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Biomedical subjects

G L Dunn

Publications and source records attributed to G L Dunn.

At least 37 records · Page 2Linked to original sources
PubMed1979

In vitro and in vivo laboratory studies on three hydroxyiminophenylacetyl cephalosporins with particular reference to SK&F 80303, an unusually long-acting cephalosporin.

Three cephalosporins with 7-(2-hydroxyiminophenylacetamido) side chains (SK&F 79433, 80000 and 80303), differing in their 3-substituents, exhibited similar broad-spectrum antibacterial activity in vitro against strains of Staphylococcus aureus, Streptococcus faecalis and various Gram-negative bacilli. All three were active in vivo (s.c., mouse) against S. aureus, Escherichia coli or Klebsiella pneumoniae, but they differed significantly in serum pharmacokinetic profiles. SK&F 80303 produced high and extremely prolonged serum levels and protected mice when administered up to 24 hours prior to challenge with beta-lactamase-producing S. aureus or K. pneumoniae. It was resistant to hydrolysis by beta-lactamases from S. aureus, and variably so to beta-lactamases from E. coli strains. SK&F 80303 was bacteriolytic to logarithmically growing S. aureus, E. coli, Proteus mirabilis, K. pneumoniae and Enterobacter cloacae (partially). SK&F 80303 illustrates further the effect of the 3-sulfoalkyltetrazole substituent on the pharmacokinetic properties of cephalosporins. Its combined biological properties make it a possible candidate for therapeutic and long-term prophylactic use.

Animals↗
PubMed1978

A comparative assessment of alfathesin for use in outpatient anaesthesia.

Alfathesin and thiopentone were compared in a double blind study where each drug was given by intravenous infusion supplemented with fentanyl and nitrous oxide, in 54 healthy female patients under-going therapeutic abortion. The two drugs were similar in terms of changes in cardiorespiratory variables, side effects, clinical efficacy, and patient acceptability. Alfathesin produced a significantly more rapid recovery from anaesthesia, without the high incidence of dreams found with thiopentone in this study. Alfathesin would seem to be the preferable drug for use in outpatients undergoing minor surgical operations.

Abortion, Therapeutic↗
PubMed1978

The influence of fentanyl on an alfathesin infusion technique.

The effects of fentanyl (1 microgram/kg) supplementing an alfathesin infusion technique were assessed in a double blind study in 53 healthy unpremedicated female patients undergoing therapeutic abortion as outpatients. The addition of fentanyl reduced the tachycardia, tachypnoea and hyperventilation seen in those patients receiving alfathesin alone, without unduly prolonging recovery time. Two patients receiving alfathesin alone developed marked coughing or laryngospasm. Fentanyl would seem to be a desirable addition to an alfathesin infusion technique in unpremedicated patients presenting for outpatient anaesthesia.

Adult↗
PubMed1978

SK&F 75073, new parenteral broad-spectrum cephalosporin with high and prolonged serum levels.

SK&F 75073, a new parenteral cephalosporin, was found to have broad in vitro and in vivo antibacterial activity including isolates usually resistant to cephalothin and cefazolin. This activity included indole-positive Proteus and Enterobacter species and some Serratia isolates. Proteus mirabilis strains were particularly susceptible, as were Haemophilus influenzae and Neisseria species. The activity of SK&F 75073 against gram-positive bacteria was poorer than that of the control cephalosporins. This cephalosporin is highly bound to serum proteins, and a loss in in vitro activity was observed in the presence of serum. Parenteral administration of SK&F 75073 to experimental animals (mice, dogs, squirrel monkeys) resulted in high and prolonged serum levels when compared with cefazolin and other injectable cephalosporins. This favorable serum profile was reflected in the excellent protection observed in mice infected with pathogenic bacteria.

Animals↗
PubMed1977

Semisynthetic cephalosporins. Synthesis and structure-activity relationships of analogues with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones.

The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.

Acetates↗
PubMed1977

Synthesis and biological activity of some broad-spectrum N-acylphenyglycine cephalosporins.

The synthesis and the in vitro and in vivo antibacterial activities of a series of N-acylated phenylglycine cephalosporins are described. These compounds exhibit activity against a broad spectrum of gram-positive and gram-negative bacteria including some strains of Pseudomonas aeruginosa, a bacterial species normally insensitive to the cephalosporin antibiotics. The cephalosporins were prepared by acylation of cephaloglycin or its 3-tetrazolylthiomethyl analogue. In several cases, the acylations produced mixtures of diastereomeric cephalosporins, the components of which, when separated, showed different levels of antibiotic activity. Optimum activity was obtained when the acyl moiety on the phenylglycine nitrogen contained an oxygen atom centrally located between the amide carbonyl and a carboxyl substituent, preferably in a three- or five-membered ring. Replacement of acetoxymethyl by (1-methyl-1H-tetrazol-5-yl)thiomethyl at the 3 position resulted in overall improvement in activity both in vitro and in vivo. Against a group of P. aeruginosa strains, the best compounds of this series showed activity on the order of carbenicillin.

Animals↗
PubMed1977

Effect of unilateral pulmonary artery occlusion on the arterial oxygen pressure of children undergoing pulmonary systemic artery shunt procedures.

Of 20 children undergoing thoracotomy who had blood-gas analysis at various intervals during their operative procedure, 18 had congenital heart disease causing cyanosis. The venous admixture was apparent on compressing the lung to expose the mediastinal structures and was diminished upon clamping the pulmonary artery to the exposed lung. This observation may be of clinical value in raising the arterial oxygen pressure when sudden deterioration occurs during performance of a systemic pulmonary shunt in cyanotic children.

Blood Gas Analysis↗
PubMed1976

Orally active 7-phenylglycyl cephalosporins. Structure-activity studies related to cefatrizine (SK&F 60771).

The synthesis of a series of related broad-spectrum 7-phenylglycyl cephalosporins with 3-heterocyclicthiomethyl substituents is described. The effects of benzene-ring hydroxylation and 3-substituent variation on the in vitro antibacterial activity, height and duration of mouse serum levels, and effectiveness in protecting against bacterial infection in the mouse are examined. Included for comparison are cephalexin, cephaloglycin and their ortho-, meta- and para-hydroxy derivatives. The biological properties examined were influenced by the position of the hydroxyl group and by the nature of the 3-substituent. The 7-(p-hydroxyphenylglycyl)-3-heterocyclicthiomethyl analogs were found to produce significantly higher serum levels on oral administration to mice than their unhydroxylated counterparts. This effect was not observed with the 7-(m-hydroxyphenylglycyl)-3-heterocyclicthiomethyl cephalosporins, nor with the p-hydroxyphenylglycyl analog of cephalexin. While m- and p-hydroxylation had little effect on in vitro activity and o-hydroxyphenylglycyl cephalosporins tested had very low antibacterial activities and were not examined further. One derivative, 7-[R-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1H-1, 2, 3-triazole-4(5)-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 60771) was found to have outstanding in vitro and in vivo activities along with oral and subcutaneous serum levels in the mouse that were significantly higher than those obtained with cephalexin. This derivative which has been given the generic name cefatrizine was selected for extensive additional biological evaluation.

Animals↗
PubMed1975

A new parenteral cephalosporin, SK&F 59962: 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Chemistry and structure activity relationships.

The synthesis, microbiological profile and in vivo effectiveness in laboratory animals of a series of cephalosporins having 7-acyl substituents derived from methylthioacetic acid are described. Structure-activity relationships examined include the effect of oxidation of the side-chain sulfur atom, replacement of the (side-chain) methyl hydrogens by fluorine and replacement of the 3-acetoxy substituent by thioheterocycles. One derivative, 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 59962), was found to have outstanding antibacterial activity in vitro and in vivo.

Animals↗
PubMed1975

Laboratory studies with cefatrizine (SK + F 60771), a new broad-spectrum orally-active cephalosporin.

Cefatrizine (SK&F 60771), a new orally-active semisynthetic cephalosporin antibiotic with broad-spectrum antibacterial activity, was compared with cephalexin and cefazolin for in vitro and in vivo antibacterial activity and pharmacokinetic behavior in laboratory animals. The average MIC values obtained with cefatrizine against gram-positive and gram-negative bacteria were superior to those obtained with cephalexin and somewhat poorer than those of cefazolin. In addition, a large percentage of the enterobacter and enterococcus isolates were found to be susceptible. Cefatrizine had a longer biological half-life and a higher peak serum level than either cefazolin or cephalexin when administered parenterally or orally to mice at 20 mg/kg. It had striking in vivo protective activity in mice infected with Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Hemophilus influenzae, Proteus morganii or Staphylococcus aureus reflecting its superior pharmacokinetic profile in this animal species. A variable pharmacokinetic response between animal species was observed when cefatrizine was administered either orally or parenterally to dogs, squirrel monkeys or rabbits.

Administration, Oral↗