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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 163 records · Page 9Linked to original sources
PubMed1988

Effect of flurithromycin, a new macrolide antibiotic, on carbamazepine disposition in normal subjects.

The effects of flurithromycin, a new macrolide antibiotic, on the disposition of a single oral dose of carbamazepine (CBZ) (400 mg) were investigated in seven normal subjects. Flurithromycin (2 x 250 mg thrice daily for 10 days) caused a slight increase in the CBZ area under the serum concentration curve and a moderate reduction in carbamazepine-10, 11-epoxide (CBZ-E) levels. These results suggest that flurithromycin can inhibit the conversion of CBZ to CBZ-E, although, at the dosage tested, the magnitude of this effect was significantly smaller than that observed after administration of erythromycin in the same subjects.

Adult↗
PubMed1987

Involvement of substance P in the excitatory action of GABAA agonists on cholinergic neurons in the guinea-pig ileum.

The possible involvement of substance P (SP) in cholinergic contractions induced by GABAA agonists in the guinea-pig ileum was further investigated. Responses evoked by 3-aminopropane sulphonic acid (3-APS) or muscimol consisted of a rapid phasic contraction followed in 70% of preparations by a tonic contraction, usually smaller in amplitude but considerably longer in duration. Phasic and tonic components were sensitive to bicuculline, neurogenic (cholinergic) in nature and susceptible to desensitization. Capsaicin (0.2 microM) pretreatment and SP receptor desensitization caused by 3 different priming SP concentrations (10 nM, 30 nM, 100 nM), depressed both components of the 3-APS-induced response, the magnitude of antagonism being greater for tonic contractions. Similar findings were obtained by using 10 microM (D-Pro4,D-Trp7.9)SP-(4-11), even though the degree of antagonism caused by this SP antagonist was consistently lower. These results indicate that depression of SP receptor function achieved by three different procedures decreases cholinergic contractile responses to GABAA agonists in the guinea-pig ileum. This provides further support for the hypothesis that GABAA receptor activation evokes both direct and indirect stimulation of enteric cholinergic neurons and that SP and/or a related peptide play an important role in mediating the indirect component of the cholinergic response.

Animals↗
PubMed1987

An epidemiological study of the clinical impact of pharmacokinetic anticonvulsant drug interactions based on serum drug level analysis.

The impact of pharmacokinetic anticonvulsant drug interactions on prescribing patterns and serum drug level distribution in a routine clinical setting was evaluated in a population of 848 patients chronically treated with phenytoin, phenobarbital, carbamazepine and valproic acid (either alone or as two-drug combinations) and referred for therapeutic drug monitoring for the first time. While dosages of each drug did not differ significantly between monotherapy and polytherapy patients, significant differences in serum level distribution were found. The proportion of patients with suboptimal serum carbamazepine and valproic acid levels (less than 4 and less than 50 micrograms/ml, respectively) was much greater in the polytherapy than in the monotherapy groups, probably as a consequence of induction of carbamazepine and valproic acid metabolism by combined anticonvulsants. Conversely, the proportion of phenobarbital levels above the upper limit of the optimal range (40 micrograms/ml) was greater among patients receiving phenytoin in combination than among patients taking phenobarbital alone, presumably as a result of phenytoin-induced inhibition of barbiturate metabolism. The therapeutic implications of these findings are discussed.

Adolescent↗
PubMed1987

Pharmacokinetic-dynamic study on different oral biperiden formulations in volunteers.

The pharmacodynamic and kinetic profiles of two oral biperiden formulations (tablet with instant-release and sugar-coated tablet with slow-release) were studied in a total of 12 healthy subjects after the administration of a 4 mg dose and compared in part to placebo. Biperiden as slow-release formulation showed much slower absorption than the instant-release tablet; whereas plasma levels peaked as early as 1-2 h after administration of the tablet, with the slow-release formulation a first peak was seen approximately 4.5 h after intake in the majority of the subjects. In some subjects this was followed by a trough, in others by formation of a shoulder at around 0.5 ng/ml. In all subjects a peak of about 1.0 ng/ml was reached after 10-12 h. The instant-release tablet and the slow-release formulation showed comparable bioavailability. Plasma concentrations for the slow-release formulation at 24 h were around 0.5 ng/ml, about twice as high as those for the instant-release formulation. The ratio of peak to 24 h values showed the marked reduction which is characteristic for a slow-release formulation compared with the instant-release tablet. The subjective well-being of the volunteers was not influenced by the slow-release formulation, whereas after the instant-release tablet slight CNS effects (dizziness, drowsiness and fatigue) were reported up to 6 h after ingestion. Furthermore, objectively quantifiable pharmacodynamic ocular parameters (near-point accomodation, pupil size) and the secretion of saliva proved to be less affected by the slow-release formulation than by the instant-release tablet, or not affected at all.

Accommodation, Ocular↗
PubMed1987

Serum protein binding of phenytoin and valproic acid in insulin-dependent diabetes mellitus.

The serum protein binding of valproic acid (VPA) and phenytoin (PHT) was determined in spiked serum samples collected from 17 patients with insulin-dependent diabetes mellitus and 16 healthy control subjects. The free fraction of VPA was significantly greater in patients than in controls (7.6 +/- 1.6% vs. 6.2 +/- 1.2%, p less than 0.01); for PHT, free fraction values were similar in the two groups (8.2 +/- 1.1% vs. 8.4 +/- 1.2%). The free fraction of VPA in diabetic patients was positively correlated with free fatty acid (FFA) concentration (r = 0.79, p less than 0.01). No significant relationships could be found between free drug fraction and either serum albumin or glycosylated protein concentration.

Adolescent↗
PubMed1987

Inhibition by erythromycin of the conversion of carbamazepine to its active 10,11-epoxide metabolite.

The serum levels of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were determined in seven subjects after a single dose of CBZ (400 mg) in the control state and during co-administration of erythromycin (500 mg three times daily for 10 days). Erythromycin treatment was associated with a decrease in CBZ clearance and a prolongation of CBZ half-life, while CBZ-E levels were markedly reduced. These data provide evidence that erythromycin inhibits the conversion of CBZ to its epoxide metabolite.

Adult↗
PubMed1987

Depressant action of oxybutynin on the contractility of intestinal and urinary tract smooth muscle.

Experiments were carried out in-vitro using segments of guinea-pig ileum, taenia caeci, ureter and detrusor. In the ileum, oxybutynin (30, 100 nM) competitively antagonized acetylcholine-induced contractions but did not alter those induced by histamine. Higher concentrations of oxybutynin (up to 10 microM) induced a non-competitive depression of responses to both agonists and caused a parallel shift to the right of the Ca2+-induced contractions in taenia caeci strips bathed in a Ca2+-free, high-K+ medium. In the ureter, oxybutynin (1-10 microM) impaired rhythmic muscular contractions in normal medium and after CaCl2 addition in Ca2+-free medium. Similarly to verapamil (10, 30 microM), oxybutynin (10, 30 microM) depressed both the cholinergic and non-adrenergic, non-cholinergic components of the electrically-induced contractions of detrusor strips. It is concluded that oxybutynin has anticholinergic properties and, at higher concentrations, exerts a direct spasmolytic activity possibly mediated by blockade of the transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Acetylcholine↗
PubMed1987

Pharmacokinetics of co-trimazine after single and multiple doses.

Plasma and urinary levels of trimethoprim (TMP), sulfadiazine (SDZ) and N4-acetylsulfadiazine (N4-SDZ) were determined after administration of 1 g co-trimazine (equivalent to 180 mg TMP and 820 mg SDZ) (Kombinax) as a single dose and again once daily for 7 days to 6 normal subjects. Both TMP and SDZ were rapidly absorbed from the gastrointestinal tract with peak plasma levels being achieved within 4 h in all subjects. Elimination half-lives ranged from 8 to 13 h for TMP and from 9 to 15 h for SDZ. Approximately 50% of the administered dose of SDZ was recovered in urine within 24 h of the single dose (32% as unchanged drug and 17% as the N4-acetylmetabolite). For TMP, the urinary recovery during the 24 h following the single dose averaged 39%. Mean plasma levels of TMP, SDZ and N4-SDZ at steady state were moderately higher than those observed after a single dose, but no change in absorption or disposition kinetics of these compounds was seen after repeated dosing.

Adult↗
PubMed1986

Inhibitory action of capsaicin on cholinergic responses induced by GABAA agonists in the guinea-pig ileum.

Pretreatment of the guinea-pig ileum with capsaicin resulted consistently in depression of the neurogenic cholinergic contractions induced by the GABAA receptor agonists 3-aminopropane sulphonic acid (3-APS) and muscimol. Since capsaicin acts mainly by releasing and depleting substance P from its stores in intestinal nerves, it is likely that substance P plays a role in the response caused by GABAA-mimetic compounds, On the whole, our results suggest that excitatory responses to 3-APS and muscimol result from both direct and indirect activation of intrinsic intestinal cholinergic neurons innervating smooth muscle cells.

Animals↗
PubMed1986

Pharmacokinetics of the antidepressant drug viloxazine in normal subjects and in epileptic patients receiving chronic anticonvulsant treatment.

In order to evaluate the influence of chronic antiepileptic drug treatment on the kinetics of the antidepressant viloxazine (VLX), six drug-free control subjects and six epileptic patients treated with one or two anticonvulsants (phenobarbital, carbamazepine or phenytoin) were given a single oral dose of VLX (200 mg). On a separate occasion, the patients were also given 200 mg VLX by IV infusion. Plasma VLX levels were determined by GLC. Following oral dosing, VLX was rapidly absorbed from the gastrointestinal tract (peak levels at 0.5-4 h); plasma level profiles showed a considerable interindividual variability but did not differ significantly between patients and controls. Terminal half-lives were 4.3 +/- 1.5 h in the patients and 4.3 +/- 1.8 h in the controls. Clearance and volume of distribution calculated after IV dosing in the patients were 124 +/- 11 ml h-1 kg-1 and 0.73 +/- 0.28 l/kg, respectively. The absolute oral availability was 85 +/- 14%. At variance with findings reported for other antidepressants, VLX kinetics do not appear to be significantly altered by concurrent treatment with enzyme-inducing antiepileptic drugs.

Adult↗
PubMed1986

Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects.

The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml X min-1 X kg-1 and 24 l X kg-1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.

Administration, Oral↗
PubMed1986

Altered serum protein binding of carbamazepine in disease states associated with an increased alpha 1-acid glycoprotein concentration.

The protein binding of carbamazepine (CBZ) in vitro was assessed in sera from 47 patients with various diseases known to alter alpha 1-acid glycoprotein (AAG) concentration and from 20 drug-free normal control subjects. In the patient group, AAG and albumin (HSA) concentrations ranged from 6 to 74 mumol/l and from 377 to 652 mumol/l, respectively; in the controls, protein concentrations were less variable, ranging from 11 to 26 mumol/l for AAG and from 623 to 754 mumol/l for HSA. In both the patient and the combined patient and control groups, free CBZ fractions were inversely correlated with the serum AAG concentration (r = -0.62). No significant relationship could be found between the free CBZ fraction and the serum HSA concentration. The free CBZ fraction was moderately but significantly decreased in patients with AAG levels above 26 mumol/l (the highest value found in controls) as compared either to patients with a normal AAG concentration or to control subjects (19 +/- 5% vs 23 +/- 4% and 23 +/- 2%), despite the finding of a higher HSA concentration in the control group. The data confirm AAG as an important determinant of interindividual variability in serum CBZ binding.

Adult↗
PubMed1986

Carbamazepine-viloxazine interaction in patients with epilepsy.

In six depressed epileptic patients stabilised on carbamazepine therapy, addition of the antidepressant agent viloxazine (300 mg/day for three weeks) induced a marked (average 55%) increase in steady-state plasma carbamazepine concentration. The concentration of the active metabolite carbamazepine-10,11-epoxide also increased during viloxazine therapy, but to a lesser extent (16%). In three patients, these effects were associated with symptoms of carbamazepine intoxication, which regressed rapidly when plasma carbamazepine and carbamazepine-10,11-epoxide levels returned to baseline values after discontinuation of viloxazine. In a seventh patient, viloxazine had to be discontinued after only two weeks because of severe side effects associated with a striking elevation of carbamazepine and carbamazepine 10,11-epoxide levels (by 197% and 137% respectively). Although viloxazine appears to be one of the few antidepressants which can be used safely in patients with epilepsy these results indicate that the drug should be prescribed with great caution in subjects treated with carbamazepine. The mechanism of the interaction probably involves inhibition of the metabolism of both carbamazepine and its active epoxide metabolite.

Adult↗