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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 199 records · Page 11Linked to original sources
PubMed1984

Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects.

The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in nine epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a three-times-daily or four-times-daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in five patients and showed an intermittent pattern in four. Side effects were never found at total carbamazepine levels less than 34 mumol/L but invariably appeared at levels greater than 38 mumol/L. At levels between 34 and 38 mumol/L adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels greater than 7.2 mumol/L. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.

Adolescent↗
PubMed1984

Free level monitoring of antiepileptic drugs. Clinical usefulness and case studies.

The free fraction of phenytoin, carbamazepine and valproic acid shows considerable interindividual variability, especially in the presence of associated disease or drug interactions. When binding is altered, the total concentration no longer reflects the amount of pharmacologically active drug in the plasma: this may mislead the clinician into making inappropriate dosage adjustments. Measuring the free drug concentration eliminates a potential source of interpretative errors and may be preferentially used to monitor therapy in selected patients.

Adult↗
PubMed1984

Plasma concentrations of propranolol and 4-hydroxy-propranolol at steady-state in neurological patients: intersubject and intrasubject correlations with dose.

Plasma concentrations of propranolol (PROP) and its active 4-hydroxymetabolite were determined in neurological patients receiving chronic therapy with relatively low PROP doses (40-240 mg/day). Plasma PROP concentrations determined before the morning dose were much lower than, but significantly correlated (r = 0.91) with the drug level two hours after dosing. 4-hydroxypropranolol (4-OH-P) was often undetectable (less than 1 ng/ml) in the early morning samples. Plasma concentrations of both parent drug and metabolite determined two hours after the morning dose correlated weakly with the prescribed daily dose. The intrapatient dose-concentration relationship, on the other hand, was strong, particularly for the parent drug. The ratio between 4-OH-P and PROP in plasma was inversely related to the PROP concentration, at least over the lower PROP concentration range (0-100 ng/ml). The usefulness of determining the concentration of the metabolite in the evaluation of the pharmacological action of low doses of PROP is discussed.

Adolescent↗
PubMed1983

Effect of a single oral dose of propranolol on essential tremor: a double-blind controlled study.

The effect of a single oral dose of propranolol (120 mg) on essential tremor was investigated in a double-blind, placebo-controlled study in 26 patients. Hand tremor was recorded by means of accelerometers, and its frequency and amplitude calculated by using spectrum analysis. Recordings were made before and 1 1/2 hours after drug or placebo administration. Pretreatment tremor ranged from 4.2 to 9.6 Hz (median, 6.9 Hz) in frequency and from 0.002 to 1.33 cm (median, 0.014 cm) in amplitude. Neither propranolol nor placebo affected the frequency of the underlying tremor. The amplitude of tremor was reduced by 43 +/- 11% (SEM) after propranolol (p less than 0.01) and by 12 +/- 8% after placebo (NS). The reduction observed after propranolol was significantly greater than that observed after placebo. The tremor response after propranolol correlated negatively with baseline frequency and positively with pretreatment amplitude, duration of tremor, and age of the patient. No significant relationships could be found between tremor response, serum propranolol levels, and degree of cardiac beta blockade as assessed by the inhibition of standing tachycardia. There was a clear tendency for patients with small tremor amplitude (less than 0.006 cm hand displacement) to show the least satisfactory response to propranolol. These results indicate that a single oral dose of propranolol is effective in producing a rapid and marked reduction of essential tremor. Measurement of pretreatment amplitude and frequency might be useful in predicting the therapeutic outcome in these patients.

Adult↗
PubMed1983

5-HT mediated GABA excitatory responses in the guinea-pig proximal ileum.

GABA (3--100 microM) and 5-HT (0.03--30 microM) caused concentration-dependent transient contractions of the longitudinal muscle of the guinea-pig ileum. The contractile response to GABA was antagonized by hyoscine (2.2 microM). TTX (0.7 microM), bicuculline (3 microM), furosemide (25 microM) and desensitization to GABA itself, while hexamethonium (20 microM) and methysergide (20 microM) were without effect. The contractile response to 5-HT was antagonized by hyoscine (2.2 microM), TTX (0.7 microM) and desensitization to 5-HT itself and was unaffected by bicuculline (10 microM), hexamethonium (20 microM), furosemide (25 microM) and methysergide (20 microM). A desensitization procedure that caused a 84.7-fold increase in the 5-HT EC50 also resulted in a 74.1-fold increase of the GABA EC50. Desensitization to GABA caused a reduction of 5-HT induced response but only in preparations desensitized by high (50 microM) concentrations of GABA. The results indicate that GABA-induced contractions in the guinea-pig ileum are mediated by activation of cholinergic motor neurones. This effect appears to be mediated by interneuronal release of 5-HT rather than by a direct stimulatory action of GABA on the effector neurones.

Animals↗
PubMed1983

Reduction of phenytoin clearance caused by cimetidine.

The effect of cimetidine on the disposition kinetics of phenytoin was investigated in 7 healthy volunteers. Each subject received a single intravenous dose of phenytoin on two occasions, in the control state, and during concurrent treatment with cimetidine 1 200 mg/day for 6 days. A slight but statistically significant decrease both in the rate of elimination and total body clearance of phenytoin was observed during the administration of cimetidine. The effect is probably due to inhibition of metabolism.

Adult↗
PubMed1983

Penicillin CSF levels following intravenous therapy in syphilitic patients.

Serum and CSF levels of penicillin have been determined in 13 syphilitic patients treated with relatively high doses of penicillin G by the intravenous route. Wide individual variability in the CSF/serum concentration ratio was observed. In all patients the concentration of the antibiotic in the CSF was equal to or greater than 0.03 IU/ml., which is considered to be the minimal therapeutic concentration. The potential clinical usefulness of different therapeutic regimens in the treatment of neurosyphilis is discussed.

Adult↗
PubMed1983

Diurnal fluctuations in free and total plasma concentrations of valproic acid at steady state in epileptic patients.

The diurnal fluctuations in free and total plasma concentrations of valproic acid (VPA) were determined by taking serial blood samples at 2-h intervals in six epileptic patients receiving maintenance therapy with sodium valproate (9.6-24.0 mg/kg in three divided daily doses). Both the free and the total concentrations fluctuated markedly during the period examined (0800-1800 h). The fluctuation of the free drug was about twice as great as that of the total drug (79 +/- 27% versus 47 +/- 21%, p less than 0.01). There was a considerable inter- and intrapatient variability in free VPA fraction. In at least four of six patients the free fraction increased in proportion to the increase in total concentration. These findings are in line with available evidence that the binding of VPA to plasma proteins is saturable within the clinically occurring concentration range. The changing and unpredictable relationship between total and free concentration suggests that VPA therapy can be monitored more rationally by measuring the free drug.

Adolescent↗
PubMed1983

Valproic acid free fraction in epileptic children under chronic monotherapy.

The total and free (nonprotein-bound) concentration of valproic acid (VPA) was determined in plasma samples collected at two different times of the day (before the morning dose and 3 h later) in 62 epileptic children receiving maintenance single-drug therapy with sodium valproate. Both the total and the free concentrations were lower in the early than in the late morning samples (total VPA: 394.4 +/- 150.0 vs. 556.9 +/- 175.2 mumol/L; free VPA: 20.1 +/- 11.1 vs. 31.3 +/- 17.4 mumol/L). The average free fraction of the drug was also lower in the early morning (4.8 +/- 1.3 vs. 5.4 +/- 1.6%, p less than 0.001). At both sampling times, the free fraction was positively correlated (p less than 0.01) with the total concentration. Evidence is presented that, at equal total plasma VPA concentration, the free fraction of the drug is significantly (p = 0.01) higher in the early than in the late morning samples. The rise in plasma free fatty acids (acting as displacing agents) after the overnight fast is probably responsible for this difference in free fraction. The implications of these findings with respect to the monitoring of free plasma VPA levels are discussed.

Adolescent↗
PubMed1983

Free fraction of valproic acid: in vitro time-dependent increase and correlation with free fatty acid concentration in human plasma and serum.

The effect of sample incubation and storage on the protein binding of the antiepileptic drug valproic acid (VPA) and on the concentration of free fatty acids (FFA) was investigated in serum and plasma collected from four normal volunteers. Both the free fraction of VPA and the concentration of FFA increased progressively with time when samples were incubated at 4 to 37 degrees C. These effects occurred to the same extent in both serum and heparinized plasma. At 4 degrees C and at room temperature, the increase in free drug fraction was relatively small (18 and 25% respectively at 24 h), whereas at 37 degrees C it was quite considerable (24% at 8 h and 40% at 24 h). At room temperature, FFA rose on average by 22% at 4 h, 34% at 8 h, and 86% at 24 h, whereas at 37 degrees C the increases at the same incubation times were 59, 90, and 160%, respectively. There was a strong positive relationship between changes in free VPA fraction and FFA content of the samples. The time-dependent changes in VPA binding capacity described in this study may lead to overestimation of the actual free concentration in vivo, especially when this is estimated by equilibrium dialysis or ultracentrifugation techniques requiring long incubation (centrifugation) times at 37 degrees C.

Adult↗
PubMed1983

Dilazep: an inhibitor of adenosine uptake with intrinsic calcium antagonistic properties.

Concentrations of dilazep which were ineffective in altering the muscular tone of the guinea-pig taenia caeci (0.03, 0.3 microM) or the phasic mechanical activity of the rabbit proximal ileum (0.03 microM) markedly potentiated the inhibitory action of adenosine on both these parameters. Dilazep, 0.3 microM or greater, dose-dependently inhibited the mechanical activity of the proximal ileum. This inhibitory action was probably mediated by more than one mechanism, as shown by the fact that theophylline (50, 100 microM) antagonized the effect at lower dilazep concentrations (up to 3 microM) leaving essentially unchanged the response to higher concentrations (6, 10 microM). Similarly, the responses to low doses of dilazep were reduced after desensitization of the organ to adenosine, whilst the responses to higher doses were unaffected by this procedure. In a Ca2+-free, high-K+ medium, dilazep (1-10 microM) caused a parallel shift to the right of the Ca2+-induced contractions of the guinea-pig taenia caeci. Adenosine showed only slight Ca2+-antagonistic properties within the mM range of concentrations. These findings suggest that, at the higher concentration tested, dilazep exhibits Ca2+-antagonistic properties unrelated to its adenosine-mediated mode of action.

Adenosine↗
PubMed1983

The response of essential tremor to propranolol: evaluation of clinical variables governing its efficacy on prolonged administration.

The factors influencing the response of essential tremor to prolonged administration of propranolol (120 mg daily for two weeks followed by 240 mg daily for a further two weeks) were investigated in a double-blind, cross-over, placebo-controlled study in 16 patients. Hand tremor was assessed by means of accelerometers with off-line computer analysis. Propranolol was found to be superior to placebo only at the higher dosage regimen (240 mg daily). At this dosage, the median reduction in tremor amplitude (as compared to the control value) was by 45%. The response to the drug (expressed as percentage change in tremor amplitude) was correlated positively with the control amplitude (rs = 0.71, p < 0.01) and negatively (but more weakly) with the control peak frequency of tremor (rs = -0.53, p < 0.05). In the patients with hand tremor greater than 6 x 10(-3) cm hand displacement the tremor amplitude was reduced by 65%, as compared to only 17% in patients whose tremor amplitude was below this limit. No statistically significant relationship could be found between percentage change in tremor amplitude and duration of the disorder, age of the patients, degree of cardiac beta-blockade or serum propranolol levels. The results suggest that patients with small tremor amplitude should not be treated with propranolol unless their tremor becomes severely aggravated under conditions of excessive adrenergic discharge.

Adult↗
PubMed1982

Mode of action of ATP on propulsive activity in rabbit colon.

ATP induced a concentration-dependent reduction of the velocity of propulsion in isolated segments of rabbit colon as assessed by the aboral displacement of an intraluminal rubber balloon, and delayed the onset of the propulsive wave. ATP depressed both the reflex contraction of the circular coat above the distended balloon and the response of the circular muscle to transmural (cholinergic) stimulation. On the contrary, ATP (up to 200 muM), while causing relaxation of the circular muscle, had no effect on either the muscular contractile response induced by carbachol and histamine or the non-adrenergic inhibitory responses elicited by electrical stimulation and by radial distension of the gut wall. Within the concentration range used (10-200 muM), ATP concentration-depression curves for propulsion and transmural excitatory stimulation were shifted to the right in the presence of theophylline (10 muM). Theophylline, however, had no influence on either the direct inhibitory action of ATP on circular smooth muscle or the non-adrenergic relaxation in response to electrical stimulation. These data are consistent with the concept that at least two populations of purinergic receptors are present in intestinal tissue. Those populations located presynaptically, unlike those located postsynaptically, are blocked by theophylline. Since the contractile machinery does not appear to be affected by ATP concentrations up to 200 muM, the mechanism by which ATP impairs propulsive activity is probably dependent on activation of presynaptic purinergic receptors located on the nervous pathways subserving the wave of contraction, without having any appreciable influence on descending inhibition.

Adenosine Triphosphate↗
PubMed1982

Determination of unbound valproic acid concentration in plasma by equilibrium dialysis and gas--liquid chromatography: methodological aspects and observations in epileptic patients.

An equilibrium dialysis technique for the separation of the free (unbound) concentration of valproic acid (VPA) in plasma is described together with a sensitive gas chromatographic assay for the quantitative determination of the drug in the dialysate. The overall coefficient of variation of the method was below 10%. By using a high permeability membrane, equilibration of the drug between the plasma and the buffer compartments was obtained after about 45 min at 37 degrees C. With this dialysis time, dilutional changes in the plasma compartment were negligible and there was no significant change in the plasma-free fatty acid (FFA) concentration. No passage of protein into the buffer solution was detected. When dialysis was prolonged for up to 4 h, a significant elevation in plasma FFA (with a corresponding rise in free VPA fraction) was observed. Storage of plasma samples at temperatures ranging from 4 to 37 degrees C for 8 h or longer before dialysis also resulted in an increased value of free VPA fraction and FFA concentration. The two effects were significantly correlated. The free fraction of VPA was found to increase with increasing total plasma concentration. This effect was observed both in vitro and in vivo in the plasma of 91 patients receiving chronic VPA therapy. The methodological problems of using equilibrium dialysis techniques for determining the free fraction of VPA are highlighted.

Blood Preservation↗
PubMed1982

Serum protein binding and free concentration of phenytoin and phenobarbitone in pregnancy.

1 The effect of pregnancy on the binding of phenytoin and phenobarbitone to serum proteins was studied in normal women and in drug treated epileptic women. 2 The binding of both drugs was reduced during pregnancy. The reduction correlated positively with the gestational age and negatively with the serum albumin concentration. 3 In spite of the increase in unbound fraction, both the total and free serum concentrations of phenytoin were decreased in late pregnancy.

Adult↗
PubMed1982

Pharmacokinetics of phenylethylmalonamide (PEMA) in normal subjects and in patients treated with antiepileptic drugs.

The pharmacokinetics of phenylethylmalonamide (PEMA), a major metabolite of primidone, were investigated following administration of single oral doses (400 mg) to six normal subjects and six patients receiving chronic treatment with antiepileptic drugs. Peak serum PEMA levels were usually attained with 2-4 h after intake. The oral bioavailability estimated on the basis of the recovery of unchanged drug in the urine of normal subjects was at least 80%. Half-life values ranged from 17 to 25 h in normal subjects and from 10 to 23 h in the patients. No statistically significant difference in any of the calculated kinetic parameters could be found between the two groups. The data indicate that PEMA is readily absorbed from the gastrointestinal tract and that it is eliminated predominantly unchanged in the urine of man.

Adult↗
PubMed1982

Controlled study of metoprolol and propranolol during prolonged administration in patients with essential tremor.

The efficacy of propranolol and metoprolol in the treatment of essential tremor was compared in a double blind crossover placebo-controlled study in 16 patients. Each treatment was given for a period of 4 weeks at two different dosage regimens (150 and 300 mg daily for metoprolol, 120 and 240 mg daily for propranolol). Each dosage regimen lasted for 2 weeks. Tremor assessment was carried out by accelerometry, clinical evaluation, patient's self-rating and a battery of performance tests. At the lower dosage, propranolol was found to be superior to placebo on the basis of performance tests and patient's self-assessment. At the higher dosage, propranolol was superior to placebo on all methods of assessment. By contrast, the tremorolytic effect of metoprolol was not significantly different from that of placebo, irrespective of the dosage or of the method of assessment used. Propranolol (120 mg daily) was better than metoprolol (150 mg daily) on the basis of clinical evaluation and patient's self-assessment. Propranolol (240 mg daily) was superior to metoprolol (300 mg daily) on the basis of patient's self-assessment. Both drugs antagonised standing tachycardia to a similar extent. These results indicate that the effectiveness of metoprolol, previously demonstrated in a single-dose study in the same patients, is not fully maintained during prolonged administration. In the absence of specific contraindications, propranolol represents a better choice in the treatment of patients with essential tremor.

Adult↗