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Biomedical subjects

J H Tyrer

Publications and source records attributed to J H Tyrer.

At least 37 records · Page 2Linked to original sources
PubMed1977

The pharmacokinetics of carbamazepine.

The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters: kabs = 0.176 +/- 0.209 h-1; k = 0.0203 +/- 0.0055 h-1; T1/2 = 37.5 +/- 13.1 h; VD = 0.825 +/- 0.1041 . KG-1; Clearance = 0.0163 +/- 0.0061 1 . kg-1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.

Adult↗
PubMed1977

Factors influencing plasma phenobarbitone levels in epileptic patients.

1 Various statistical techniques were used to study the effects of age, sex and concurrent therapy with other anticonvulsants on the relation between plasma phenobarbitone levels and doses of (i) phenobarbtione, (ii) methylphenobarbitone or (iii) primidone, in epileptic patients. 2 Methylphenobarbitone and primidone are converted to phenobarbitone in the body. The mean doses of phenobarbitone, methylphenobarbitone and primidone which produced the same plasma phenobarbitone level (15 microgram/ml) were, respectively, 1.75,2.75 and 7.75 mg kg-1 day-1. 3 For both phenobarbitone and methylphenobarbitone dose requirement to achieve a given plasma phenobarbitone level fell progressively with age. Sex influenced the relation between plasma phenobarbitone level and phenobarbitone or methylphenobarbitone dose. Interactions were detected between primidone and both phenytoin and carbamazepine. 4 In individual patients, within the limits of dosage studied, the relation between plasma phenobarbitone level and drug dose was not rectilinear if phenobarbitone itself was taken, but was rectilinear if methylphenobarbitone was taken.

Adolescent↗
PubMed1977

Plasma anticonvulsant concentrations during pregnancy.

Plasma anticonvulsant levels were followed during pregnancy in 11 epileptic women taking phenytoin and/or phenobarbital or a drug metabolized in the body to phenobarbital. As judged from the relationship between plasma level and drug dose, phenytoin requirement increased in all 10 women taking this drug during pregnancy. The requirement fell again in the puerperium. Plasma phenobarbital levels decreased during pregnancy in all five women taking a constant daily dose of phenobarbital or a congener. These findings should be borne in mind if epileptics are to be protected against seizures during pregnancy and against anticonvulsant overdosage during the puerperium.

Epilepsy↗
PubMed1977

Factors influencing plasma carbamazepine concentrations.

Steady-state plasma carbamazepine levels were correlated with carbamazepine dose, expressed on a body weight basis, in 217 patients (some of whom were taking other anticonvulsants). Although there was a linear relation between plasma carbamazepine level and drug dose in the whole population studied, no such relation was found for patients taking carbamazepine alone. The factors responsible for this difference could not be identified in full, but interactions between carbamazepine and phenytoin were partly responsible.

Adolescent↗
PubMed1977

Pharmacokinetics of drugs used for petit mal 'absence' epilepsy.

Ethosuximide, clonazepam and valproic acid differ in their chemical structures and properties. They appear to be well absorbed when given by mouth, but their patterns of distribution within the body are different. If these 3 drugs have a common mode of action, the virtual restriction of valproate to extracellular water suggests that this common mode of action is likely to involve receptors on the neuronal cell surface. Even if there is no common mode of action the apparent volume of distribution of valproate is consistent with its known effects on enzymes of the GABA shunt, and in particular on those shunt enzymes which are involved in the transmitter GABA pool in the region of synapses. The 3 drugs also show differences in elimination rate, which make it desirable to give valproate 3 times a day and clonazepam twice a day, whereas ethosuximide could reasonably be given once daily without undesirably wide fluctuations in plasma drug level over the dosage interval. Further studies of the pharmacokinetics of ethosuximide, clonazepam and valproate are still needed, but sufficient data are already available to provide some basis for rational use of these drugs in treating petit mal 'absence' epilepsy.

Administration, Oral↗
PubMed1976

Plasma drug concentrations in therapeutics.

The literature describing drugs assay in plasma and its value for optimal therapy for individual patients is expanding rapidly. The present review seeks to clarify the rationale underlying the assay of plasma concentrations of drugs, and it attempts to define principles for judging the likely value of assaying a particular drug. Examples are given of drugs which are being usefully measured in clinical practice. The most commonly used assay techniques are briefly described, and their principal advantages and limitations are indicated.

Biological Assay↗
PubMed1976

Hereditary motor peripheral neuropathy predominantly affecting the arms.

A kinship is described in which there was slowly progressive wasting and weakness of the muscles of the upper and occasionally of the lower limbs. Some members had hyperreflexia. There were no sensory abnormalities. Electrophysiological study suggested the presence of motor peripheral polyneuropathy. The condition appeared to be inherited as an autosomal dominant. The disorder does not appear typical of any of the known hereditary polyneuropathies and it is possible that it may represent a unique hereditary, dominantly motor, polyneuropathy. The significance of the hyperreflexia is uncertain, but raises the possibility of minor central involvement as well as peripheral neuropathy.

Adolescent↗
PubMed1976

The effects of phenobarbitone dose on plasma phenobarbitone levels in epileptic patients.

The relation between plasma phenobarbitone level and phenobarbitone dose was studied in 121 patients. The relation changed with age, the dosage requirement (on a day weight basis) tending to fall as patients grew older. Males under 5 years had a higher dosage requirement than females of the same age, but otherwise sex did not affect the relationship, nor did the concurrent intake of the anticonvulsants phenytoin, carbamazepine or sulthiame. In the individual, plasma phenobarbitone levels tended to increase out of proportion of dosage increases. These findings can provide a basis for prescribing appropriate phenobarbitone doses in epileptics.

Adolescent↗
PubMed1975

Plasma protein binding of carbamazepine.

The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.

Adolescent↗
PubMed1975

Quantitative oxidative enzyme histochemistry of the spinal cord. Part 1. Distribution of enzyme activity in anterior horn cells.

Cytophotometric measurements of the activities of 5 oxidative enzymes (succinate, malate, lactate, NAD+-linked isocitrate and NADH dehydrogensases) have been made in anterior horn cells of the lumbar and cervical spinal cord of the rabbit. The thickness of tissue sections was measured by an interference microscope and various optical and chemical precautions were taken to diminish the possible errors that might be involved in cytophotometry. The findings of the study indicated a unimodal distribution of the activities of all of the enzymes studied in anterior horn cells, though there was a wide range of enzyme concentration among different cells. Thus the findings in the rabbit are consistent with the "constant proportion" hypothesis of the activity of certain oxidative enzymes, and are contrary to a previous finding that there may be two populations of succinate dehydrogenase-containing anterior horn cell.

Animals↗
PubMed1975

Quantitative oxidative enzyme histochemistry of the spinal cord. Part 2. Relation of cell size and enzyme activity to vulnerability to ischaemia.

Cytophotometric measurements of the activities of 5 enzymes (succinate, malate, and NAD+-linked isocitrate dehydrogenases from the tricarboxylic cycle, lactate dehydrogenase from the Embden-Meyerhof pathway, and NADH dehydrogenase) were correlated with cell volume for neurones in the anterior horn of rabbit lumbar and cervical spinal cord. The data for succinate and isocitrate dehydrogenases indicated that these enzymes were at higher concentrations in the smaller neurones, which consist largely of interneurones. No preferential localization to particular sizes of cell could be assigned to the other enzymes studied. The relationship between enzyme distribution patterns and their possible role in contributing toward susceptibility to ischaemia of particular sizes of neurones is discussed.

Animals↗
PubMed1975

Decreased capacity to metabolize diphenylhydantoin in a patient with hypersensitivity to warfarin.

A 48 year old man with normal hepatic function presented with abnormally prolonged bleeding following orally administered warfarin. Warfarin and diphenylhydantoin are known to be hydroxylated in the liver. To investigate the possibility of the patient having a metabolic (hydroxylating) defect, his ability to metabolize diphenylhydantoin was studied, as it would have been unethical to administer warfarin again. Parallel studies were carried out on two healthy subjects as a basis for comparison. On three separate occasions the elimination half-life for diphenylhydantoin in the patient (158, 87, 72 hours) was significantly longer than those obtained in the normal subjects (31 and 32 hours). This difference was most probably due to decreased hydroxylation of diphenylhydantoin to 5-(p-hydroxy-phenyl)-5-phenylhydantoin since his urinary elimination of this substance was demonstrated to be significantly less than that of the normal subjects. The results suggest that this patient had a reduced capacity to hydroxylate diphenylhydantoin, and this defect in liver hydroxylation may explain his increased sensitivity to warfarin.

Half-Life↗
PubMed1975

The bioavailability of carbamazepine.

Two aspects of the correlation of plasma carbamazepine level with drug dose in patients taking carbamazepine tablets indicated the possibility that the drug may be incompletely and variably absorbed from the alimentary tract of man. To investigate this possibility, pharmacokinetic studies were undertaken in six volunteers, who were given increasing single doses of carbamazepine in tablet form at appropriate intervals. These studies gave evidence of slow, and probably incomplete, absorption of carbamazepine. After administration of carbamazepine in a specially-prepared solution to 5 of the subjects, rapid absorption of the drug occurred, and in 4 subjects more drug was absorbed than when the same normal dose was given as tablets. It was concluded that the pharmaceutical formulation of carbamazepine tablets limits the bioavailability of the drug, and that problems may arise if the bioavailability of the drug is to be increased.

Biological Availability↗
PubMed1975

Interactions between anticonvulsants.

Anticonvulsant drug interactions have been investigated using multiple linear regression analyses. The one statistically significant interaction found was that in which phenytoin dosage decreased plasma carbamazepine concentrations. There was a suggestion that carbamazepine and phenobarb dosage tended to increase phenytoin levels. No interaction was detected between phenytoin and sulthiame. Studies in individuals suggested that ethosuximide may increase plasma phenytoin concentration and that clonazepam tends to decrease carbamazepine and phenytoin concentrations.

Anticonvulsants↗