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Advertising↗
Biomedical subjects
D R Waud
Publications and source records attributed to D R Waud.
Quantal bioassay and stroke.
BACKGROUND: Experimental investigation of stroke, in particular the evaluation of therapeutic maneuvers, is difficult because even well-controlled experiments show considerable variability. Optimal use of resources requires efficient statistical analysis. SUMMARY OF REVIEW: A body of experience in pharmacology that is directly applicable to stroke studies is reviewed. The general approach, though well known to pharmacologists, is less familiar to neurologists. This paper attempts to give a survey so that neurologists encountering studies using this general class of analysis will better be able to put the technique into context. The general nature of a quantal bioassay is described, the underlying conceptual models are discussed, and specific examples are given. CONCLUSIONS: The pharmacologist's approach to the analysis of quantal bioassays can easily be adapted to the quantification of results in studies of stroke.
Biological Assay↗
Analysis of one-component saturable systems such as ligand binding, enzyme kinetic, uptake, and transport data.
Statistical methods for analyzing enzyme kinetic or drug binding assays involving simple first-order kinetics have been reviewed. The Eadie-Hofstee format combines many attractive features. Specifically, this plot is as efficient as any of the alternatives, shows no tendency to produce grossly aberrant values, does not require explicit weighting, does not require an iterative fitting process, gives the parameters of interest and their errors of estimate directly, and is unbiased (after correction). A correction for the bias inherent in the Eadie-Hofstee format has been developed. A numerical example and computer program are given in appendices.
Biological Transport↗
Dose-response curves and pharmacokinetics.
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Alfentanil↗
Tubocurarine sensitivity of the diaphragm after limb immobilization.
The effect of immobilization of a limb on subsequent sensitivity of the diaphragm to d-tubocurarine was examined in the guinea pig. A forelimb was immobilized in a plaster cast for 1 or 3 weeks. An isolated nerve-diaphragm preparation was then set up and the sensitivity to d-tubocurarine measured. Parallel assays on a nerve-lumbrical muscle preparation from the limb in the cast were also examined for comparison. The diaphragm from unimmobilized animals showed the normal decreased sensitivity relative to the lumbrical. After immobilization the sensitivity of the lumbrical decreased, whereas that of the diaphragm did not change. Thus in contrast to previously observed behavior in limb muscles, changes in d-tubocurarine sensitivity produced by immobilization do not involve the diaphragm.
Analysis of Variance↗
Interaction among agents that block end-plate depolarization competitively.
The influence of gallamine, metocurine, pancuronium, and tubocurarine on depolarization of a mammalian muscle end-plate region was examined to determine whether the antagonists given in combination exerted a degree of block consistent with the simple classical competitive model. Depolarization was produced by carbachol in isolated guinea pig lumbrical muscles and recorded by the moving fluid electrode technique. The dose-response values obtained were fitted to a regression embedded in a split plot factorial experimental design such as both to control and to measure effects of variation among preparations, order of administration, time, and level of block. Of the six possible pairings of the four drugs, four showed the simple additivity expected from a competitive mechanism, while two (pancuronium plus metocurine and metocurine plus gallamine) showed potentiation beyond additivity. In these latter two pairs the combination shifted the carbachol dose-response curve, respectively, 41 and 21% further than predicted from the classical model. The significance of this deviation in the light of alternative receptor models is discussed, and a model consistent with the observed results is outlined.
Animals↗
Atracurium-receptor kinetics: simple behavior from a mixture.
The apparent atracurium-receptor dissociation constant was assayed at the end-plate region of isolated guinea pig muscles. In a parallel series of experiments, the ED50 for producing neuromuscular block in the lumbrical muscle was also determined. The ratio of these two values was similar to the ratio found with classical competitive neuromuscular blocking agents like d-tubocurarine or pancuronium. We conclude that the commercial preparation of atracurium, though a mixture containing isomers of different configurations, behaves kinetically in a manner indistinguishable from what would be expected from a single substance.
Animals↗
Disuse and d-tubocurarine sensitivity in isolated muscles.
The effect of immobilization on subsequent sensitivity of limb muscles to d-tubocurarine was examined in a guinea pig model. A foreleg was immobilized in a cast for 1-4 weeks. At the end of this period, isolated nerve-lumbrical muscle preparations were set up and sensitivity to d-tubocurarine assayed. Immobilization increased the ED50 of the drug not only in muscles from the limb in the cast but also those from contralateral forelimbs and from hindlimbs. The increase in ED50 was not accompanied by atrophy. In a parallel series of experiments measuring the effect of d-tubocurarine on depolarization by carbachol, the apparent d-tubocurarine-receptor dissociation constant was determined. Immobilization produced no change in this parameter. Because immobilization of one extremity produced sensitivity changes in others, the anesthesiologist must be careful not to assume that monitoring from any limb will yield normal values in a patient with partial immobility.
Analysis of Variance↗
Quantitative examination of the interaction of competitive neuromuscular blocking agents on the indirectly elicited muscle twitch.
Gallamine, metocurine, pancuronium, and d-tubocurarine were compared when given alone and in combination with isolated guinea pig nerve-lumbrical preparations stimulated via the nerve. The experimental design was set up to control the effects of variation among preparations, order of administration, and time of administration (i.e., fresh vs. older preparation). The result was an assay able to measure potentiation with a coefficient of variation of 3%. A format for a graphic presentation to summarize such results is presented and discussed. Two combinations, gallamine plus d-tubocurarine and gallamine plus pancuronium, showed no sign of an interaction beyond that to be expected from a simple competitive interaction. Two others, metocurine plus pancuronium and gallamine plus metocurine, showed about a twofold greater potency when combined than would have been expected. The last two sets, pancuronium plus d-tubocurarine and metocurine plus d-tubocurarine, showed a slight degree of potentiation. These studies demonstrate that the deviation from simple additivity seen in vivo persists when examined in a system free from artifacts associated with uptake and distribution in the whole organism.
Animals↗
A precise and sensitive method for measurement of spinal cord blood flow.
Spinal cord blood flow can be accurately and rapidly measured in rabbits by intravenous injection of [14C]iodoantipyrine, collection of sequential arterial samples, and abrupt termination of blood flow to the spinal cord by severing the aorta with a previously implanted ligature. The radioactive tracer concentrations in arterial and spinal cord samples can be rapidly measured in a scintillation counter. The spinal cord blood flow can then be calculated from these blood and tissue tracer concentrations. This method is suitable for use in anesthetized or unanesthetized small animals.
Animals↗
Lithium and neuromuscular transmission.
The actions of lithium on end-plate depolarization and on indirect and direct twitch response of isolated guinea pig muscle were investigated. At clinical concentrations lithium did not cause depolarization, nor did it affect the depolarizing action of carbachol. Lithium also had no effect on the twitch response to nerve stimulation throughout its therapeutic serum concentration range and it did not alter the ED50 of pancuronium. When animals were chronically pretreated with lithium there appeared to be a slight reduction in dosage requirement for d-tubocurarine. At concentrations well above therapeutic serum levels, end-plate depolarization as well as indirect and direct twitch responses were depressed. It is concluded that, at therapeutic levels, there is minimal interaction of lithium with competitive neuromuscular blocking agents.
Animals↗
A comparison of the neuromuscular blocking and vagolytic effects of ORG NC45 and pancuronium.
ORG NC45, a neuromuscular blocking agent not producing tachycardia, was examined first, to establish the kinetics of the anatagonism it produces, and second, to test the hypothesis that the tachycardia seen with pancuronium and gallamine reflects an action on vagal postganglionic nerve endings. The action of ORG NC45 was studied on end-plate depolarization and neuromuscular transmission in the guinea pig lumbrical muscle. Also, the effect of ORG NC45 on the response of the cardiac pacemaker to carbachol and on the response of the pacemaker to pre- and postganglionic vagal stimulation was examined in isolated guinea pig atria. ORG NC45 was a potent neuromuscular blocking agent (twice as potent as pancuronium) in this species and showed typical competitive kinetics with a dissociation constant of 0.0103 micro M. However, ORG NC45 affected the atrial system only at very high concentrations and did not affect release of transmitter from vagal nerve terminals. These results thus confirm the hypothesis that presence or absence of vagolytic action goes hand-in-hand with tachycardia or its absence clinically.
Animals↗
Effects of volatile anesthetics on directly and indirectly stimulated skeletal muscle.
Isolated guinea pig nerve-lumbrical muscle preparations were exposed to halothane, methoxyflurane, isoflurane, enflurane, fluroxene, and diethyl ether. The temporal courses of the effects on indirectly and directly elicited twitch responses were determined over a range of concentrations for each agent. When the anesthetics were compared at concentrations equivalent in terms of minimum alveolar concentration (MAC), a spectrum was observed in which halothane, methoxyflurane and isoflurane depressed the indirect twitch response at 3.5--5 MAC and the direct twitch response at 8--10 MAC. Diethyl ether and fluroxene depressed the indirect twitch response at 2--3.5 MAC and the direct twitch response at 3--6 MAC. Enflurane depressed the indirect response at 1.5--2.5 MAC and the direct response at 6--8 MAC. When the anesthetics were compared at concentrations equivalent in terms of their abilities to depress end-plate depolarization, however, all anesthetics were equipotent. Depression of the indirect twitch response occurred only when anesthetic concentrations were great enough to depress depolarization by 50 per cent.
Anesthetics↗
The role of uptake of noradrenaline of its positive inotropic effect in relation to muscle geometry. Statistical evaluation.
1. The influence of saturable drug uptake on the drug concentration near the receptor sites was shown theoretically to depend on the geometry of the preparation; increases in the volume/surface ratio (V/S) of the preparation decrease the sensitivity of the preparation to an agonist inactivated in the tissue. 2. The positive inotropic effect of (-)-noradrenaline was found to depend on the ratio V/S of the preparation; papillary muscles with larger V/S were less sensitive to the drug and showed steeper noradrenaline concentration-effect curves. 3. An algorithm for the statistical estimation of the parameters of the saturable uptake process was derived. It was applied to the positive inotropic noradrenaline effect in relation to muscle geometry. As an analysis of variance showed, the model explained a significant proportion of the shift of (-)-noradrenaline concentration-effect curves associated with variation in size of the preparation.
Animals↗
A vagolytic action of neuromuscular blocking agents at the pacemaker of the isolated guinea pig atrium.
To examine the basis of tachycardia seen clinically with some neuromuscular blocking agents, the potencies of d-tubocurarine, dimethyltubocurarine, gallamine, and pancuronium in antagonizing the effects of vagal stimulation on the guinea pig atrial pacemaker were determined and expressed as an ED50 for vagal blockade. These ED50 values were compared with the respective potency values of these agents at the motor endplate. This comparison showed that in clinical doses, gallamine and pancuronium may reach levels that produce vagal blockade. Comparison with atropine indicated that the vagolytic action of the neuromuscular blocking agents was not attributable to receptor occlusion, but reflected instead an action on the vagus nerve itself.
Animals↗
The effects of diethyl ether, enflurane, and isoflurane at the neuromuscular junction.
The actions of diethyl ether, enflurane, and isoflurane at the neuromuscular junction were examined in isolated guinea pig lumbrical muscles. These anesthetics depressed the ability of carbachol to depolarize the endplate region; this depression of depolarization did not show competitive kinetics. None of the anesthetics altered the affinity of the acetylcholine receptor for d-tubocurarine, i.e., the dissociation constant of d-tubocurarine was unchanged. Since diethyl ether, enflurane, and isoflurane produced no observable alteration of the receptor, the antagonism of the drug-induced depolarization of the neuromuscular junction appears to be exerted at a stage subsequent to reaction with the receptor. (Key words: Anesthetics, volatile, diethyl ethers; Anesthetics, volatile, euflurane; Anesthetics, volatile, isoflurane; Neuromuscular relaxants, d-tubocurarine; Neuromuscular junction.).
Acetylcholine↗
Depolarization block and phase II block at the neuromuscular junction.
The effects of repeated doses of decamethonium or succinylcholine in muscles of the cat, dog, and rabbit have been examined. In particular, the relation of degree of neuromuscular block to intensity of the electrical change at the end-plate region has been found to be more consistent when the peak spatial gradient of depolarization is used as a measure of electrical effect than when the peak depolarization is used; the reason for this difference is discussed. A plot of twitch height against electrical change provides a convenient frame of reference for following the development of phase II block quantiatively. Examples presented show that the extent and kinetics of phase II block can vary considerably among species or among muscles in a given species.
Anesthesia, Intravenous↗