[Interactions among epileptic drugs. Retrospective study of the serum levels of a large patient population].
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Anticonvulsants↗
Biomedical subjects
E Perucca
Publications and source records attributed to E Perucca.
Depression by morphine of the excitability of intrinsic inhibitory neurons in the guinea-pig colon.
The mechanical responses to morphine were examined in isolated preparations of longitudinal and circular muscle of the guinea-pig colon. In the longitudinal coat, morphine induced a relaxation which was prevented by naloxone, hyoscine and tetrodotoxin. Conversely, in the circular coat morphine caused a contraction which was antagonized by naloxone, mimicked by tetrodotoxin and left unaltered by hyoscine, chlorpheniramine and methysergide. In both muscular layers, morphine depressed (and tetrodotoxin abolished) the non-adrenergic relaxation induced by field stimulation. The action of morphine in the two preparations can thus be explained in terms of inhibition of the tonic excitatory cholinergic or inhibitory non-adrenergic neural control prevailing in the longitudinal and circular muscle respectively.
Animals↗
Alpha 1-acid glycoprotein concentration and serum protein binding of carbamazepine and carbamazepine-10,11 epoxide in children with epilepsy.
The relationship between the serum protein binding of carbamazepine (CBZ) and carbamazepine-10,11 epoxide (CBZ-E) and the concentration of alpha 1-acid glycoprotein (AAG) and albumin (HSA) was examined in 39 CBZ-treated epileptic children aged 4 months to 12 years. A significant inverse correlation was found between the free fraction of both compounds and serum AAG, even though changes in AAG concentration explained only part of the variation in binding. No correlation was found between the free fraction of CBZ and CBZ-E and HSA, probably due to the small intersubject variation in HSA concentration. In vitro experiments showed that both CBZ and CBZ-E were bound to HSA and to a lesser extent to AAG. At equivalent HSA concentrations, the binding of CBZ and its metabolite increased proportionately with increasing AAG concentration within the range occurring clinically.
Carbamazepine↗
A controlled study of the suppression of tinnitus by lidocaine infusion: (relationship of therapeutic effect with serum lidocaine levels).
The relationship between serum lidocaine levels and tinnitus relief was assessed in 5 patients during intermittent intravenous infusions of the drug. Experiments were conducted under controlled conditions in that neither the attending physician nor the patient was aware of whether active drug or placebo was being infused at any particular time. A significant relationship between serum level and effect was observed in two patients. In the remaining patients this relationship was not readily apparent but there was still a trend for a better response to be seen at higher levels. A satisfactory response was generally seen at levels above 1 microgram/ml. The results are consistent with the hypothesis that the transient nature of the symptomatic relief caused by lidocaine is related to the fast clearance of the drug from the body.
Adult↗
Determination of total and free plasma carbamazepine concentrations by enzyme multiplied immunoassay: interference with the 10,11-epoxide metabolite.
The performance of the enzyme multiplied immunoassay technique (EMIT) in the measurement of total and free plasma carbamazepine (CBZ) levels was assessed in 140 clinical specimens and compared with a reference high pressure liquid chromatography (HPLC) technique. Free drug was measured in plasma filtrates obtained by the Free Level system. Both total and free CBZ levels as determined by EMIT correlated strongly with corresponding HPLC values (r = 0.88 and 0.92, respectively). Plasma CBZ concentrations, however, were higher by EMIT than by HPLC. The degree of CBZ overestimation by EMIT was relatively small (about 14%) in whole plasma but quite considerable (35% on average) in the filtrates. As a result, estimated values of free CBZ fraction were also higher for EMIT than for HPLC. Separate experiments in vitro suggested that the discrepancies between the two methods were due to cross-reaction of the EMIT reagent with the 10,11-epoxide metabolite of CBZ. The greater degree of overestimation for the free drug can be explained by the higher proportion of less protein-bound metabolite in the filtrates. These results need to be taken into account in the interpretation of free CBZ level data from laboratories using different techniques.
Carbamazepine↗
Quality control in antiepileptic drug monitoring in Italy.
Measurement of drug concentrations in physiological fluids is increasingly becoming part of the routine management of drug therapy, thus calling for particular care to ensure reliability and avoid misguided management. As part of a long-term national project to set up a network of hospitals where clinical chemists, pharmacists, and physicians could interact and evaluate their activities in connection with therapeutic drug monitoring, the results of a quality control scheme for antiepileptic drugs, which included 50 national hospital laboratories, are described here.
Anticonvulsants↗
Time-dependent interaction between phenytoin and valproic acid.
The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.
Adolescent↗
Lateral gaze nystagmus in carbamazepine-treated epileptic patients: correlation with total and free plasma concentrations of parent drug and its 10,11-epoxide metabolite.
The incidence of lateral gaze nystagmus and its correlation with free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine-10, 11-epoxide (CBZ-E) were examined in 97 epileptic patients receiving chronic treatment with CBZ alone (n = 54) or in combination with phenobarbital (PB) (n = 43). All patients had plasma CBZ concentrations within the clinically optimal range (less than 50 mumol/L). Nystagmus was seen in 26% of patients receiving monotherapy and in 33% receiving combination therapy. Within each group, however, nystagmus was much more frequent among patients with higher CBZ concentrations. For patients receiving PB in combination the CBZ levels above which nystagmus was particularly frequent appeared to be lower than in the monotherapy patients--a finding that could not be attributed to differences in plasma PB concentrations. The correlation of CBZ-E levels (or the sum of CBZ + CBZ-E) with the occurrence of nystagmus was no better than that observed with CBZ levels alone. Free drug levels did not appear to be superior to total levels in discriminating between patients with or without nystagmus. These results indicate that the occurrence of nystagmus is concentration-dependent within the therapeutic plasma CBZ concentration range and suggest that the threshold at which this neurological sign appears is reduced in the presence of PB, possibly as a result of a pharmacodynamic interaction.
Adult↗
Alterations of drug toxicity in neuropsychiatric disease states.
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.
Autonomic Nervous System Diseases↗
Single-dose kinetics of primidone in acute viral hepatitis.
The pharmacokinetics of primidone (PRM) after oral administration of a single 500 mg dose was studied in 7 patients with acute viral hepatitis and 7 healthy control subjects. The elimination half-life and the apparent clearance of unchanged PRM in the patients were 18.0 +/- 3.1 h and 42 +/- 14 ml X h-1 X kg-1, respectively (mean +/- SD) and did not differ significantly from the values in the controls (half-life 17.0 +/- 2.4 h; clearance 35 +/- 8 ml X h-1 X kg-1). The metabolite phenylethylmalonamide (PEMA) was detected in the serum of all normal subjects within 2-24 h. By contrast, serum levels of this metabolite were undetectable (less than 2 mumol/1) in all but one of the patients. Serum levels of phenobarbital (PB) remained below the limit of detection (less than 2 mumol/1) in all subjects. The findings indicate that accumulation of PRM with its attendant toxicity is unlikely to occur in epileptic patients who develop acute viral hepatitis, despite evidence that the metabolism of the drug is affected by this condition. The possibility of impaired conversion to PB and its implications are discussed.
Acute Disease↗
Mechanism of altered drug binding to serum proteins in pregnant women: studies with valproic acid.
The mechanism underlying the impaired serum protein binding of valproic acid (VPA) in pregnancy was examined in samples collected from 24 healthy women in the last 3 weeks of gestation and 15 age-matched nonpregnant female controls. Experiments were performed in vitro using a rapid equilibrium dialysis technique free from in vitro alterations in free fatty acids (FFA). At a total drug concentration of approximately 420 mumol/L, the free VPA fraction was 10.2 +/- 2.9% (SD) in pregnant women and 4.8 +/- 1.0% in controls (p less than 0.001). Pregnancy was associated with a marked reduction in serum albumin levels but with only a slight, nonsignificant elevation in FFA. Free VPA fraction was negatively correlated with serum albumin levels. A positive correlation between free VPA fraction and FFA was observed in the pregnant group but not in the controls. The only sample collected during labour showed a striking elevation of both free VPA fraction and FFA, in spite of a normal albumin concentration. Scatchard's plots showed VPA bound to two classes of binding sites on the albumin molecule. The number of primary (n1) and secondary (n2) binding sites in pregnant women (n1 = 2.0; n2 = 10.7) was virtually identical to that observed in the controls (n1 = 1.9; n2 = 9.8). The association constants of the primary (k1) and secondary (k2) sites were lower in pregnant women (15.9 X 10(3) and 0.19 X 10(3) L/mol, respectively, vs. 22.6 X 10(3) and 0.33 X 10(3) L/mol in controls) but the difference was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Free and total plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients: diurnal fluctuations and relationship with side effects.
The diurnal fluctuations in free and total plasma levels of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) and their relationship with intermittent side effects were examined in 10 epileptic patients stabilized on chronic CBZ therapy alone or in combination with phenobarbital (PB). With a t.i.d. or q.i.d. dosing schedule, total plasma levels of CBZ and CBZ-E fluctuated to a similar extent (average 34% and 29%, respectively). The diurnal changes in free levels of both compounds mirrored closely those of the total levels. Free fraction values ranged from 13 to 26% for CBZ and from 24 to 66% for CBZ-E. Owing to the lower protein binding of the metabolite, CBZ-E/CBZ ratios were higher in plasma water (0.49) than in whole plasma (0.22). A good correlation was found between both total and free CBZ levels and dose-related side effects (diplopia, nystagmus). On the other hand, no apparent relationship was found between side effects and either total or free plasma CBZ-E. The correlation with the presence of neurological signs of toxicity for the sum of CBZ + CBZ-E levels was no better than that observed for CBZ levels alone. These data do not support the hypothesis that CBZ-E contributes significantly to the development of dose-related side effects in CBZ-treated patients.
Adult↗
Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission.
The kinetics at steady state of prednisone and its metabolite prednisolone were determined in nine nephrotic children during the active phase of the disease and in remission. There were no differences in serum prednisone levels between the two occasions. Prednisone levels were lower than prednisolone levels. Total serum prednisolone levels were significantly lower during the active phase than in remission (AUC: 2452 +/- 207 vs 3392 +/- 293 ng ml-1 h respectively). Half-life values were similar on both occasions. The binding of prednisolone to serum proteins was markedly impaired during the active phase as compared to the remission. Free fraction values correlated positively with total drug concentration. A negative correlation between free fraction and serum albumin level was found during the active phase. Free prednisolone levels during the active phase did not differ significantly from those observed during remission (AUC: 937 +/- 128 vs 847 +/- 81 ng ml-1 h respectively). These data indicate that pharmacokinetic changes are unlikely to be responsible for alterations in steroid responsiveness in nephrotic patients with hypoalbuminaemia.
Adolescent↗
Pharmacokinetics of valproic acid in the elderly.
The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.
Adult↗
Differential transplacental binding of valproic acid: influence of free fatty acids.
The unbound fraction of valproic acid (VPA) was found to be significantly lower in cord serum (6.0 +/- 0.8%) than in maternal serum collected before oxytocin (12.2 +/- 2.7%) or after delivery (9.9 +/- 2.3%). The difference was probably due to the concentration of free fatty acids (acting as displacing agents) being higher in maternal serum. The transplacental binding gradient explains the clinical observation that total VPA levels at delivery are higher in the newborn than in the mother.
Dialysis↗
A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients.
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).
Anticonvulsants↗
Effect of valproate on free plasma 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.
Adult↗
Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations.
The kinetics and dynamics (inhibition of exercise tachycardia) of two controlled-release preparations of propranolol (Elanolol and Inderal LA) were examined in six normal volunteers. Conventional propranolol (Inderal) was also studied for comparison purposes. As compared to conventional propranolol (120 mg), single doses of Elanol (120 mg) and Inderal LA (160 mg) produced a smoother serum level profile, with lower and delayed peak times. Dose-corrected AUC0-24 values were greater after Elanol than after Inderal LA (651 +/- 147 vs 402 +/- 159 ng ml-1 h, means +/- s.e. mean, P greater than 0.05). The profile of inhibition of exercise tachycardia mirrored closely that of the serum levels. At steady state, all regimens studied (Inderal 40 mg three times daily; Elanol 120 mg once daily; Inderal LA 160 mg once daily) ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose-corrected AUC0-24 values were 797 +/- 148 ng ml-1 h after Inderal, 908 +/- 113 ng ml-1 h after Elanol and 602 +/- 122 ng ml-1 after Inderal LA. The bioavailability of Inderal LA was significantly lower than that of the other preparations. These results demonstrate that long-acting formulations of propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first-pass metabolism.
Adult↗