This is a continuation of efforts to characterize the pharmacology, especially the pharmacokinetics and pharmacodynamics, of clinically important neuromuscular blocking drugs and their antagonists. There are three specific aims. First, a conceptual model developed during the present granting period will be used to correlate the pharmacokinetics and pharmacodynamics of the antagonists neostigmine, pyridostigmine and edrophonium. The pharmacokinetics of these drugs have been previously determined but have not been correlated with the pharmacodynamics due to the lack of a suitable model -- which this laboratory has now designed and tested. The data obtained in normal patients using this model will be compared with those in patients with altered pathology (e.g. renal failure) or physiology (e.g. hypothermia). Second, the previously described expertise in assay development (e.g. chemical ionization selected ion mass spectrometric assay for pancuronium) will be extended to develop a gas chromatographic and a gas chromatographic mass spectrometric assay for the identification and quantitation of pancuronium, vecuronium and their metabolites. This added analytical capability will facilitate the rapid determination of the pharmacokinetics and metabolic profiles of pancuronium and vecuronium. Third, the basic and clinical pharmacology of atracurium will be studied focusing on the quantitative and qualitative analysis of its spontaneous and enzyme-mediated breakdown products and metabolites. In addition, the pharmacokinetics and clinical pharmacology of the predominant metabolite, laudanosine, a known central nervous system (CNS) stimulant, will be determined. These studies will facilitate the safe administration of neuromuscular blocking drugs and their antagonists, and will help to avoid adverse effects such as prolonged neuromuscular blockade and postoperative respiratory failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026403-10
Application #
3273885
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1979-04-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Segredo, V; Caldwell, J E; Wright, P M et al. (1998) Do the pharmacokinetics of vecuronium change during prolonged administration in critically ill patients? Br J Anaesth 80:715-9
Heier, T; Caldwell, J E; Sharma, M L et al. (1994) Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans. Anesth Analg 78:973-7
Heier, T; Caldwell, J E; Eriksson, L I et al. (1994) The effect of hypothermia on adductor pollicis twitch tension during continuous infusion of vecuronium in isoflurane-anesthetized humans. Anesth Analg 78:312-7
Segredo, V; Caldwell, J E; Matthay, M A et al. (1992) Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 327:524-8
Segredo, V; Shin, Y S; Sharma, M L et al. (1991) Pharmacokinetics, neuromuscular effects, and biodisposition of 3-desacetylvecuronium (Org 7268) in cats. Anesthesiology 74:1052-9
Heier, T; Caldwell, J E; Sessler, D I et al. (1991) Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology 74:815-9
Heier, T; Caldwell, J E; Sessler, D I et al. (1990) The effect of local surface and central cooling on adductor pollicis twitch tension during nitrous oxide/isoflurane and nitrous oxide/fentanyl anesthesia in humans. Anesthesiology 72:807-11
Fahey, M R; Canfell, P C; Taboada, T et al. (1990) Cerebrospinal fluid concentrations of laudanosine after administration of atracurium. Br J Anaesth 64:105-6
Magorian, T T; Lynam, D P; Caldwell, J E et al. (1990) Can early administration of neostigmine, in single or repeated doses, alter the course of neuromuscular recovery from a vecuronium-induced neuromuscular blockade? Anesthesiology 73:410-4
Segredo, V; Matthay, M A; Sharma, M L et al. (1990) Prolonged neuromuscular blockade after long-term administration of vecuronium in two critically ill patients. Anesthesiology 72:566-70

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