Biomedical subjects
Publications and source records attributed to A Richens.
The possible influence of sucralfate on phenytoin absorption was investigated in a double-blind, placebo controlled study. Concomitant administration of 1 g sucralfate reduced the absorption of 300 mg phenytoin capsules by 20% as measured by the area under the curve from 0-48 h. This could be of significance in epileptic patients stabilised on phenytoin in whom sucralfate is used in ulcer treatment.
The effects of six nightly doses of temazepam (20 mg), nitrazepam (10 mg) and placebo on saccadic eye movements, critical flicker fusion, choice reaction time and on subjective feelings were studied in a double blind cross-over study in eight volunteers. Testing was performed on nights 1 and 6 of treatment. Nitrazepam, a benzodiazepine with a long elimination half-life produced a residual performance impairment on night 1 that had disappeared by night 6, despite higher serum concentrations of the drug on the sixth night of treatment. Temazepam, with a shorter elimination half-life produced no significant performance impairment on night 1, but by night 6 a significant impairment of saccadic eye movements (P less than 0.05), was seen 1 h after drug intake. We conclude that tolerance developed to the sedative action of nitrazepam over the 6 night period of the study. No evidence of tolerance was seen with temazepam.
The effects of intravenous propranolol 100 micrograms kg-1, sotalol 500 micrograms kg-1, timolol 7.8 micrograms kg-1, atenolol 125 micrograms kg-1 and placebo on essential, physiological and isoprenaline-induced tremor were studied. These beta-adrenoceptor blocker doses produced equal reduction of standing-induced tachycardia in essential tremor patients. Atenolol produced significantly less reduction of essential and isoprenaline-induced tremor than the non-selective drugs, confirming the importance of beta 2-adrenoceptor blockade in these effects. Propranolol and sotalol produced equal maximal inhibition of isoprenaline-induced tremor but propranolol was significantly more effective in reducing essential tremor. The rate of development of the tremorolytic effect was similar in essential, physiological and isoprenaline-induced tremors but all tremor responses developed significantly more slowly than the heart rate responses. It is proposed that these results indicate that the tremorolytic activity of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is exerted via the same beta 2-adrenoceptors located in a deep peripheral compartment which is thought to be in the muscle spindles.
The respiratory and psychomotor effects of a single oral dose of meptazinol (200 mg) and dextropropoxyphene (65 mg)/paracetamol (650 mg) mixture, was compared alone and in combination with ethanol (0.8 g kg-1). Peak saccade velocity following meptazinol or the dextropropoxyphene/paracetamol mixture was not significantly different from placebo. When each of the treatments was followed by ethanol administration, a significant decrease in saccade velocity (P less than 0.01) was seen. Given alone, neither of the analgesic drugs produced a significant change in the slope of the ventilatory response to hypercapnia. Ethanol did not affect the ventilatory response to hypercapnia when given alone or in combination with meptazinol, but when given with the dextropropoxyphene/paracetamol mixture, a significant reduction in the slope of the ventilatory response to hypercapnia occurred at 1.5 h (P less than 0.05) and 2 h (P less than 0.01) after administration of the analgesic drug. No pharmacokinetic interaction was demonstrated between ethanol and meptazinol or the dextropropoxyphene/paracetamol mixture in the doses used. In contrast to meptazinol, the dextropropoxyphene/paracetamol mixture interacts with ethanol on the ventilatory function.
Three groups of subjects have been studied to evaluate the role of long term hospitalization and chronic anti-epileptic therapy on calcium metabolism. The first group consisted of 32 epileptic patients, randomly selected from a population of inpatients in a hospital for the mentally handicapped, receiving various combinations of anti-epileptic drugs for at least 3 years. The second group was made up of 32 non-epileptic residents of the same hospital, individually matched for age and sex with epileptic patients and who had not received any anti-epileptic drugs in the last 3 years. The third group of 22 normal subjects was randomly selected from the staff of the University Hospital of Wales, matched for age and sex against the epileptic group, who had not received any anti-epileptic medication within the last 3 years. None of the subjects received any drugs (except anti-epileptic drugs) known to have effect on calcium metabolism. Significant differences in the serum levels of the total calcium, ionised calcium, total alkaline phosphatase and its liver iso-enzyme were seen. Serum total alkaline phosphatase and its liver iso-enzyme were significantly elevated in the epileptic group, showing the effect of anti-epileptic drugs. On the other hand serum total calcium was significantly lower in both residential groups compared to the normal population, epileptics being lower than non-epileptics showing the combined effect of hospitalization and anti-epileptic drugs. No significant difference was detected among the groups in the serum concentration of the bone alkaline phosphatase iso-enzyme.
Intravenous thymoxamine reduced the power of essential tremor but increased that of physiological and isoprenaline-induced tremor. These findings indicate that essential and physiological tremor have dissimilar pathophysiological mechanisms. They also suggest that central adrenergic mechanisms are involved in the pathophysiology of essential tremor and that isoprenaline-induced tremor is not a good model of essential tremor. Furthermore, alpha-adrenoceptor blockers may be a useful therapy for essential tremor.
Single doses of phenytoin (500 and 1.000 mg), carbamazepine 400 and 1.00 mg) and sodium valproate (600 mg) were given orally to 5 healthy young volunteers and serum concentrations determined between 1-8h after administration. The design was double-blind and placebo-controlled. Serum concentrations considered "therapeutic" were obtained after sodium valproate and the 100 mg dose of carbamazepine. The results suggest the loading-doses of phenytoin (1500-2000 mg) and carbamazepine (800 mg) are useful in the subacute control of frequent epileptic seizures on an out-patient basis, and that carbamazepine may be used for lasting control of seizures of status epilepticus treated initially with diazepam or other rapidly-acting preparation.
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Measurements of drug concentrations from the Heathcontrol quality assessment schemes were analysed to detect the presence of intralaboratory, interlaboratory, or intermethod errors. We developed weighted least-squares regression procedures as significance tests for evaluating intralaboratory noise, curvature vs linearity, proportional errors and additive errors. The latter intercept test for additive errors was unsatisfactory and an effective alternative based on the difference between measurements and estimates of the true drug concentrations was developed. Significance of residuals was tested against the population noise, which was defined by smooth mathematical functions fitted to the standard deviation (SD) data for the drug samples. We evaluated these tests for 1,647 sets of data. Only small amounts of curvature were present, validating the linear-regression approach. Both random and proportional errors were demonstrated. The most frequent errors were additive in nature, components of which were demonstrated to be the result of intermethod differences.
Twenty-four patients with frequent drug-resistant seizures took part in a randomised double-blind placebo-controlled crossover trial of the GABA-transaminase inhibitor, gamma-vinyl GABA. It was added to their usual drug treatment in a dose of 3 g daily. The total number of seizures during the 9-week active treatment period was less than that in the placebo period (p less than 0.001, two-way analysis of variance). The greatest effect was on complex partial seizures. Mean weekly seizure frequency (complex partial and tonic-clonic) was 6.2 fits/week for the placebo period and 3.5 fits/week for the gamma-vinyl GABA period. Adverse effects, particularly drowsiness and mood changes, occurred more often during administration of active drug. Serum concentrations of phenytoin were lower during gamma-vinyl GABA treatment than during placebo (p less than 0.05), but the concentrations of other anticonvulsants given concomitantly did not change. These results suggest that gamma-vinyl GABA is an effective antiepileptic compound.
Potentially adverse alterations in drug response in patients with neuropsychiatric disease can be divided into two categories: those arising from the pathological state itself (e.g., enhanced responsiveness to phenylephrine in patients with chronic autonomic failure) and those arising from interactions with the pharmacological treatment used for such disease (e.g., reversal of the antihypertensive action of guanethidine by imipramine). Sound knowledge of the pharmacological profile of individual compounds and of the pathophysiology of the disease is essential if drug therapy is to be used safely and effectively in these patients.
The accuracy and precision of gas-liquid chromatography with and without derivatization (GLC + D, GLC-ND), high-pressure liquid chromatography (HPLC), and enzyme multiplied immunoassay (EMIT) for the measurement of serum levels of theophylline were compared below, within, and above the therapeutic range (55-110 mumol/L) using data from 63 samples from the Heathcontrol quality assurance scheme. Within the therapeutic range, the methods did not differ in either precision or accuracy. Coefficients of variation (CV) of measurements were between 12 and 16%, and measurements did not differ from spiked values. Below the therapeutic range, the methods differed significantly. The GLC methods had the lowest precision (CV 23-25%), while the CV for HPLC was 19% and for EMIT 14%. GLC + D and HPLC also overestimated drug level by 11 and 8%, respectively. Above the therapeutic range, the precision of the methods did not differ (CV 10-13%), although both EMIT and HPLC underestimated theophylline level by 5-6%. In a comparison of individual laboratories based on a ranking of overall precision, laboratories employing GLC commonly exhibited less precise rank positions than laboratories using EMIT. Laboratories making HPLC measurements showed a bimodal distribution but no methodological differences were identified to explain this difference in precision.
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The antipyrine clearance and the urinary excretion of D-glucaric acid (D-GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and in 21 drug-free control subjects. Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine clearance and excreted larger amounts of D-GA as compared to controls. While antipyrine clearance values did not differ significantly from one drug group to another, D-GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH. In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D-GA excretion to be higher in these patients but the difference was not statistically significant. Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose-dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D-GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90).
The pharmacokinetics of clobazam were studied in six healthy volunteers and six age and sex matched enzyme-induced epileptic patients. In the epileptic patients the area under the plasma concentration-time curve for clobazam was significantly smaller and the area under the plasma concentration-time curve for N-desmethylclobazam was significantly greater than in the healthy volunteers. Plasma N-desmethylclobazam concentrations were found to be much higher than those of clobazam in the epileptic patients, raising the possibility that the antiepileptic properties of clobazam are to be attributed more to its metabolite than the parent drug.
Analysis of human horizontal saccadic eye movements can provide measurements of central nervous system depression and stimulation. Effects on saccadic eye movements have been observed in normal volunteers with barbiturates, benzodiazepines, opiates and related compounds, carbamazepine, amphetamine and ethanol. A suite of programmes have been developed to allow the generation, collection and analysis of saccadic eye movements using a CBM 3032, 8032 or BBC B microcomputer. The system allows almost continuous sampling and rapid analysis of movements.
The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinic. The free phenytoin fraction was measured by equilibrium dialysis at 37 degrees C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean +/- s.d. = 0.145 +/- 0.12). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P less than 0.05). The total concentration of phenytoin varied from 0.3 to 29.4 micrograms/ml (median 12 micrograms/ml, mean +/- s.d. = 13.31 +/- 6.13 micrograms/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P less than 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.
The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/- 0.019 (s.d.) to 0.182 +/- 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3-26.2 micrograms/ml to 3.4-19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.