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L Endrenyi

Publications and source records attributed to L Endrenyi.

At least 55 records · Page 3Linked to original sources
PubMed1987

Decompression of the spinal cord improves recovery after acute experimental spinal cord compression injury.

The value of decompression after spinal cord injury in patients is still an unresolved issue. It has previously been shown in our laboratory that functional recovery in rats after cord compression varied with both the force and time until decompression. However, the longest duration studied was only 15 minutes, which is far less than that usually encountered in clinical practice, and therefore, the present study was undertaken to determine the value of decompression after more prolonged periods of compression. A factorially designed experiment with five rats per cell was used with the clip compression injury model. Forces of 2.3, 16.9 or 53.0 gms were applied at C7-T1 until decompression was performed after 15, 60, 120, or 240 minutes of compression. Functional recovery was assessed weekly for 8 weeks using the inclined plane technique. Maximum and minimum performance limits were established in normal rats and rats with cord transection, respectively. Univariate analysis and multiple comparison tests were used to analyse the data. The major determinant of recovery was the force of the injury. For example, the animals injured by the 2.3 gm clip performed significantly better than those injured at higher forces for all times until decompression (p less than 0.0001), and there was a significant difference in recovery between the groups injured by the 16.9 and 53.0 gm clips, although only for the 15 minutes until decompression group (p less than 0.05). The time until decompression also affected recovery, but only for the lighter compression forces (2.3 and 16.9 gm). For example, animals decompressed after 60 minutes of 2.3 gm compression recovered significantly better than those decompressed after 240 minutes (p less than 0.05). Thus, if the initial injury force is small, decompression is beneficial even after prolonged injury.

Animals↗
PubMed1986

Design of experiments for the precise estimation of dose-response parameters: the Hill equation.

Optimal experimental designs were evaluated for the precise estimation of parameters of the Hill model. The optimally effective designs were obtained by using the criterion of D-optimization. For the Hill model, optimal designs replicate 3 sampling points. These points were shown to be quite sensitive to the behavior of the experimental error. Since an investigator is often uncertain about error conditions in biological studies, a practical approach would use the sampling scheme calculated for an intermediate error condition. Thus, if the behavior of error variances is not known, precise parameters of the Hill model are obtained by choosing concentrations which yield fractional responses (responses divided by their asymptotic, maximum value) of 0.086, 0.581 and 1.0. When experimental constraints limit the maximum attainable concentration and response, all design points are lowered. Appropriate designs can be constructed based on the design which is optimal when constraints result in a maximum attainable fractional response of 0.5. The optimal designs were found to be robust when the parameter values assumed by the investigator did not equal their true values. The estimating efficiencies obtained by using two frequently applied designs were assessed. Uniformly spaced concentrations yielded imprecise parameters. Six-point, geometrically spaced designs gave generally good results. However, their estimating efficiency was generally exceeded by the recommended sampling schemes even in the presence of uncertainty about error conditions. The method exemplified in this paper can be used for other models.

Dose-Response Relationship, Drug↗
PubMed1986

Robust regression of enzyme kinetic data.

A method described previously [Cornish-Bowden & Endrenyi (1981) Biochem. J. 193, 1005-1008] for fitting theoretical equations to enzyme kinetic data without prior knowledge of weights or error distribution has been tested by computer simulation. With the equations for various kinds of linear inhibition as an example, the method performed well under all of the conditions examined, giving results that were often much better than those given by widely used least-squares alternatives, and were never appreciably worse. Although equations for two-substrate kinetics were not explicitly tested, the results for inhibition equations can be generalized to include two-substrate equations because the two are formally equivalent for simulation purposes. As a check on the results with inhibition equations the method was also tested for fitting bell-shaped pH-activity profiles and gave correspondingly good results.

Computers↗
PubMed1986

An enzyme-distributed system for lidocaine metabolism in the perfused rat liver preparation.

The influence of enzymic distribution on lidocaine metabolism was investigated in the once-through perfused rat liver preparation. Low input concentrations of 14C-lidocaine (1-2 microM) and preformed monoethylglycine xylidide (MEGX; 2.3-2.8 microM) were delivered by normal and retrograde flow directions to the liver preparations at 10 ml/min per liver. Upon reversal of normal to retrograde delivery of lidocaine, the rates at which lidocaine, MEGX, and glycine xylidide (GX) left the liver almost doubled, whereas the rates of appearance of (total) hydroxylated lidocaine and MEGX in bile and perfusate increased to lesser extents. Upon reversal of normal to retrograde delivery of preformed MEGX, the rates of appearance of MEGX and GX were virtually unchanged. Computer simulations on lidocaine and preformed MEGX metabolism were performed on both evenly distributed ("parallel tube" model) and enzyme-distributed systems. An even or parallel distribution of N-deethylation and hydroxylation activities for lidocaine metabolism failed to predict the observed increased hepatic availability of lidocaine. Rather, the distribution of a low-affinity, high-capacity N-deethylation system anterior to a high-affinity, low-capacity hydroxylation system for lidocaine metabolism adequately predicted the increased hepatic availability of lidocaine. Further extension of these consistent enzyme-distributed models on the metabolism of lidocaine metabolites suggests that the N-deethylation and hydroxylation activities for the metabolism of lidocaine, MEGX, 3-hydroxyidocaine, and 3-hydroxy MEGX are not identically distributed. When these enzyme-distributed models were appraised with reference to the "parallel tube" and "well-stirred" models of hepatic drug clearance, predictions from these enzyme-distributed models proved to be superior to the "parallel tube" and "well-stirred" models for the present data on lidocaine metabolites with normal and retrograde perfusions. Previously published data on lidocaine and MEGX metabolism after inputting 4 micrograms/ml (17 microM) lidocaine at flow rates of 10, 12, 14, and 16 ml/min were reexamined with respect to the adequacy of these enzyme-distributed models. They were found to be superior to the evenly-distributed or "parallel tube" model in predicting hepatic availability of lidocaine and the rate of appearance of MEGX. However, the enzyme-distributed systems were not as consistent as the "well-stirred" model in predicting lidocaine hepatic availability in these flow experiments.

Animals↗
PubMed1985

Plasma concentration-response relationships of two formulations of propranolol.

The time-course of beta blockade induced by two formulations of propranolol was compared to their plasma concentration-time curves. Graded infusions of isoproterenol were used to assess the degree of beta blockade at different times after oral administration of 80 mg of propranolol to 11 healthy volunteers. The time-course of drug effect was measured as the decline of the systolic pressor dose 20 (SPD 20) and the chronotropic dose 20 (CD 20). Variability of plasma propranolol concentration was small, varying within subjects from 27% to 36% and between subjects from 19% to 28% at the various sampling times. Pharmacodynamic effects showed a similar reproducibility: intra-individual variation was 15% to 28% for CD 20 and 17% to 32% for SPD 20; interindividual variation was 10% to 24% for CD 20 and 13% to 23% for SPD 20. Pooling of the data of all subjects indicated a parallel decline of drug concentration and effect. However, three of the 11 subjects showed drug effects declining at a faster rate than drug levels. This dissociation between serum concentrations and effects points out the clinical relevance of complementing kinetic studies of propranolol with pharmacodynamic studies. The good reproducibility within subjects and the small interindividual variation suggests that isoproterenol dose-response curves may be a useful tool for such studies.

Adult↗
PubMed1985

A statistical comparison of parameter estimation for the Michaelis-Menten kinetics of human placental hexosaminidase.

To enable the most effective method of kinetic discrimination between a group of isozymes such as those of human placental hexosaminidases (HEX), three methods estimating the parameters of the Michaelis-Menten equation were evaluated. Computer-simulated experiments were performed under various conditions. They indicated that, in the presence of constant absolute or relative errors, the method of unweighted nonlinear least squares yielded slightly more precise and accurate parameters than the method of the direct linear plot. Parameters calculated from the Lineweaver-Burk plot were very imprecise and inaccurate. The direct linear plot was comparatively resistant to outlier observations; however, only when outliers were substantial did the method become superior to nonlinear least squares. The calculation of a confidence limit is necessary for the evaluation of any resulting differences in the kinetic parameters for a set of isozymes. This can easily be calculated from either the Lineweaver-Burk plot or the nonlinear least-squares method. However, those calculated from the Lineweaver-Burk plot are biased, especially at higher levels of experimental errors. Therefore, the nonlinear least-squares method is the one most suited for the discrimination of a group of enzymes based on their kinetic parameters.

Computers↗
PubMed1984

Assessment of immediate post-anaesthetic recovery in young children following intravenous morphine infusions, halothane, and isoflurane.

Within 15 minutes of terminating general anaesthesia, progressive recovery of consciousness, spontaneous ventilation and cough, and limb movements were assessed in 60 young children (age range 0-5 years, mean +/- SEM; 2.83 +/- 0.34; weight 13.86 +/- 0.41 kg). All patients were ASA physical status class I-III, received a standard intravenous induction (atropine 0.02 mg X kg-1, thiopental sodium 5 mg X kg-1, diazepam 0.2 mg X kg-1), were intubated with an orotracheal tube following the administration of metocurine, 0.4 mg X kg-1, and were maintained under general anaesthesia with nitrous oxide and oxygen in a 70:30 mixture administered by a T-piece circuit. They were ventilated mechanically to maintain normal blood-oxygen tension and normocarbia. The patients were assessed in three equal groups according to the anaesthetic supplement they received. Group I received intravenous infusions of morphine sulfate (loading dose 60 micrograms X kg-1 administered over 5 minutes followed by a continuous intravenous infusion of 2 micrograms X kg-1 X min-1. Patients in Groups II and III had 0.5 per cent halothane and 1.0 per cent isoflurane respectively added to the nitrous oxide/oxygen fresh gas mixture rather than morphine sulphate infusions. By the end of the study period, there was no significant difference in the degree of recovery between the morphine and the isoflurane groups but the patients in the halothane group had recovered to a lesser degree. Generally, the patients in the morphine group were awake but not crying, while those in the other two groups were less sedated.

Anesthesia, General↗
PubMed1984

Dantrolene--in vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle.

Dantrolene sodium, a hydantoin analogue, is efficacious in the therapy of malignant hyperthermia (MH). In order to improve our knowledge of the mode of action of dantrolene, we have examined the influence of dantrolene sodium on: (1) twitch and resting tensions, in the absence and the presence of caffeine, of intact skeletal muscle fascicles; and (2) caffeine induced tension rises of single chemically skinned skeletal muscle fascicles. We have found that dantrolene appears to exert its beneficial action on malignant hyperthermia susceptible (MHS) skeletal muscle by an indirect action on the sarcoplasmic reticulum (SR). Thus dantrolene inhibits twitch tensions of skeletal muscle fascicles, probably by indirectly preventing the release of calcium from the SR. To a lesser extent dantrolene inhibits caffeine induced contractures of skeletal muscle fascicles, probably by indirectly accelerating the uptake of calcium into the SR. Because the former effect is greater than the latter in vivo dantrolene sodium is effective only when given prior to total loss of calcium from the SR. Vigilant temperature and EKG monitoring of all patients during anaesthesia is, therefore, essential.

Animals↗
PubMed1983

Pharmacokinetics of intravenous morphine in balanced anesthesia: studies in children.

Intravenous morphine in combination with muscle relaxants, nitrous oxide, and oxygen in so-called balanced anesthesia is commonly used in children between the ages of 0 and 5 yr during surgery. We define dosing rules for a loading dose followed by a continuous intravenous infusion of morphine sulfate to achieve a serum morphine concentration of 75 micrograms/L. This concentration is well above the minimum serum morphine concentration of 50 micrograms/L for moderate analgesic effects in adults. It also exceeds the concentration of 65 micrograms/L claimed to provide adequate analgesia in children during surgery. The clearance of morphine in 8 children between 0 and 5 yr of age was 20.5 +/- 2.8 mL/kg/min (means +/- SD). This result is threefold larger than the clearance value obtained after a single intravenous dose and 1.5 times greater than clearance values found after multiple intravenous doses of morphine, previously reported by others in children between the ages of 1 and 15 yr. Having established a dosing regimen that achieves a steady-state serum morphine concentration of approximately 75 micrograms/L, we plan to investigate the relationship between morphine serum concentration and pharmacologic effect. Intraoperatively the action of morphine at its receptor site will be assessed according to a scoring system including EEG changes, heart rate, blood pressure, response to sensory stimuli, and maintenance of vital functions. The effect of intravenous morphine will further be estimated according to the postanesthetic scoring system described in this report. Using intraoperative and postanesthetic scores to evaluate the pharmacodynamics of morphine for anesthesia in relation to morphine serum concentration will lead to a better understanding and improvement in use of intravenous morphine in young children.

Anesthesia, Intravenous↗
PubMed1982

Comparison of the caffeine skinned fibre tension (CSFT) test with the caffeine-halothane contracture (CHC) test in the diagnosis of malignant hyperthermia.

We have compared and contrasted two diagnostic tests for Malignant Hyperthermia (MH) - the Caffeine-Halothane Contracture Test and the Caffeine Skinned Fibre Tension Test. Both tests show a strongly positive relationship both with the occurrence of MH reactions and with each other. The former test is more rapid and requires less skill. The latter test can be performed on much less muscle and permits storage of the muscle over prolonged periods of time.

Anesthesia↗
PubMed1981

Fitting of enzyme kinetic data without prior knowledge of weights.

A method is described for fitting equations to enzyme kinetic data that requires minimal assumptions about the error structure of the data. The dependence of the variances on the velocities is not assumed, but is deduced from internal evidence in the data. The effect of very bad observations ('outliers') is mitigated by decreasing the weight of observations that give large deviations from the fitted equation. The method works well in a wide range of circumstances when applied to the Michaelis-Menten equation, but it is not limited to this equation. It can be applied to most of the equations in common use for the analysis of steady-state enzyme kinetics. It has been implemented as a computer program that can fit a wide variety of equations with two, three or four parameters and two or three variables.

Catalysis↗
PubMed1980

Comparison of effects of several inhalation anaesthetics on caffeine-induced contractures of normal and malignant hyperthermic skeletal muscle.

We have compared the combined effects of halothane, enflurane, isoflurane and methoxyflurane on caffeine-induced contractures of normal and malignant hyperthermia susceptible (MHS) skeletal muscle fascicles. We have found that caffeine contractures without and with the addition of any of these four anaesthetics are higher in MHS than in normal muscle. The differences between the normal and MHS muscle are about the same for all drug combinations. For all four anaesthetics the degree of increase of the contracture is about the same in the normal as in the MHS muscle. For both the MHS and the normal muscle the caffeine contractures are from greatest to least: halothane greater than isoflurane greater than enflurane greater than methoxyflurane. Examination of the relationships among the caffeine specific concentrations in the presence of the various anaesthetics shows significant differences for the comparisons of halothane with the other three anaesthetics but, for the most part, the comparisons among methoxyflurane, enflurane and isoflurane are not meaningful statistically.

Anesthesia, Inhalation↗