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Biomedical subjects

C A Shanks

Publications and source records attributed to C A Shanks.

At least 73 records · Page 4Linked to original sources
PubMed1982

Gallamine administered by combined bolus and infusion.

A technique combining an intravenous bolus and intravenous infusion regimen of gallamine based on its pharmacokinetics was developed to produce continuous relaxation during surgery. The combination of a bolus dose of gallamine, 2.5 mg/kg, and infusion, 0.8 mg/kg/hr, was tested in 11 patients. In 10 patients, surgery continued long enough to allow demonstration of an apparent plateau in the serum gallamine concentrations. At the cessation of the infusion, the mean gallamine concentration of 11.8 microgram/ml was associated with an average paralysis intensity of 92%. Pharmacokinetic analysis of the gallamine serum concentration-time data was fitted to a three-compartment model. In this study of 50- to 76-year-old patients, the most striking difference from other studies was that the elimination halflife averaged 247 minutes in this study whereas 128 to 141 minutes has been reported previously.

Aged↗
PubMed1981

Dose-response curves for four neuromuscular blockers using continuous i.v. infusion.

Cumulative dose-response curves were constructed in man for tubocurarine, pancuronium, gallamine and alcuronium from data obtained during barbiturate-narcotic-nitrous oxide anaesthesia. Fifty-six adult patients received one of these drugs, administered by constant-rate infusion, a technique enabling response levels and results pooled to derive a composite dose-response curve for each drug. Using the mechanical twitch response, the ED50 for each neuromuscular blocking drug was: tubocurarine 0.236 mg kg-1, pancuronium 0.048 mg kg-1, gallamine 1.3 mg kg-1 and alcuronium 0.161 mg kg-1. The slopes of the composite curves for pancuronium and alcuronium were significantly steeper than those for tubocurarine and gallamine. In the alcuronium studies the simultaneous compound electromyogram was recorded, and usually this was more depressed than the mechanical twitch response, giving an ED50 of 0.135 mg kg-1.

Action Potentials↗
PubMed1981

Gallamine disposition in surgical patients with chronic renal failure.

1 Plasma levels of gallamine and the elicited neuromuscular response have been measured in seven patients with compromised renal function who received a single 2 mg/kg dose and in a further patient who received an initial dose of 2 mg/kg followed by two additional doses of 1 mg/kg. 2 The plasma level-time data from all patients was adequately explained by a biexponential equation interpreted as a two-compartment open mammillary model. 3 Comparison of the model-independent pharmacokinetic parameters for gallamine between these patients and a group of normal patients revealed that the elimination phase half-life (T and one-half beta) was significantly prolonged in renal failure with a marked reduction in the plasma clearance of gallamine. 4 Gallamine had larger apparent volumes of distribution in the presence of renal failure than those found in normal patients. 5 The peak paralysis levels attained and the associated plasma concentrations of gallamine were similar in patients with and without renal failure. 6 At this low dosage the rate of recovery from paralysis in renal failure patients, though similar to that noted normally, appeared to be somewhat slower in some patients. 7. The results suggest that gallamine is not to be preferred to other nondepolarizing muscle relaxants in patients with renal failure.

Adult↗
PubMed1981

Pharmacokinetics and pharmacodynamics of gallamine triethiodide in patients with total biliary obstruction.

Pharmacokinetics and pharmacodynamics of gallamine were assessed in seven patients undergoing surgery for correction of total biliary obstruction. Results were compared to those obtained in a previous study of 17 patients without obstruction. A significant increase in the steady-state volume of distribution of gallamine was noted in patients with biliary obstruction as compared to the group without obstruction, but no significant differences between the groups were apparent for the biologic half-life and total clearance of the drug. Duration of action of gallamine and rate of recovery together with onset characteristics were similar in both patient groups. Slight accumulation of gallamine was noted in two of the four patients with biliary disease receiving multiple doses of gallamine, but this was also characteristic of data obtained in the patients without obstruction. At completion of surgery to relieve the biliary obstruction all patients showed a measurable degree of recovery from paralysis, and no difficulties were experienced in the reversal of relaxant effect. Contrary to the observed "resistance" of patients with liver disease to the action of d-tubocurarine no such finding was apparent in this study with gallamine. Gallamine may be the relaxant of choice for surgery to relieve total biliary obstruction provided no complicating renal pathology is also present.

Adult↗
PubMed1980

Pharmacokinetic studies in man with gallamine triethiodide. I. Single and multiple clinical doses.

Plasma concentrations of gallamine were determined in 6 patients undergoing anaesthesia for elective surgery receiving a single intravenous bolus dose of 2 mg/kg and in a further 11 patients requiring additional doses (0.5 to 2 mg/kg) of the relaxant. The two-compartment open model was found to characterize adequately both the single and multiple dose data. No significant differences were noted when the model-independent pharmacokinetic parameters between the two groups of patients were compared with the exception of the distribution phase half-life (t1/2 alpha) (6.70 min single vs 9.19 min multiple p less than 0.05). Mean values for the pooled data for the half-life (t1/2 beta), plasma clearance (Clp) and volume of distribution (Vd beta) were 134.58 min, 1.20 ml/min/kg and 225.28 ml/kg respectively. Evoked twitch response was monitored in each patient to assess the degree of neuromuscular blockade. In only one patient was the bolus dose sufficient to produce complete (100%) blockade, thus the degree of maximal response varied between 78 to 100% and took some 3 to 10 minutes after dose administration. The concurrently measured gallamine plasma concentrations ranged from 9.30 to 19.20 micrograms/ml. Linear regression of the offset data (20 to 80% paralysis) in 10 patients revealed a recovery rate of 0.35 to 1.33%/min. For 5 patients where offset data was available over the entire range of response (0 to 100%) the calculated mean effective plasma concentrations for gallamine at 50 and 95% paralysis (ECp50, ECp95) were found to vary between 3.43 to 10.28 micrograms/ml, and 5.66 to 23.37 micrograms/ml respectively.

Adolescent↗
PubMed1980

Pharmacokinetic studies in man with gallamine triethiodide. II. Single 4 and 6 mg/kg i.v. doses.

Fourteen patients undergoing elective surgery were studied at two levels of gallamine dosage. Seven patients received a single bolus dose of 4 mg/kg, and the remainder received 6 mg/kg. The venous plasma concentration-time data from both groups were characterized in terms of a two-compartment open model. No significant differences in the various pharmacokinetic parameters were noted. However the distribution and clearance terms from these two patient groups were significantly higher than those obtained with a previous group of patients receiving lower (2 mg/kg) single and multiple doses. Assessment of neuromuscular twitch response showed that maximum blockade was attained in all patients within 5 min with the time to peak effect being dose dependent. Recovery from paralysis as assessed at 99, 95 and 90% paralysis indicated that the duration of action was similarly dose dependent. The concurrently measured plasma concentrations showed wide variation but were higher at more profound levels of paralysis. Arterial blood samples for 5 patients receiving the 4 mg/kg gallamine dose were taken simultaneously with the venous samples over the first sixty minutes. No significant arterio-venous differences in gallamine plasma concentration were noted at any time interval in all subjects.

Adolescent↗
PubMed1980

Clinical pharmacokinetics of alcuronium chloride in man.

The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t 1/2 beta), apparent volume of distribution (Vd beta), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 microgram/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 microgram/ml.

Adult↗
PubMed1980

Pharmacokinetics of tubocurarine administered by combined i.v. bolus and infusion.

Pharmacokinetic data were used to calculate an i.v. bolus dose and infusion regimen for tubocurarine (dtc). This produced continuous paralysis in 12 anaesthetized patients. In nine of the patients the duration of infusion was sufficient to achieve a "steady-state" dtc concentration in the plasma (mean 1.09 microgram ml-1). At the completion of the infusion, twitch response had been abolished in half of the group, but 30 min later all had a measurable response. All plasma concentrations decreased rapidly after infusion, from a mean of 1.35 microgram ml-1, in either a mono- or bi-exponential manner. In all instances, a two-compartment open model was used to describe the plasma concentration-time data. The pharmacokinetic parameters derived from this study did not differ significantly from those reported for a single dose except that the plasma clearance was less.

Adolescent↗
PubMed1980

Tubocurarine and pancuronium: a pharmacokinetic view.

This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

Dose-Response Relationship, Drug↗
PubMed1980

Electromyographic and mechanical twitch responses following suxamethonium administration.

Electromyographic and mechanical evoked twitch responses at the hand were observed simultaneously following suxamethonium. The intensity of neuromuscular blockade was assessed by comparison with their control heights of the responses obtained from both the force of thumb adduction and from the compound electromyogram (EMG). Surface electrodes placed dorsally over the lateral hand provided two EMG signals, one of which was assessed in terms of its amplitude, the other as the rectified and integrated energy envelope. While the mechanical and electrical events were roughly in agreement there was better conformity between the two EMG techniques in the assessment of paralysis.

Adult↗
PubMed1979

Dose-response and plasma concentration-response relationships of pancuronium in man.

The dose-response and plasma concentration-response relationships for pancuronium in man were studied during its intravenous administration to eight patients at a rate of 1.62 microgram/kg/min. The (log) dose-response relationships resulted in a sigmoid curve that was linear in its central range. At 20, 50 and 80 per cent paralysis the cumulative dosages (mean +/- SEM) were 0.04 (+/- 0.01), 0.06 (+/- 0.01), and 0.08 (+/- 0.02) mg/kg, respectively. Administration of pancuronium, 56 microgram/kg, to another 12 patients at a more rapid rate resulted in a maximum intensity of blockade of more than 50 per cent. The (log) plasma concentration-response curve was not parallel to the dose-response curve, with mean (+/- SEM) concentrations at 20, 50 and 80 per cent paralysis of 0.21 (+/- 0.04), 0.25 (+/- 0.04), and 0.30 (+/- 0.04) microgram/ml, respectively during the onset of paralysis. Following cessation of the infusion, plasma concentrations of pancuronium were usually lower for the same intensity of paralysis. Using data for the entire response range during recovery from paralysis, the mean effective plasma concentration of pancuronium for a 50 per cent response was 0.20 microgram/ml. Recovery from blockade to 95 per cent paralysis (5 per cent of control twitch height) was associated with a plasma concentration of 0.25 microgram/ml, a value in agreement with plasma concentrations obtained following a single bolus administration of pancuronium, 6 mg, to 30 patients. For 27 patients the rate of decline of paralysis from 80 to 20 per cent showed a highly statistically significant relationship to the apparent rate of decline in the plasma concentrations of pancuronium.

Adult↗
PubMed1979

Studies in man with a constant-rate infusion of tubocurarine.

Tubocurarine (dTC) was administered to twenty patients by intravenous infusion at a predetermined constant rate, and the twitch responses recorded at stimulus intervals of 10 seconds (0.1 Hz). In half the group dTC plasma concentrations were measured both during and following the infusion. This provided data for derivation of the pharmacokinetic parameters, two plasma concentration-response curves and the dose-response curve. The mean effective dTC plasma concentration for 50% paralysis during the infusion (onset) was 0.93 micrograms/ml, but was lower post-infusion (offset) (0.54 micrograms/ml, p less than 0.001). The steady state dTC plasma concentration which should produce 95% paralysis was predicted to lie between 0.95 and 1.67 micrograms/ml. In the range 20 to 80% paralysis the slopes of the two (log) concentration-response lines were similar, although steeper than the associated (log) dose-response regression line, the test for parallelism showed no statistical difference. Combination of the plasma concentration-response curve with pharmacolkinetic models was used to predict the time course of paralysis in patients with normal and impaired renal function. Dose-response curves for the other 10 patients were also constructed to stimulus frequencies from 0.02 to 5 Hz. In the range 20 to 80% paralysis the regression lines appeared to be parallel. The results were pooled for all patients at a stimulation rate of 0.1 Hz, giving a mean effective dose of dTC at 95% paralysis of 0.53 mg/kg, and an ED50 of 0.22 mg/kg.

Action Potentials↗
PubMed1978

The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. I. Lignocaine.

The pharmacokinetics and metabolism of lignocaine in premature neonates was studied after subcutaneous administration. The collection of serial urine together with a limited number of blood samples from neonates enabled simultaneous computer fitting of data to a pharmacokinetic model. The disposition kinetics of lignocaine in four neonates were compared with similar data reported for adults. Neonates had prolonged t1/2 (neonate mean: 3.16 h; adult mean: 1.80 h), and an increased total volume of distribution (neonate mean: 2.75 l/kg; adult mean: 1.11 l/kg) compared with adults. Total plasma clearance (Cltp) normalised on body weight showed no significant difference between neonates (mean: 0.610 l/h/kg) and adults (mean: 0.550 l/h/kg). The urinary excretion of lignocaine and several of its metabolites was studied in 8 neonates and 11 adults. Neonates were shown to excrete much more unchanged lignocaine (mean: 19.67%) compared with adults (mean: 4.27%) and the proportion of the dose excreted as 4-hydroxyxylidine is considerably reduced in neonates (neonate mean: 8.89%; adult mean: 63.78%). The use of the two pharmacokinetic parameters, t1/2 and Cltp, as indices of drug elimination ability are discussed.

Adult↗
PubMed1978

Plasma concentrations of pancuronium during predetermined intensities of neuromuscular blockade.

The plasma concentrations of pancuronium were monitored during i.v. infusions of the relaxant in dogs. Pancuronium was administered at rates which maintained the degree of neuromuscular blockade at three predetermined levels. The concentrations of the drug in the blood were consistent for any one animal but showed considerable overlap for the three levels of paralysis between animals. Concentrations obtained during infusion and which maintained the twitch response at 20% and 80% of control were compared, in the same dogs, with concentrations obtained during recovery from a bolus injection of pancuronium. When the infusion maintained the twitch response at 20% of the control value, the mean plasma concentration of pancuronium was 0.152 microgram ml-1. That measured after the bolus injection was 0.156 microgram ml-1. The concentrations at 80% of control were 0.094 microgram ml-1 and 0.083 microgram ml-1 respectively. The agreement between these results suggests a relationship between the plasma concentration of the relaxant and its effect during the termination of the action after a large bolus injection of the drug. As this occurs chiefly during the postdistribution equilibrium, the relatively slow decrease in plasma concentration would appear to become the rate-limiting factor in recovery from paralysis.

Animals↗