Off-pump coronary artery bypass grafting for acute heparin-induced thrombocytopenia.

Surgical revascularization of coronary arteries is problematic for patients with heparin-induced thrombocytopenia because the available nonheparin anticoagulants cannot be reversed pharmacologically. We used three-vessel off-pump coronary artery bypass grafting in a patient with heparin-induced thrombocytopenia, as it allowed us to use substantially lower doses of nonheparin anticoagulant (danaparoid sodium), compared with procedures requiring cardiopulmonary bypass.

Determination of carboxypeptidase A using N-acetyl-phenylalanyl-3-thiaphenylalanine as substrate: application to a direct serum assay.

N-Acetyl-L-phenylalanyl-L-3-thiaphenylalanine has been shown to be a substrate for carboxypeptidase A. Hydrolysis of the compound obeys Michaelis-Menten kinetics with a KM of 0.22 mM and a kcat of 6720 min-1 at 22 degrees C. A colorimetric assay, employing Ellman's reagent to detect the thiophenol released upon cleavage of the peptide, has been developed. The assay can be used for the direct determination of carboxypeptidase A in serum.

Determination of leucine aminopeptidase using phenylalanyl-3-thia-phenylalanine as substrate.

The peptide mimetic L-phenylalanyl-L-3-thiaphenylalanine has been shown to facilitate a sensitive and simple determination of leucine aminopeptidase. A colorimetric assay, employing Ellman's reagent to detect the thiophenol released upon hydrolysis of the dipeptide, has been developed. Under the experimental conditions employed the substrate has a Km of 0.054 mM and a kcat of 5800 min-1 and can distinguish sharply between leucine aminopeptidase and aminopeptidase M.

Studies on the active site of succinyl-CoA:tetrahydrodipicolinate N-succinyltransferase. Characterization using analogs of tetrahydrodipicolinate.

Cyclic and acyclic analogs of tetrahydrodipicolinate (THDPA) are evaluated in a study of the active site of succinyl-CoA:tetrahydrodipicolinate N-succinyltransferase. In addition to the natural substrate, THDPA, one cyclic and several acyclic compounds are also succinylated. 2-Hydroxytetrahydropyran-2,6-dicarboxylic acid is a potent competitive inhibitor having a Kis of 58 nM. Based on the results of this study, a stereochemical model for the succinylation of THDPA is proposed. The major features of this model are as follows. 1) The succinylase binds THDPA (L-configuration). 2) Hydration of the imine group follows to give 2-hydroxypiperidine-2,6-dicarboxylic acid in which the two carboxyl groups are trans. 3) Succinylation then occurs and the ring opens to give the acyclic product. It is suggested that 2-hydroxytetrahydropyran-2,6-dicarboxylic acid is a transition state analog by virtue of the fact that it structurally resembles the hydrated intermediate.

Peptides of 2-aminopimelic acid: antibacterial agents that inhibit diaminopimelic acid biosynthesis.

Succinyl-CoA:tetrahydrodipicolinate-N-succinyltransferase is a key enzyme in the biosynthesis of diaminopimelic acid (DAP), a component of the cell wall peptidoglycan of nearly all bacteria. This enzyme converts the cyclic precursor tetrahydrodipicolinic acid (THDPA) to a succinylated acyclic product. L-2-Aminopimelic acid (L-1), an acyclic analogue of THDPA, was found to be a good substrate for this enzyme and was shown to cause a buildup of THDPA in a cell-free enzyme system but was devoid of antibacterial activity. Incorporation of 1 into a di- or tripeptide yielded derivatives that exhibited antibacterial activity against a range of Gram-negative organisms. Of the five peptide derivatives tested, (L-2-aminopimelyl)-L-alanine (6) was the most potent. These peptides were shown to inhibit DAP production in intact resting cells. High levels (30 mM) of 2-aminopimelic acid were achieved in the cytoplasm of bacteria as a result of efficient uptake of the peptide derivatives through specific peptide transport systems followed, presumably, by cleavage by intracellular peptidases. Finally, the antibacterial activity of these peptides could be reversed by DAP or a DAP-containing peptide. These results demonstrate that the peptides containing L-2-aminopimelic acid exert their antibacterial action by inhibition of diaminopimelic acid biosynthesis.

Intramuscular cimetidine and ranitidine as prophylaxis against gastric aspiration syndrome--a randomized double-blind study.

Preoperative cimetidine 300 mg or ranitidine in 50 and 100 mg doses were administered intramuscularly to 120 patients in a randomized double-blind study. The volume and pH of gastric aspirate samples obtained after tracheal intubation and before extubation were measured. The pH of gastric aspirate was higher following ranitidine 100 mg than ranitidine 50 mg or cimetidine 300 mg at both intubation and extubation (p = 0.006). In addition, fewer patients tended to be "at risk" of pulmonary aspiration syndrome (pH less than or equal to 2.5) after ranitidine 100 mg than ranitidine 50 mg or cimetidine 300 mg. Preoperative intramuscular ranitidine 100 mg was found to be suitable for use in protection against gastric aspiration syndrome.

Antimicrobial activity of SK&F 88070, an expanded-spectrum cephalosporin with high and prolonged levels in blood.

SK&F 88070 (7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3- [[[1-(2-sulfaminoethyl)-1H-tetrazol-5-yl]thio] methyl]-3-cephem-4-carboxylic acid) is a new parenteral cephalosporin with an expanded-spectrum profile of antibacterial activity, including activity against Pseudomonas aeruginosa, and with high and prolonged levels in sera of experimental animals. The activity of SK&F 88070 was compared with those of cefotaxime and other cephalosporins against more than 500 clinical isolates in vitro by microtiter twofold dilution tests in Mueller-Hinton broth. SK&F 88070 was extremely potent against all of the members of the family Enterobacteriaceae that were tested, including beta-lactamase-producing strains. Its activity against P. aeruginosa was comparable to those of cefotaxime, ceftizoxime, and moxalactam. SK&F 88070 was less potent than cefotaxime or ceftizoxime against Staphylococcus species but was comparable to moxalactam. It had in vivo activity against the same Bacteroides strains as did cefotaxime, although it was less potent. Both SK&F 88070 and cefotaxime had less activity when tested with high inoculum levels of most of the rarer gram-negative bacteria. There was a greater decrease in the activity of SK&F 88070 than of cefotaxime in the presence of human serum, reflecting the higher degree of binding of SK&F 88070 to serum proteins. SK&F 88070 had peak levels and half-lives in serum much greater than those of cefotaxime in experimental animals after parenteral administration. In mouse protection studies, SK&F 88070 was more effective than cefotaxime against gram-negative bacteria but less effective than cefotaxime against Staphylococcus aureus.

Zomepirac as an analgesic premedication: a comparison of three dosage regimens.

Three regimens of oral zomepirac premedication - 100 mg and 200 mg administered one hour preoperatively, and 100 mg administered 30 minutes preoperatively - were compared in terms of the control of postoperative pain. Primary outcomes were postoperative analgesic requirements, pain intensities and side effects. Sixty patients undergoing laparoscopic sterilization by Fallop ring were studied, using a double blind randomized design. All patients received a standardized general anaesthetic in which narcotic supplementation was avoided. Zomepirac 100 mg, when administered 30 minutes preoperatively, was the preferred regimen in terms of postoperative remedication rates, pain intensity, and side effects. However, the overall rate of remedication was high and was probably a result of the severe pain experienced by these patients in the early postoperative period. Plasma levels of zomepirac at termination of anaesthesia were consistent with the differences in remedication profiles and showed significant correlations with initial postoperative pain intensity, as assessed by an ordinal descriptive scale (r = 0.431, p = 0.025) and time to remedication (r = 0.541, p = 0.004), thus adding validity to the model.

A double-blind comparison of cimetidine and ranitidine as prophylaxis against gastric aspiration syndrome.

Preoperative cimetidine, ranitidine, or placebo were administered, orally or intravenously to 190 patients in a double-blind study. The volume and pH of gastric aspirate samples, obtained after tracheal intubation and before extubation, were measured. Both cimetidine and ranitidine produced higher mean pH levels and thus fewer patients "at risk" should gastric aspiration occur (pH less than or equal to 2.5) than did placebo. Intravenous ranitidine (in both 40- and 80-mg doses) produced fewer patients at risk in the event gastric aspiration should occur than did cimetidine, 300 mg, and the 80-mg dose produced a higher mean pH level. Oral ranitidine, 150 mg, produced a significantly higher mean pH level than did oral cimetidine, 300 mg, and tended to give fewer patients at risk. The volumes of gastric contents aspirated were similar following each of the drugs except that the volume was significantly less two hours following oral ranitidine, 150 mg, than after oral cimetidine, 300 mg.

Alfathesin and etomidate for minor outpatient anaesthesia.

Etomidate was compared with alfathesin for induction and maintenance of anaesthesia in a double-blind fashion in 48 fit patients undergoing minor gynaecological operations as outpatients. The patients were randomized to receive either etomidate 0.3 mg . kg-1 or alfathesin 75 microliters . kg-1 as intravenous induction agents. All patients received fentanyl 1 microgram . kg-1 and breathed 70 per cent nitrous oxide in oxygen. Cardiovascular changes were minimal in both groups and there was less depression of minute volume with etomidate. The incidence of side effects including pain upon injection, involuntary movements, and postoperative nausea and vomiting was higher following etomidate. Recovery was equally rapid in both groups. No adverse reactions were seen. Alfathesin would appear to be preferable to etomidate as an induction and maintenance agent in unpremedicated fit outpatients undergoing minor gynaecological operations.

The pharmacokinetics and pharmacodynamics of minaxolone.

Plasma concentrations of minaxolone were measured in 15 female patients during and for up to 3 hours after a minaxolone and nitrous oxide anesthetic. Nine patients received a single dose and six patients two or three doses of minaxolone. Plasma minaxolone decay can be described by two-compartment kinetics. Distribution is rapid, with a mean half-life of 2.1 minutes, and the elimination half-life is short (47 minutes). Plasma clearance is high (1.55 l./min). Plasma levels of minaxolone at recovery were similar in patients receiving both single and multiple doses, suggesting a valid relationship between plasma level and effect. It is suggested that minaxolone may be a suitable agent for administration by continuous infusion.

Strain-induced anisotropy measurement in oxide films grown on silicon.

A multiangle single-wavelength ellipsometric method has been applied to the evaluation of anisotropy and stress in SiO(2) films grown on silicon substrate. The method is nondestructive, and it does not require a priori knowledge of the dielectric functions of the oxide layer. A novel theoretical anisotropic multiple-layer program is used to calculate the Fresnel reflection coefficients at various angles of incidence; and an iterative least-squares algorithm compares the theoretical calculations to the experimental data. The data-fitting process yields the index, the thickness, and the anisotropy of the oxide layer and also the index and thickness of the SiO(x) transition layer.

Paediatric outpatient surgery under general anaesthesia.

An innovative health care programme to provide anaesthesia and surgery to small children on an outpatient basis is described, together with the results of formal evaluations of the programme. It is concluded that, with attention to the education of the child and parents at a pre-anaesthetic clinic and the involvement of one parent with the induction and recovery of the child, the anaesthesia and surgery experience has negligible adverse psychological impact for the child, a positive influence on parental understanding and appreciation of the quality of anaesthesia care, in addition to a reduced incidence of cross infection and reduced cost to the health care system.

An early clinical assessment of the steroid anaesthetic Minaxolone.

Minaxolone, a new water-soluble steroid anaesthetic, was studied in combination with nitrous oxide in 30 healthy female patients. The objective of the study was to assess induction dosage, clinical efficacy, recovery characteristics, and frequency of side effects. It proved to be an effective anaesthetic causing only minimal cardiovascular and respiratory depression. Those side effects which occurred during operation were felt to be due in part to light anaesthesia and lack of analgeia. Excitatory movements and hypertonus occurred in seven patients during operation and in ten patients in the early recovery phase. Late recovery was impressive, both in quality and lack of side effects, and all patients were considered fit for discharge from hospital within four hours of the operation. Minaxolone appears to be a promising new anaesthetic worthy of further study.

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.