34164 were compared to tetracycline, minocycline and doxycycline. Against aerobic Gram-negative rods Sch 36969 had a geometric mean MIC (GMM) of 4.2 micrograms/ml, about 8-fold more potent than Sch 33256, and similar to all the other compounds. Sch 36969 also had good activity against methicillin-resistant (GMM, 0.21 micrograms/ml) and -susceptible Staphylococci (GMM, 0.14 micrograms/ml), Streptococci (GMM, 0.06 micrograms/ml), and most anaerobic bacteria (GMM, less than 0.5 micrograms/ml). In general, Sch 36969 was similar to, or more potent than, all the other compounds tested. Serum levels of Sch 36969 in squirrel monkeys were 4-fold lower (AUC, 4.5 micrograms.hours/ml) than those of chlortetracycline (AUC, 16.1 micrograms.hours/ml). In mouse protection tests (PD50s) against various strains of bacteria, Sch 36969 was similar in activity to tetracycline, but up to 6-fold less active than chlortetracycline. The structure activity relationships for these new chlortetracyclines are described.

Animals↗
PubMed1986

Prohibiting psychiatric diagnosis in insanity trials. With special reference to John W. Hinckley, Jr.

Over 12 different diagnoses were offered in expert testimony during the Hinckley insanity trial. This multitude of diagnoses, many of them overlapping, served to focus attention on the labels themselves rather than on the psychological processes of the defendant. As a result, differences in opinion among the experts were exaggerated; more important, the testimony confused the jury. I believe that stating--or even explaining--a diagnosis is not only unnecessary but also misleading in courtroom testimony. In an application of Roy Schafer's "action language" approach (1976; Miller 1979, 1983) and consistent with the law, I recommend that diagnoses be excluded from insanity trials.

Adult↗
PubMed1986

Effect of NaCl supplementation of Mueller-Hinton broth on susceptibility of staphylococci to aminoglycosides.

The addition of NaCl to cation-supplemented Mueller-Hinton broth increased the MICs of gentamicin, amikacin, and netilmicin for coagulase-positive and -negative staphylococci in a concentration-dependent manner. At 2% NaCl, geometric mean MICs were elevated 14.1- to 25.6-fold. Mueller-Hinton broth containing added NaCl should not be used for testing the susceptibility of staphylococci to aminoglycosides.

Amikacin↗
PubMed1986

A model for predicting utilization of psychiatric facilities.

This paper develops a parsimonious model for predicting utilization of a regional system of psychiatric facilities based on census data. The model combines conceptual simplicity with readily-available data sources. In practical terms, the model removes the need to undertake comprehensive and expensive utilization surveys. In theoretical terms, the model indicates that the fundamental relationship between utilization rates and key social indicators is stable through time. Although further testing is necessary, it would seem that these key indicators can provide reasonable estimates of psychiatric morbidity for up to ten years in the future.

Forecasting↗
PubMed1985

Gram-negative bacilli resistant to third-generation cephalosporins: beta-lactamase characterization and susceptibility to Sch 34343.

We studied 192 recent clinical isolates, comprising six species of Gram-negative bacilli resistant either to cefotaxime or latamoxef (Moxalactam), from several hospitals. All isolates were resistant to several other third-generation cephalosporins or a monobactam. Two to five types of chromosomal beta-lactamases, as defined by isoelectric focusing, were readily identified in each species. Isolates of Citrobacter, Enterobacter and Serratia produced higher levels of chromosomal beta-lactamase than corresponding cefotaxime-susceptible strains. In addition, 20 of 57 produced one or two plasmid-determined beta-lactamases, TEM-1, OXA-2, or a novel enzyme, OHIO-1. The penem and carbapenem antibiotics, Sch 34343 and imipenem, were more active than cefotaxime, ceftazidime, ceftriaxone, latamoxef and aztreonam against isolates of Acinetobacter, Citrobacter, Ent. aerogenes, Ent. cloacae and Morganella, whereas imipenem, ceftazidime, and aztreonam were more active against Serratia isolates. The addition of plasmid-determined beta-lactamase increased resistance to piperacillin, cefoperazone and cefamandole but not to cefotaxime, ceftazidime, ceftriaxone, latamoxef, aztreonam, Sch 34343, or imipenem. Of 24 strains susceptible to aminoglycosides, none produced a plasmid-determined beta-lactamase, whereas 20 were found among the 33 strains resistant to aminoglycosides. Resistance of clinical isolates to newer beta-lactams appears to be due primarily to a high level of chromosomal cephalosporinase present without inducing agents. The plasmid-determined beta-lactamases, TEM-1 and OHIO-1, contributed little to resistance to most of the newer beta-lactams but were strongly associated with aminoglycoside resistance in these selected isolates. The greater in-vitro efficacy of the penem and carbapenem antibiotics, Sch 34343 and imipenem, against most of these isolates makes them promising candidates as first line agents against these pathogens.

Acinetobacter↗
PubMed1985

Evaluation of the in-vivo efficacy of Sch 34343.

Sch 34343 showed a linear dose response (with respect to AUCs) in mice following both intravenous and subcutaneous administration. It was 100% bioavailable following subcutaneous administration. Peak serum levels, AUCs, beta-phase half-life and recovery of Sch 34343 from the urine of mice indicated that it was similar to cephalothin and cefamandole. In experimental mouse infections, against Gram-negative strains, Sch 34343 was more active than cephalothin, equal to or more active than cefamandole and cefoxitin, but less active than latamoxef (moxalactam) and cefotaxime following single or multiple dose therapy. It was the most active compound against Staphylococcus. Sch 34343 was equally active against strains sensitive to beta-lactams and strains producing beta-lactamases. In an anaerobic abscess model in mice, Sch 34343 was more active than cefoxitin and clindamycin against Bacteroides fragilis. In Escherichia coli meningitis in rabbits, it cured rabbits with a single intravenous dose of 50 mg/kg.

Animals↗
PubMed1985

Interspecies pharmacokinetic scaling of Sch 34343.

Pharmacokinetic parameters of Sch 34343 have been determined for mice, rats, rabbits, monkeys, dogs and humans and correlated among species as an exponential function of body weight. The pertinent pharmacokinetic parameters tested are apparent and steady-state volumes of distribution, total body clearance, elimination phase half-life, and mean residence time. This study showed that the extrapolation of animal data to humans on a new investigational drug, Sch 34343, can be potentially useful.

Animals↗
PubMed1985

Evaluation of the in-vitro antibacterial activity of Sch 34343.

The in-vitro activity (as measured by geometric mean MICs, mg/l) of Sch 34343 against aerobic and anaerobic bacteria was compared with that of 14 other selected beta-lactam antibiotics including aztreonam, latamoxef (moxalactam), ceftazidime and imipenem. Sch 34343 had good activity (less than 2 mg/l) against most Gram-negative aerobic bacteria whether or not they contained high levels of plasmid-mediated or chromosomally-mediated beta-lactamases. It was slightly less potent against strains of Morganella and Serratia (less than 4 mg/l) and inactive against Pseudomonas (greater than 64 mg/l). A very small inoculum effect was observed against strains containing beta-lactamases indicating stability. Unlike the third-generation cephalosporins, Sch 34343 had excellent activity (less than or equal to 0.18 mg/l) against staphylococci, comparable to that of imipenem and ampicillin. While Sch 34343 had equally good potency (0.17 mg/l) against penicillinase-positive staphylococci, it was inactive against methicillin-resistant staphylococci (greater than or equal to 35 mg/l). Sch 34343 also had good activity against streptococci. The most unusual aspect of the in-vitro activity was its activity against Bacteroides (including Bact. fragilis) and other anaerobes. Sch 34343 had mean MICs less than or equal to mg/l for all Bacteroides and Clostridium spp. tested except CI. difficile (3.4 mg/l).

Anti-Bacterial Agents↗
PubMed1985

In-vitro activity of Sch 34343 against Gram-negative bacteria producing characterized beta-lactamases.

The activity of Sch 34343 against 13 strains producing large amounts of characterized beta-lactamases was compared with that of imipenem, latamoxef (moxalactam), aztreonam and other third-generation cephalosporins. Sch 34343, like imipenem, was active against all strains, including many resistant to all other beta-lactams. MICs of Sch 34343 determined for 16 different inocula were rarely increased even at very high inocula. Sch 34343 was rapidly bactericidal against Escherichia coli TEM-2, Enterobacter agglomerans (with an induced beta-lactamase) and two strains of Bacteroides fragilis with highly active cephalosporinases. Like cefoxitin, Sch 34343 was only slowly inactivated by concentrated crude penicillinases which inactivated cefotaxime within 1 h. Sch 34343 was even more stable to cephalosporinases than was cefoxitin. Stability of the antibiotics to the different beta-lactamases was also determined by pre-incubating them with dilutions of the beta-lactamases before determination of MICs against E. coli 25922. Very large amounts of all enzymes were required to increase the MICs significantly for Sch 34343 and imipenem. These results indicate the good stability of Sch 34343 to beta-lactamases.

Anti-Bacterial Agents↗
PubMed1985

Comparison of aminoglycoside resistance patterns in Japan, Formosa, and Korea, Chile, and the United States.

The resistance mechanisms of more than 2,000 aminoglycoside-resistant gram-negative aerobic bacteria were estimated by a method that assigned a biochemical mechanism based on susceptibility to selected aminoglycosides. Strains from hospitals in Japan, Formosa, and Korea (the Far East) were compared with strains from Chile and the United States. Of the strains from Chile, 90% had an aminoglycoside resistance pattern indicative of the 3-N-acetyltransferase [AAC(3)-V] enzyme. Of the strains from the Far East, 78% had susceptibility patterns suggesting the presence of AAC(6') enzymes. In contrast, strains from the United States had a wider variety of resistance mechanisms including 2''-O-adenylyltidyltransferase [ANT(2'')], AAC(3), AAC(6'), and AAC(2'). Reflecting these differences in resistance patterns, the frequencies of resistance to gentamicin, tobramycin, dibekacin, and amikacin in strains from the United States were different from those in strains from the Far East. These differences seem to be correlated with different aminoglycoside usage in the two regions. In the United States, where gentamicin was the most widely used aminoglycoside, 92% of the strains were resistant to gentamicin, 81% were resistant to dibekacin, and 8.8% were resistant to amikacin. In the Far East, dibekacin and kanamycin were widely used in the past and more recently amikacin has been frequently used. Of the strains from this region, 99% were resistant to dibekacin, 85% were resistant to gentamicin, and 35% were resistant to amikacin.

Aminoglycosides↗