Biomedical subjects
Publications and source records attributed to S Agoston.
The effects of 4-aminopyridine (a non-anticholinesterase antagonist of curare-like agents) on the evoked muscle action potentials (EMAP) in a patient with Eaton Lambert Syndrome are reported. On two separate occasions the i.v. administration of 0.31 mg kg(-1) and 0.62 mg kg(-1) was followed by a 300% increase of EMAP for about 2 h without serious side-effects.
The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 microgram kg(-1) respectively. The addition of 100 microgram kg(-1) of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7.4 microgram kg(-1). The addition of 200 microgram kg(-1) of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 microgram kg(-1). We conclude that both neostigmine and pyridostigmine interact with 4-aminopyrine synergistically.
Data about plasma concentration, renal and biliary elimination of tubocurarine, gallamine, alcuronium and pancuronium are taken from the literature for synoptical pharmacokinetic analysis. All plasma concentration curves can be described by triexponential functions according to an open three-compartment pharmacokinetic model in line, the elements of which are an application and measuring compartment, a pharmacologically specific compartment and a non-specific one. The corresponding results for all drugs represent the same range and there is no substantial basis for a further differentiation of clinically significant drug specific characteristics, neither regarding the time course of neuromuscular blockade nor the excretory or metabolic disposition. Thus no particular advantage or disadvantage of any drug can be stated from the kinetic or metabolic point of view and especially none seems to have a striking advantage in patients with impaired renal function. Drug specific peculiarities are more likely to be found in the field of side effects.
Pharmacokinetic data of tubocurarine, gallamine, alcuronium and pancuronium in patients with normal and without renal function are taken from the literature. They are adapted to an open three compartment pharmacokinetic model, and the proportional intercompartmental distribution is calculated as a function of time from 1 min to 8 h. All drugs show similar kinetic properties: During the first 10 min rapid disappearance from compartment 1 results in saturation of compartment 2. Maximum saturation of compartment 3 is achieved after 1 to 2 h followed by a gradual disappearance of the relaxants from the whole system. 20-25% of the dose undergo sequestration apart from intercompartment equilibrium. In normal individuals sequestration is observed after 2 to 3 h whereas in anuric patients it is already demonstrated during the first hour. Intercompartmental redistribution is the basic principle governing the pharmacodynamic profile of all of the four drugs if given in clinical dosage.
Plasma concentration curves of patients with normal and impaired renal function are fitted to a tri-exponential function according to an open three compartment pharmacokinetic model. A detailed discussion of the relationship between theoretical distribution volumes, clinical pharmacodynamics and morphological or biochemical structures provides the basis for the concept of a central application and measuring compartment, a pharmacologically specific compartment and a non specific one. The distirbution of pancuronium from the application compartment to the specific compartment results in the onset of muscular paralysis. The recovery is governed by renal elimination of the unchanged drug as well as by its redistribution into the non specific compartment. In anuric patients the spontaneous recovery after 3--4 h is the effect of redistribution only. Neither metabolic degradation nor increased biliary elimination can sufficiently compensate for the lack of the renal pathway. The clinician should always keep in mind that after the recovery from pancuronium-induced muscular paralysis, both in patients with or without renal pathology, considerable residues of the active drug are stored at nonspecific and even specific receptor sites for many hours.
We tested the effect of hypothermia on the pharmacokinetics and pharmacodynamics of pancuronium in the cat. In 14 cats given pancuronium, 120 microgram/kg i.v., we found that neuromuscular block lasted between 2.5 and 3.0 times longer at 29 degrees C (N = 5) than at 34 degrees C (N = 5) or 39 degrees C (N = 4). The apparent plasma elimination half-life was 46 +/- 7 min (S.E.) at 29 degrees C as compared to 21 +/- 2 and 25 +/- 6 min at 34 and 39 degrees C, respectively. The volume of distribution of the central compartment and total volume of distribution at steady state were less at 29 and 34 dgrees C than at 39 degrees C. Total plasma clearance was 4.3 +/- 0.4 ml/kg/min at 29 degrees C and 10.7 +/- 0.9 and 10.9 +/- 1.5 ml/kg/min at 34 and 39 degrees C, respectively. The reduced plasma clearance resulted at least in part from a markedly reduced biliary and urinary excretion of pancuronium at 29 degrees C as compared to 34 and 39 degrees C. In four other cats, the plasma concentration of pancuronium was correlated with depression of twitch tension under steady-state conditions. The ED50 of pancuronium (plasma concentration required for a 50% depression of twitch tension) was 0.035 and 0.073 microgram/ml at 29 and 38 degrees C, respectively. We conclude that a pancuronium neuromuscular block is prolonged at 29 degrees C because of an increased sensitivity of the neuromuscular junction to pancuronium and delayed biliary and urinary excretion.
To determine the potency of pancuronium and its metabolites, 3-OH-, 17-OH- and 3,17-OH-pancuronium, cumulative dose-response curves were determined in five anesthetized patients with each drug. Pancuronium (ED50 = 0.041 mg/kg) was 2 times more potent than 3-OH-pancuronium (ED50 = 0.082 mg/kg), 50 times more potent than 17-OH-pancuronium (ED50 = 2.0 mg/kg) and 54 times more potent than 3,17-OH--pancuronium (ED50 = 2.15 mg/kg). In 21 other patients, one equipotent dose of either pancuronium or one of its metabolites was given as an i.v. bolus. Onset time and duration of neuromuscular blockade from 3-OH- and 3,17-OH-pancuronium did not differ significantly from that of pancuronium; 17-OH-pancuronium had a shorter duration of action than did pancuronium. Although pancuronium tended to have a slightly longer elimination half-life, the pharmacokinetics of the four drugs did not differ significantly. The elimination half-lifes were 110, 68, 73 and 71 min for pancuronium and its 3-OH, 17-OH and 3,17-OH derivatives, respectively. We conclude that although pancuronium is more potent than its 3-OH, 17-OH and 3,17-OH metabolites, the pharmacokinetics of these three metabolites do not differ from each other and from that of pancuronium.
The relationship between the time course of the decay of serum concentrations of pancuronium and its neuromuscular blocking effect has been investigated after the intravenous administration of 50, 80 and 100 microgram/kg doses to anesthetized patients. Following administration of these doses, maximal neuromuscular block in the adductor pollicis muscle developed in about 7, 2.5, and 2 minutes and lasted about 20, 40, and 60 minutes, respectively. The times from start of recovery to return of twitch tension to 25, 50, and 75 per cent of control were similar in the different dosage groups, but occurred progressively later with increasing doses. At times of 25, 50, and 75 per cent recovery mean serum concentrations (pooled values) were 0.13 +/- 0.01,0.11 +/- 0.01, and 0.10 +/- 0.01 microgram/ml (+/- SEM), respectively. Neuromuscular transmission to the adductor pollicis muscle started to recover at a mean serum pancuronium concentration of 0.21 +/- 0.03 microgram/ml. The data obtained in this study are in agreement with the experimental and clinical findings of similar studies with d-tubocurarine, and indicate that there is a correlation between the serum concentrations of muscle relaxants and the intensity of their neuromuscular activities.
The renal and hepatic elimination and biotransformation, as well as the relation between disposition and duration of action of pancuronium and two of its analogues, dacuronium and ORG.6368, have been investigated in the cat. In pharmacokinetic studies, appreciable amounts of the latter two compounds were found in the urine, bile and liver 8 h after their intravenous administration. Various proportions of the injected dose of the respective drugs were metabolized. In another series of experiments it was shown that the early hepatic uptake (during the first 3 min after the injection) of ORG.6368 was significantly greater than that of dacuronium and pancuronium. The intensity and duration of action of the neuromuscular blocking effect of the three compounds were studied after intravenous and "close" intraarterial injection. On the basis of these pharmacokinetic and neuromuscular studies, it was concluded that the short duration of action of ORG.6368 is due primarily to its early hepatic uptake. The possibility cannot be excluded, however, that differences in the kinetics of the drug action of ORG.6368 and the other two compounds also contributed significantly to the differences seen in the duration of action of these compounds.
Dantrolene sodium in different concentrations was administered to the spontaneously beating heart placed in a modified Langendorff apparatus. Heart frequency and contractility were recorded. Dantrolene sodium was also administered to the rat diaphragm. Twitch tension after indirect supramaximal stimulation was recorded. Dantrolene sodium produced a long lasting dose-dependent reduction of the contractility of the isolated rat heart up to 75% of control values. It had no effect on the heart frequency. The drug also decreased the force of contraction of the rat skeletal muscle in vitro to the same extent. The diaphragm appeared to be more sensitive to low concentrations of dantrolene sodium than was heart muscle i.e. the dose-response curve on rat diaphragm was flatter. It may be concluded however that higher concentrations of dantrolene sodium may effect the contractility of heart muscle as well and that this may have clinical implications.
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1. The effects of 4-aminopyridine on the contractility of the fast-contracting tibialis anterior and the slow-contracting soleus muscles of cats under chloralose anaesthesia have been studied. 2. 4-Aminopyridine, in doses of 0.5 mg/kg and above, produced a slowly developing increase in the twitch tension of directly stimulated chronically denervated and of indirectly stimulated innervated tibialis anterior muscles, but had little or no effect on twitches of soleus muscles. The effect of innervated tibialis anterior muscles was more pronounced than that on chronically denervated muscles, but it was nevertheless concluded that the whole effect on innervated muscles was the result of a direct action on the muscle fibres. The simultaneously occurring facilitatory action on neuromuscular transmission, which is manifested in the anti-curare action of 4-aminopyridine, had a faster time-course and occurred in both the tibialis anterior and the soleus muscles. 3. 4-Aminopyridine antagonized dantrolene sodium on on the tibialis anterior muscle but not on the soleus muscle. The antagonism could be described as physiological antagonism since it simply reflected the opposing actions on contractility of the two drugs. 4. 4-Aminopyridine was without effect on maximal tetanic tension of either the tibialis anterior or the soleus muscle. 5. It seems clear from the literature that a species difference exists with regard to the ability of 4-aminopyridine to increase muscle contractility. The results described in this paper show that muscle differences within the same species also exist.
The interaction between 2,4 diaminopyridine (2,4-DAP) and neostigmine or edrophonium was studied in vivo in the rat sciatic nerve-tibialis anterior muscle preparation using the constant infusion technique of pancuronium. The ED50 value (dose of drug which produces 50% antagonism) decreased from 17 to 7 micrograms/kg with neostigmine and from 70 to 20 micrograms/kg with edrofonium, when these 2 compounds were co-administered with 40 micrograms/kg 2,4-DAP. The ED50 value of 2,4-DAP decreased from 160 to 90 micrograms/kg when 3.5 micrograms/kg neostigmine was added. From these experiments we conclude that 2,4 DAP acts synergistically with both neostigmine and edrophonium. In experiments using the train of four (T4) stimulation, we compared the antagonistic potencies of the drugs alone and in combination with each other. Neostigmine proved to be the most potent. 2,4-DAP given alone was not able to restore the muscle contraction completely (T4 ratio greater than 70%) up to a dose of 400 micrograms/kg. The doses of neostigmine and edrophonium could be halved, when they were combined with a small amount of 2,4-DAP without apparent lose of antagonistic potency.