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J M Becket

Publications and source records attributed to J M Becket.

5 recordsLinked to original sources
PubMed1996

Genetically engineered serine protease inhibitor for hemostasis after cardiac operations.

BACKGROUND: The serine protease inhibitor aprotinin has been widely reported for its beneficial action in limiting blood loss after cardiopulmonary bypass (CPB). A potent human serine protease inhibitor known as protease nexin II or amyloid precursor protein has been recently isolated. A recombinant protein known as recombinant Kunitz protease inhibitor (rKPI; Scios Nova, Mountain View, CA) with sequence homology to the protease nexin II-amyloid precursor protein molecule has been manufactured. METHODS: Recombinant Kunitz protease inhibitor was assessed in an ovine model of CPB as a hemostatic agent after CPB. Sheep (n = 22) underwent CPB for 90 minutes. Two thoracic drains were sited and drain losses collected for a period of 3 hours after CPB. Wounds were subjectively assessed before closure for "dryness" using a visual analogue scale. Sheep were randomized to control (n = 8), aprotinin (n = 8), and rKPI (n = 6) groups. RESULTS: Control animals had a drain loss of 409.4 +/- 39.4 mL/3 h, compared with 131.3 +/- 20.3 mL/3 h for the aprotinin group and 163.7 +/- 34.3 mL/3 h for the rKPI group (p = 0.16). Hemoglobin loss was 11.6 +/- 3.6, 6.02 +/- 2.1, and 4.6 +/- 1.2 g/3 h for the control, rKPI, and aprotinin groups respectively (p = 0.25). The subjective analysis of the wounds at the end of CPB found aprotinin (1.25 +/- 0.16; p < 0.05) and rKPI (1.17 +/- 0.17; p < 0.05) animals to score significantly lower than control animals (2.63 +/- 0.42). CONCLUSIONS: On the basis of these in vivo findings, genetic modification may yield a more efficacious serine protease inhibitor with the inherent advantages of using a human-based protein.

Animals↗
PubMed1995

The haemodynamic effects of the thromboxane A2 receptor antagonist GR32191B during cardiopulmonary bypass in the dog.

This study examined whether treatment with the specific thromboxane (TX) A2 receptor antagonist GR32191B would result in an improvement in peripheral haemodynamics during and after cardiopulmonary bypass (CPB) in anaesthetized dogs compared with animals given either saline (control) or aspirin. Following thoracotomy, heparinization and aortic cannulation, and 35 minutes before CPB, dogs received intravenously either GR32191B (15 micrograms/kg/min), saline (50 ml bolus) or aspirin (225 mg bolus) (n = 6 per group). Cardiac output (dye dilution), femoral artery blood flow (electromagnetic flowmeter), gastrocnemius muscle tissue perfusion (133Xe clearance), retinal blood flow (fluorescein angiography), and thromboxane biosynthesis (urinary excretion rates of TXB2 and the metabolite 2,3-dinor-TXB2) were measured before, during and after a standard 90 minute period of CPB at 2.4 l/min/m2 and 28 degrees C. The aspirin-treated group manifested an eightfold reduction in TXB2 excretion compared with controls, indicating a decrease in TXA2 biosynthesis. There were few haemodynamic differences between the groups, though the aspirin-treated group had better maintained muscle tissue perfusion post-CPB and significantly fewer retinal microcirculatory occlusions than GR32191B-treated animals. We conclude that specific TXA2 receptor antagonism provides no significant improvement in peripheral haemodynamics; rather aspirin provides a modest haemodynamic benefit.

Animals↗
PubMed1991

Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog.

Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data.

Adrenergic beta-Antagonists↗
PubMed1991

Comparison of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs.

STUDY OBJECTIVE: The aim was to measure cardiac output while rebreathing tidal volumes, by correction of soluble gas uptake for gaseous mixing. DESIGN: Simultaneous measurements of cardiac output by indocyanin green and freon 22 uptake during rebreathing were made. Mixing for a hypothetical gas of identical gaseous diffusivity to freon 22 was calculated by interpolation between concentrations of two insoluble gases, helium and sulphur hexafluoride. Mixing efficiency was estimated by the number of breaths for helium to become 99% equilibrated with lung gas (n99-He). EXPERIMENTAL MATERIAL: Five anaesthetised dogs rebreathed at intervals with 300 ml of test gas. MEASUREMENTS AND MAIN RESULTS: 63 comparisons of cardiac output using indocyanin green and freon 22 uptake (over breaths 7-13 using the mean mixed volume of distribution), gave a mean (95% confidence interval) underestimation of 0.345 (0.093-0.597) litre.min-1 (14%). Exclusion of 12 points in which n99-He was greater than 15 resulted in a mean underestimation of 0.052(-0.163-0.267) litre.min-1 (2%). Without correction for gaseous mixing, freon 22 uptake for these data overestimated blood flow by a mean of 1.31 litre.min-1 (overestimation = 2.7 over breaths 5-11). Use of the equilibrium volume of distribution resulted in an overestimation of blood flow relative to green dye of 1.2 litre.min-1 (breaths 5-11) and 0.76 litre.min-1 (breaths 7-13). CONCLUSIONS: Estimates of cardiac output by soluble gas uptake are optimal when correction is made for mixing of gas of identical diffusivity. The mean mixed gas volume gives the best correlation with the reference method, implying a selective distribution of blood flow to the better ventilated areas.

Animals↗