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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 235 records · Page 13Linked to original sources
PubMed1980

Reversal by phenytoin of carbamazepine-induced water intoxication: a pharmacokinetic interaction.

The hypothesis that phenytoin may antagonise the antidiuretic effect of carbamazepine has been examined by comparing the free water clearance response to a standard water load in 36 patients stabilised on different drug regimes. The diuretic response to the water load was significantly greater in patients receiving chronic treatment with carbamazepine and phenytoin in combination than in matched control subjects receiving carbamazepine as a single drug. Acute administration of phenytoin (1,100 mg), however, had no significant influence on carbamazepine-induced antidiuresis. Evidence is presented that reversal of the antidiuretic effect of carbamazepine by chronic phenytoin administration is secondary to a marked reduction of the serum carbamazepine concentration during combined therapy. These results suggest that the risk of developing water intoxication is greater in patients receiving carbamazepine alone than in those receiving phenytoin in combination. Since the antidiuretic effect is correlated with the serum carbamazepine concentration rather than with the prescribed daily dose, monitoring the serum level of the drug is likely to provide the best rational approach to the prevention of excessive water retention.

Adult↗
PubMed1980

Drug interactions in epilepsy.

Interactions with antiepileptic drugs are common and may have important clinical consequences. The physician should always consider carefully the need for and the implications of adding a new drug to any therapeutic regime and should be prepared to think about the possibility of an interaction whenever an unusual response is seen. Serum drug levels can be an invaluable tool in the recognition and the management of most types of interactions, but in no case can they be a substitute for careful observations and evaluation of the patient's symptoms and physical findings.

Anticonvulsants↗
PubMed1980

Plasma protein binding of phenytoin in health and disease: relevance to therapeutic drug monitoring.

It is generally accepted that only the unbound drug in plasma is in equilibrium with drug in the biophase. Under these circumstances, routine measurement of total drug levels in plasma can be justified only if the interpatient variability in protein binding is small. In the case of phenytoin, this is not always true. Important alterations in the plasma protein binding of phenytoin may occur in the perinatal period, in late pregnancy, in hepatic disease, in renal failure, in the nephrotic syndrome and other conditions associated with hypoalbuminemia, and in the presence of displacing agents such as valproic acid, phenylbutazone, and salicylic acid. Changes in protein binding may alter substantially the relationship between the plasma concentration of total drug and the magnitude of pharmacological effect. This possibility needs to be taken into account when interpreting serum phenytoin levels in clinical practice.

Aging↗
PubMed1979

Interpretation of drug levels: relevance of plasma protein binding.

Many centrally acting drugs bind extensively to plasma proteins, particularly albumin. It is generally the free concentration rather than the total concentration which determines the intensity of pharmacological action and the distribution and rate of elimination of a drug. Measurement of the total plasma concentration may therefore give a false idea of the amount of active drug available. Furthermore, variation in the degree of binding from one subject to another, and displacement of drug molecules by a second drug, may complicate the interpretation of serum levels when both bound and free drug are measured together. The strict use of therapeutic ranges of serum levels may therefore be harmful when a larger than normal proportion of the drug is free. In theory, monitoring the free concentration would have advantages, but on a routine basis this is not practical at present for technical reasons. Cerebrospinal fluid is an ultrafiltrate of plasma but lumbar puncture for routine monitoring purposes cannot be justified. Monitoring salivary concentrations is a practical alternative but for some drugs variation in the degree of ionization of the compound may make salivary levels unreliable.

Blood Proteins↗
PubMed1979

Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs.

1 The serum concentration profile of paracetamol has been determined after administration of single 1000 mg intravenous and oral doses in six normal subjects and six epileptic patients on chronic antiepileptic drug therapy. The urinary excretion of free and conjugated paracetamol has also been determined. 2 Following intravenous administration, serum paracetamol concentration declined with first-order kinetics. Both elimination rate and total body clearance were higher in the epileptic patients, although in neither case was the difference statistically significant. 3 The oral bioavailability (mean +/- s.e. mean) was significantly lower in the epileptic patients than in the normal subjects (0.77 +/- 0.03 and 0.89 +/- 0.02 respectively, P less than 0.01), whereas the urinary excretion total (free+conjugated) paracetamol was almost identical in the two groups. 4 It is suggested that the lower bioavailability of paracetamol in the epileptic patients results from enhancement of first-pass metabolism, secondary to enzyme induction.

Acetaminophen↗
PubMed1979

Modification of phenytoin clearance by valproic acid in normal subjects.

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.

Adult↗
PubMed1979

Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients.

1. The pharmacokinetics of lignocaine following single oral and intravenous doses have been investigated in six normal volunteers and in six patients receiving chronic antiepileptic drug therapy. 2. After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean +/- s.d.) was slightly higher in the patients (0.85 +/- 0.09 v 0.77 +/- 0.07 l/min) but the difference was not statistically significant. 3. Lignocaine bioavailability after oral administration was more than two-fold in the patients than in the normal subjects (0.15 +/- 0.06 v 0.37 +/- 0.09, P < 0.001). 4. It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first-pass metabolism by antiepileptic drugs.

Administration, Oral↗
PubMed1978

Is phenytoin metabolism dose-dependent by enzyme saturation or by feedback inhibition?

The suggestion from animal experiments that phenytoin metabolism may be dose-dependent in man due to feedback inhibition by the major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin, was examined in 3 normal subjects by measuring phenytoin clearance during an intravenous infusion of the metabolite and during a control infusion of solvent. Clearance was measured using both carbon-labeled and unlabeled phenytoin. The infusion of metabolite did not produce any consistent change of phenytoin clearance, suggesting that feedback inhibition does not occur in man.

Adult↗
PubMed1978

Disposition of sodium valproate in epileptic patients.

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half-lives averaged 9.0 +/- 1.4 h (s.d.). Volumes of distribution were 0.175 +/- 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half-lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5--2 h. Biological availability was 96 +/- 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.

Adult↗
PubMed1978

Water intoxication in epileptic patients receiving carbamazepine.

Plasma sodium and osmolality were determined in 80 adult epileptic patients receiving chronic treatment with carbamazepine and in 50 control patients treated with other anticonvulsant drugs. Mean plasma osmolality was significantly lower in the carbamazepine-treated patients but mean plasma sodium did not differ in the two groups. Hyponatraemia was found in five of the carbamazine-treated patients and hypo-osmolality in six. None of the control patients had hyponatraemia and only one had a borderline low osmolality. Three of the 13 patients receiving carbamazepine alone were hyponatraemic. Plasma sodium concentration correlated negatively with both daily carbamazepine dose and serum carbamazepine level. Free water clearance after an oral water load was determined in six patients on carbamazepine alone and in six normal subjects not receiving drug therapy. The capacity of some of the patients to excrete the water load was found to be grossly impaired.

Adolescent↗
PubMed1977

Comparison of quinidine plasma concentration curves following oral administration of some short- and long-acting formulations.

1 The time-course of quinidine plasma concentrations and selected kinetic parameters were studied in healthy male volunteers given single oral doses of four different quinidine formulations. Comparison was made with quinidine sulphate in a rapidly dissolving form. 2 Plasma half-lives did not significantly differ among treatments. 3 Quinidine polygalacturonate appears to be equivalent to quinidine sulphate in respect to both the absorption and elimination kinetics. When both quinidine bisulphate (Kinidin Durules) and quinidine arabogalactansulphate (Longacor) were administered plasma levels peaked significantly later than after quinidine sulphate. However, while the former seems to be absorbed to the same extent as quinidine sulphate, the latter exhibits lower bioavailability in respect to all other preparations.

Administration, Oral↗