Biomedical subjects
Publications and source records attributed to L Endrenyi.
The extent to which debrisoquine (D) is metabolized to 4-hydroxydebrisoquine (4OHD) was found to be influenced by the ethnic origin of the subjects. Following ingestion of 20 mg of debrisoquine sulfate, Orientals excreted, on the average, significantly more D and less 4OHD in 0- to 8-h urine than Caucasians; however, the sums of D + 4OHD did not differ.
A clip compression method was used to produce acute spinal cord compression injury in rats. The force and duration of the spinal cord compression were independently varied, and functional recovery of the cord was assessed using the inclined plane technique. Mathematical modeling produced a curve defining the relationship between force, duration, and functional recovery for each week after injury. The study clearly showed the beneficial effect of decompression and that increasing either the force or duration of compression, or both, caused a reduction in recovery.
The two main metabolites of amobarbital excreted in urine are 3'-hydroxyamobarbital (C-OH) and 1-(beta-D-glucopyranosyl) amobarbital (N-glu). When testing the metabolite ratio in small single samples of urine, it was found that the urine in a Caucasian population contained about one-third glucose conjugation and two-thirds hydroxylation product, while an Oriental population excreted both metabolites in equal proportion. Attempts to learn the causes for the different metabolite ratios led to an investigation of metabolite concentrations in urine. The sums of the average urinary concentration of C-OH was greater in Caucasians than in Orientals, no matter how the data were expressed; the reverse was true for the N-glu metabolite. C-OH data was scattered more widely among Orientals than Caucasians; this might indicate bimodality of the distribution curves. There also was a trend toward more N-glu metabolite in urine of females than of males. Measuring the metabolite/creatinine ratios narrowed the distribution range of the data, particularly after correction for sex difference in creatinine, but population differences were not changed. Expected relationships between metabolite content of urine, sampling times, and plasma half-life (t1/2) were established by calculation. A Caucasian female with no capacity for N-glucosidation was found during the first part of this population survey. An Oriental male with only trace capacity for amobarbital hydroxylation was found in the second part.
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The elimination of amobarbital in dogs was investigated by injecting various doses of amobarbital into a given animal. At low doses (3 mg/kg) serum levels declined in a first-order fashion. Superficially, at high doses (20 mg/kg) the relationship between serum concentration and time could be quantitatively characterized by simple one-compartment saturable kinetics. Indeed, qualitatively, saturation of the amobarbital-metabolizing enzymes was indicated by a shallower initial slope of the semilogarithmic concentration--time profile at the high than at the low dose. However, in addition, an acute enzyme induction phenomenon was observed which was indicated by a shorter terminal half-life of amobarbital at the high dose than after the low dose and also by a shortening in antipyrine half-life.
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Intravenous glucose tolerance tests were carried out in 61 chronic alcoholic patients, divided into two groups, and in a third group consisting of healthy, nonalcoholic volunteers. Members of one experimental group were drinking alcohol throughout the study. The patients of the other experimental group received no alcohol and were in withdrawal from alcohol. The glucose tolerance tests were carried out on each patient on admission to the hospital and 1 wk later. During the test, blood was drawn at 10 min intervals for glucose, immunoreactive insulin, and glucagon determinations. The results indicated that there was transient carbohydrate intolerance in the great majority of both patient groups, and it became evident that the carbohydrate intolerance was the result of continuous alcohol consumption and was not part of the withdrawal syndrome. Significant decrease in insulin secretion was found in the early part of the glucose tolerance tests in the majority of the patients in both alcohol and withdrawal groups. Based on results of this study and evidence from the literature, it is suggested that chronic alcoholism is dabetogenic in susceptible individuals and that the transient carbohydrate intolerance found in our study represents and early step in the development of adult-onset diabetes eventually developing in a significant number of chronic alcoholics.
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Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of orally available over intravenously injected amobarbital was established as 0.99 +/- 0.11 (SD), by comparing integrated concentration-time curves, indicating complete absorption and absence of a first-pass effect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first-order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 +/- 1.8 [SD]ml/min) exhibited remarkable constancy, while biologic half-lives (26.5 +/- 3.1 hr) and distribution volumes (73.6 +/- 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half-lives (23.8 +/- 6.7 hr) appeared to be normally distributed, while the clearances (36.7 +/- 10.0 ml/min) might not follow a normal distribution.
Following the intravenous administration of 125 mg amobarbital sodium in 7 pairs of dizygotic and 7 pairs of monozygotic twins, the time-course of plasma concentrations was observed. The number of detectable compartments varied from subject to subject but was consistently 1 or 2 or 3 within a given individual. The terminal slope of the semilogarithmic concentration-time plot (corresponding to biologic half-life of 22.8 hr) did not represent the elimination rate constant even in persons with apparently single-compartmental characteristics. The redistribution of amobarbital was rapid in comparison with its elimination. The rate of the latter (characterized by kel = 0.051 hr-1, plasma clearance = 37.7 ml/min) could be closely identified with the rate of metabolism. The twin data showed that genetic control was exerted on kinetic parameters characterizing the rate of amobarbital elimination and, therfore, the rate of its metabolism. Correlation analysis suggested that this control was independent of size factors, which were themselves substantially heritable. The genetic analysis of twin data included, in addition to intracelass correlations and Holzinger's H factors, newly developed lower (and upper) bounds of the broad-sense heritability. In pharmacogenetic studies, assessment of model-independent kinetic parameters, such as plasma clearance with or without adjustment for body weight, is recommended.
We investigated 56 families afflicted with malignant hyperpyrexia. One hundred and twenty-four individuals within these families had had an episode of malignant hyperthermia, of whom we saw seventy-two. Serum creatine phosphokinase (CPK) was statistically higher in affected individuals and in close relatives than in normal volunteers. The magnitude of the serum CPK elevations varied significantly between families. While in some families the serum CPK was clearly elevated in affected individuals, in other families the serum CPK was normal or only moderately or inconsistently raised. In these latter families serum CPK measurement was therfore of little or no value in identifying afflicted members. The incidence of musculoskeletal abnormalities was greater in affected individuals and in close relatives than in the general population. Thus, the concomitant individual belonging to a family known to be susceptible to malignant hyperthermia was a better indicator of the MH trait than was the presence of only one of these parameters. For reasons which we do not fully understand, MHS individuals were found to require fewer anaesthetics than normal persons. The incidence of MH crises within each family fell significantly following investigation, counselling, and issuance of Medic-Alert bracelets.
The adenosine triphosphate (ATP depletion ratio, which is the ratio [ATP] in skeletal muscle equilibrated with carbogen and 4% halothane for 30 minutes divided by [ATP] in skeletal muscle equilibrated with carbogen alone for 30 minutes is less than normal in most but not in all rigid MHS patients. The ratio is normal in non-rigid MHS patients. This diagnostic tool is, therefore, useful in the diagnosis of rigid MH. It is not, however, such a sensitive diagnostic parameter as the caffeine contracture test.
1. The Hill coefficient (nH), an often-used measure of deviations from hyperbolic behaviour (nonhyperbolicity) in kinetic and binding systems, is usually estimated from the maximum or minimum slope of the Hill plot. The method depends strongly on the assumed magnitude of the asymptotic velocity (V) or binding (P) whose evaluation may be difficult in nonlinear/co-operative systems. Therefore, alternative procedures were devised for the estimation nH which do not require the prior knowledge of V or P. 2. When pairs of velocity/binding readings (v and w) are obtained at concentrations of c and alpha c, respectively (where alpha is a fixed constant), then the relation between w and v is described by a hyperbola, provided that Hill's equation is valid. In this case, linearizing plots, v/w versus v, w versus, w/v, and 1/w versus 1/v, can be used for estimation of the degree of the equation. However, if the Hill expression is applicable, these methods are not efficient and traditional procedures, particularly nonlinear regression, should be used. 3. The 'linearizing' plots of the Hill equation can be applied advantageously for the evaluation of the Hill slope and of nH also in the general case, when the Hill expression is actually not valid, provided that deviations from hyperbolic behaviour are positive. Appropriately extrapolated intercepts of the first two plots estimate alphanH. Furthermore, the slope of the third plot yields, similarly to the method of Kurganov et al., a continuous measure of the Hill slope (including its maximum) at all concentrations. The agreement is, at positive nonhyperbolicities, excellent theoretical values of Hill slopes and coefficients and those estimated by the proposed methods. 4. A coefficient of nonhyperbolicity (theta) is defined for 2nd-degree rate equations which provides a quantitative measure of positive or negative deviation from first-degree, hyperbolic characteristics. It is closely related to the Hill coefficient.
Total calcium content of both human and porcine MHS skeletal muscle is significantly less than normal. This data is consistent with the concept that some organelle (probably the sarcoplasmic reticulum, the mitochondrion or even the sarcolemma) within the MHS muscle stores less than normal amounts of calcium. The large variability between muscle specimens rules out measurement of total calcium content of skeletal muscle as a routine diagnostic test for malignant hyperthermia susceptibility.
MHS and normal pigs were anaesthetized with nitrous oxide and diazepam. Halothane 1% was then administered for 1 hr. Immediately before and immediately after the halothane inhalation, 10 g of vastus lateralis muscle was excised. SR was isolated from this muscle. Calcium accumulation by the MHS sarcoplasmic reticulum in the absence of halothane was greater than normal. Halothane in vitro produced a similar increase in calcium uptake into both the MHS and the normal SR. Halothane in vivo significantly reduced calcium accumulation by hyperthermic SR but had no significant effect on calcium uptake into the normal SR. Thus the action of halothane on the MHS sarcoplasmic reticulum is indirect, occurring only in the intact cell. It is possibly a result of the deleterious effect which lack of ATP, a low pH or a high temperature is likely to have on the calcium accumulating mechanism of the SR membrane. Our results suggest that the primary defects of porcine and human malignant hyperthermia are not entirely synonymous.
Adult male rats were pair-fed liquid diets, providing 37% of calories as ethanol or sucrose, for 1 month. Alcohol dehydrogenase (ADH) activity in the cytosol fractions of liver homogenates from the two groups did not differ with respect to total activity per 100 g body weight, Km for ethanol, or Ki for pyrazole. Other rats, fed in the same way, were fasted for 18-24 H, then given an intraperitoneal injection of pyrazole followed 1 h later by an injection of ethanol, 3g/kg. Blood alcohol curves showed an unexplained slower rise to maximum level in the chronic alcohol group. Both groups showed a period of several hours in which the blood alcohol stayed at the respective maximum concentrations, which were higher in the control group. After 7-8h the alcohol concentration began to fall in both groups, significantly more rapidly in the chronic alcohol-fed animals. A kinetic analysis shows that the results are adequately explained by the known effects of pyrazole on the ADH-mitochondrial system. The results are interpreted as evidence against the function of any microsomal ethanol oxidizing system in vivo.
Intravenous glucose tolerance tests were given to 31 nondiabetic alcoholics and 11 healthy nonalcoholic controls. In almost half of the alcoholics peak glucose concentration was higher and glucose elimination from the plasma was slower than in the controls.
Vastus lateralis muscle was excised from normal pigs and from pigs susceptible to malignant hyperthermia. Anesthesia consisted of diazepam, N2O:O2, and a lidocaine field block. In the susceptible (MHS) pigs, respiratory control in mitochondria of excised muscle was normal, while electron transport was accelerated. Glutamate log Q3's and log Q4's were in inverse linear relationship to porcine weights. In the presence of glutamate, state 3 respiration was 3.5 times, and state 4 respiration 3.2 times, higher in MHS than in normal mitochondria (independent of weight or halothane dose). Thus, the MHS mitochondria were able to produce ATP more efficiently than normal mitochondria. In vitro, halothane inhibited glutamate Q3's and R.C.I.'s, slightly increased succinate Q3's and R.C.I.'s, had no significant effect on glutamate or succinate Q4's, and, moderately lowered glutamate and succinate P/O ratios. These changes were similar to those observed in normal pigs. Calcium uptake into MHS mitochondria was markedly less than normal but was not significantly altered by in-vitro halothane. These results suggest a mitochondrial membrane component for the defect of procine malignant hyperthermia since calcium is normally associated with the formation of the phospholipid lattice of this membrane. (Key words: Hyperthermia, malignant; Metabolism, mitochondrial; Muscle, skeletal, mitochondria; Anesthetics, volatile, halotbane; Ions, calcium.)