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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 109 records · Page 6Linked to original sources
PubMed1994

Omeprazole does not enhance the metabolism of phenacetin, a marker of CYP1A2 activity, in healthy volunteers.

Omeprazole has been reported to increase cytochrome P450IA2 (CYP1A2) activity in vitro, but whether this effect also occurs in vivo is controversial. To clarify this issue, the effect of omeprazole (20 mg/day for 8 days) on the kinetics and metabolism of phenacetin, an in vivo marker of CYP1A2 activity, was examined in 10 healthy volunteers. The pharmacokinetic parameters of phenacetin and metabolically derived paracetamol on the 8th day of omeprazole administration were very similar to those observed in a control session in the absence of omeprazole administration, the only significant difference being a higher peak plasma phenacetin concentration during omeprazole treatment. It is concluded that at the dosage used omeprazole does not increase the rate of oxidative and conjugative reactions involved in the metabolism of phenacetin and paracetamol respectively. These data are consistent with the hypothesis that omeprazole is generally devoid of inducing effects on CYP1A2 activity in vivo, at least in a Caucasian population with a low prevalence of the omeprazole-mephenytoin poor metabolizer phenotype.

Acetaminophen↗
PubMed1994

Decreased plasma concentrations of imipramine and desipramine following cholestyramine intake in depressed patients.

The effect of cholestyramine (4 g t.i.d. for 5 days) on the steady-state plasma concentrations of imipramine and desipramine was assessed in six depressed patients receiving chronic treatment with imipramine (75-150 mg/day). Compared with baseline, cholestyramine treatment was associated with an average 23% decrease in plasma imipramine levels [from 211 +/- 95 to 159 +/- 67 nmol/L, (mean +/- SD), p < 0.05], whereas desipramine levels decreased only marginally. These data suggest that administration of cholestyramine at therapeutic doses impairs the gastrointestinal absorption of concurrently prescribed imipramine by an extent that is potentially clinically significant.

Adult↗
PubMed1994

Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy.

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady-state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10, 11-dihydro-10-hydroxy-carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double-blind cross-over placebo-controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.

Adult↗
PubMed1994

Clinical pharmacokinetics of fluvoxamine.

Fluvoxamine is a selective inhibitor of serotonin reuptake that is widely used in the management of depression. Following oral administration, the drug is absorbed efficiently from the gastrointestinal tract. Peak plasma concentrations are usually observed within 2 to 8 hours postdose for capsules and film-coated tablets and within 4 to 12 hours for enteric-coated tablets. Despite complete absorption, oral bioavailability may be incomplete probably because of first-pass metabolism. Approximately 77% of fluvoxamine is plasma protein bound. Only negligible amounts of fluvoxamine are excreted unchanged in urine. The drug is extensively biotransformed, mostly by oxidation, and at least 11 different metabolites have been detected in human urine. None of the metabolites is known to possess significant pharmacological activity. Following administration of single doses, fluvoxamine shows a biphasic elimination with a mean terminal elimination half-life of about 15 to 20 hours. Steady-state plasma fluvoxamine concentrations are achieved 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single-dose data. Preliminary data also suggest that plasma drug concentrations may increase nonlinearly with increasing daily dosage. The relationship between plasma fluvoxamine concentration and clinical response has not been clearly defined. Fluvoxamine pharmacokinetics are substantially unaltered in the elderly, whereas higher plasma drug concentrations (relative to dose) are observed in patients with alcoholic cirrhosis of the liver. Fluvoxamine inhibits oxidative drug metabolising enzymes and, therefore, causes a number of clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants, alprazolam, bromazepam, diazepam, theophylline, phenazone (antipyrine), propranolol, warfarin, methadone and carbamazepine.

Animals↗
PubMed1994

[Eclampsia: 8-year experience].

Eighty-one cases of eclampsia were managed from april 1985 to may 1993 with an incidence of 1.0 in 1.000 deliveries, at the Department of Obstetric, Gynecology and Neonatology of Barros Luco-Trudeau Hospital, Santiago, Chile. 84.6% of patients were primipara and 45.7% were less than 20 years of age. Convulsions occurred during pregnancy in 61.7% of patients, during labor 22.2% and 16.1% post partum. Eleven cases (13.6%) had convulsions while receiving magnesium sulfate therapy. Prior to convulsion 21.3% of patients showed blood pressure below 140/100 mmHg. 25.9% of patients had normal urine protein. Cesarean section was performed in 75.3%, and the most frequent indication was poor cervical conditions. Fetal distress respiratory and the intrauterine growth retardation were the most frequent neonatal morbidity. Perinatal mortality was 13.2%. Maternal mortality was 3.7%.

Adolescent↗
PubMed1994

[Obstetrical and perinatal aspects in renal transplantation].

This study evaluates the record of 14 pregnant women all of whom have received living donor renal transplants, and their control and delivery was done in our Service. Five women have had more than one pregnancy. The latency period between renal transplantation and pregnancy was 39.3 months. Blood pressure figures were acceptable in 73% of the patients before pregnancy and 28% evolved during their postpartum period with blood pressure over 140/90. In those cases where pregnancy was longer than first trimester the percentage of successful gestation was 93% with 41% premature births, 38% growth retardation at birth, and there was 10% spontaneous abortions. Eighty three percent of pregnancies delivered by cesarean section.

Adolescent↗
PubMed1994

Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers.

The plasma concentrations of free (unconjugated) and conjugated silybin after intake of a single oral dose of a lipophilic silybin-phospatidylcholine complex (silipide, 80 mg expressed as silybin equivalents) were evaluated in 12 healthy volunteers by using a sensitive and specific HPLC method. Free silybin concentrations reached a peak of 141 +/- 31 ng/ml (mean +/- SEM) at 2.4 hours after dosing and declined thereafter with a half-life of about 2 hours. Peak concentrations of conjugated silybin were greater (255 +/- 35 ng/ml) and occurred at a later time (about 3.8 hours). The elimination of conjugated drug tended to be slower than that of free drug. AUC values for conjugated sylibin were about three-fold greater than those of free drug. It is concluded that after oral intake of silipide, silybin undergoes extensive conversion to conjugated derivative(s) which are retained in the circulation at relatively large concentrations.

Administration, Oral↗
PubMed1994

Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction.

The pharmacokinetics of silybin, the main active component of silymarin, following administration of a lipophilic silybin-phosphatidylcholine complex (silipide) was evaluated in fourteen patients with cholestasis secondary to biliary extrahepatic obstruction. Each patient received a single oral dose of silipide (120 mg, expressed as silybin equivalents). Blood samples for high performance liquid chromatography (HPLC) determination of free (unconjugated) and total (free+conjugated) silybin were collected at frequent intervals for up to 24 h after dosing. Absorption from the gastrointestinal tract occurred rapidly, peak concentrations of free drug being observed within 3 h in most patients. Thereafter, the decline in plasma free silybin levels was relatively rapid, and at 12 h the concentration of free drug had already approached the limit of quantitation (2 ng/ml). At all sampling times, the total (free+conjugated) concentration was much higher than the free concentration. Total silybin levels reached a peak at about 3 to 4 h and persisted at relatively high values (> or = 400 ng/ml) throughout the entire sampling period. On average, the area under the curve for total silybin was more than 40-fold greater than the area under the curve for free silybin. These data suggest that extrahepatic biliary obstruction is associated with a reduced clearance of conjugated silybin, probably due to impaired excretion of the conjugate in bile.

Adult↗
PubMed1994

The disposition of theophylline in patients with lung and breast cancer.

The influence of extrahepatic neoplastic disease on the biotransformation of theophylline was assessed by comparing the pharmacokinetic and metabolic profile of the drug in six patients with advanced breast or bronchial carcinoma, without detectable liver metastases, and in six appropriately matched control subjects. Each subject was given a single dose of theophylline (5 mg/kg) in oral solution; blood and urinary samples were collected for up to 24 h after dosing. Theophylline was absorbed rapidly in all subjects and within 2 h reached comparable peak concentrations in both groups (cancer patients: 57.8 +/- 14.4 mumol/l; controls; 65.0 +/- 10.6 mumol/l; N.S., means +/- s.d.). No significant differences were observed between cancer patients and controls for theophylline apparent volume of distribution (0.44 +/- 0.07 vs 0.40 +/- 0.06 l/kg), total body clearance (40.8 +/- 12.8 vs 34.8 +/- 13.0 ml kg-1 h-1) and elimination half-life (8.0 +/- 1.6 vs 8.5 +/- 1.8 h). The excretion of the major metabolites 3-methyl-xanthine and 1,3-dimethyl-uric acid was also very similar in the two groups. These data do not provide any evidence for an altered rate or pattern of theophylline biotransformation in patients with advanced extrahepatic neoplastic disease.

Adult↗
PubMed1993

Effects of phenytoin on the in vivo kinetics of thiamine and its phosphoesters in rat nervous tissues.

The in vivo effects of chronic (30 days) and subchronic (10 days) intragastric treatment with phenytoin (PHT) (500 mg/kg) b.wt., suspended in 10% arabic gum water solution) on the uptake and metabolism of thiamine (T), T monophosphate (TMP) and T pyrophosphate (TPP) were evaluated in rat nervous regions (cerebral cortex, brainstem, cerebellum and sciatic nerve) by determining the radioactivity of T and its phosphoesters in plasma and tissues at fixed time intervals (0.25-240 h) after an i.p. injection of thiazole-[2-14C]thiamine (30 micrograms: 1.25 microCi). A nutritionally adequate diet containing T in excess was given to the animals in order to produce a virtually stable content of T compounds in the tissues. Analytical data were processed by using a compartmental model which allowed the calculation of fractional rate constants (FRC), turnover rates (TR) and turnover times. Compared with vehicle-treated controls, animals treated chronically with PHT exhibited lower levels of radiolabelled T compounds in all nervous regions except for the cerebral cortex. These alterations were not found in animals receiving subchronic treatment. Evaluation of FRC values indicated that PHT-induced effects on T metabolism differed depending on the length of PHT treatment and the nervous region considered. Overall, PHT appeared to interfere mainly with T and TMP uptake, TPP dephosphorylation to TMP and TPP turnover times, these effects being particularly prominent in the cerebellum and in the brainstem of chronically treated animals. Since all changes in T uptake and metabolism were observed in the absence of overt behavioural toxicity, these findings may have potential clinical relevance in highlighting possible mechanisms by which PHT therapy can alter brain metabolism.

Animals↗
PubMed1993

The clinical pharmacology of the new antiepileptic drugs.

Conventional anticonvulsants have important limitations in terms of efficacy and tolerability, and there is a clear need for new agents to be developed. After a quiescent period which lasted for more than two decades, several promising new compounds have undergone clinical evaluation and a few of these (vigabatrin, lamotrigine, oxcarbazepine, zonisamide) are now commercially available in some countries. Some of the new agents represent structural analogues of pre-existing drugs in an attempt to improve the therapeutic index of the latter (e.g., oxcarbazepine), while others were rationally designed to interfere selectively with inhibitory (vigabatrin) or excitatory (NMDA receptor antagonists) neurotransmission in the brain. Many other compounds were discovered more or less serependitiously and their mode of action is poorly understood. The present article provides a concise review of the clinical pharmacology of the new anticonvulsants which have undergone most extensive clinical testing in patients with epilepsy. Topics discussed include clinical pharmacokinetics, drug interactions, efficacy data in selected epileptic syndromes or seizure types, and adverse effects profile. Although the precise role of these new agents in the overall management of epilepsy remains to be clearly defined, their availability already provides a valuable tool which can be usefully exploited to improve prognosis, especially in patients with the more severe forms of the disease.

Anticonvulsants↗
PubMed1993

A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study.

Subjective and objective measures of daytime sleepiness and psychomotor function were determined in normal control subjects and in epileptic patients on chronic monotherapy with phenobarbital or valproate (n = 10 in each group). All patients had primary generalized epilepsy with a normal resting EEG and were seizure-free for at least 1 year. After nocturnal polysomnographic recording, each subject was evaluated at 2 h intervals between 10:00 and 16:00 h by using multiple sleep latency tests (MSLT), a visual analogue rating scale for alertness (VARS), an anxiety scale (STAI-X1) and a battery of psychomotor tests. Nocturnal sleep parameters before daytime assessment were comparable in the 3 groups. At MSLT, patients on phenobarbital showed a shorter mean sleep latency (9.0 +/- 1.7 min) compared with the valproate group (12.5 +/- 1.3 min) and controls (12.9 +/- 1.2 min), though within-group variability was considerable. Compared with controls, patients on phenobarbital showed longer motor movement times, impaired attention (cancellation test, CT), reduced processing speed (digit-symbol substitution, DSS) and a trend towards lower critical flicker fusion threshold. Patients on valproate showed some impairment in attention and a trend towards longer motor movement time. In patients, no correlation was found between assessed parameters and serum drug concentrations, which were 19.3 +/- 1.7 micrograms/ml for phenobarbital and 85.7 +/- 4.7 micrograms/ml for valproic acid.

Adult↗
PubMed1993

Daytime sleepiness in epileptic patients on long-term monotherapy: MSLT, clinical and psychometric assessment.

A multiparametric investigation of daytime sleepiness was carried out in 10 patients with a generalized epilepsy treated by phenobarbital, 10 with a cryptogenic partial epilepsy treated by carbamazepine and 10 healthy controls. After a standard ambulatory night-time polysomnography, an objective and subjective estimate of daytime sleepiness was made in each subject by means of the Multiple Sleep Latency Test (MSLT) and visual analogue rating scale (VARS), respectively. Furthermore, a parallel assessment of mood and cognitive tasks involving attention and psychomotor speed was also carried out. The data show that patients on chronic treatment with phenobarbital have a greater daytime sleep tendency and they show a worse score at the digit symbol substitution test, than patients on carbamazepine and healthy controls.

Adolescent↗
PubMed1993

Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects.

The effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine caused a significant prolongation of imipramine half-life (from 22.8 +/- 6.4 to 40.5 +/- 5.0 h, means +/- SD, p < 0.01) and a marked decrease in imipramine apparent oral clearance (from 1.02 +/- 0.19 to 0.28 +/- 0.06 L/h/kg, p < 0.0001). No significant changes in desipramine kinetics were observed during fluvoxamine treatment. These findings indicate that, at the dosage tested, fluvoxamine markedly inhibits the demethylation of imipramine without affecting significantly the CYP2D6-mediated hydroxylation of desipramine.

Adult↗
PubMed1993

The pharmacokinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid.

The kinetics of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-carbazepine (10-OH-CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10-OH-CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10-OH-CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10-OH-CZ were lower than in controls (2.9 +/- 0.4 vs 5.1 +/- 0.7 microg ml(-1) h and 89 +/- 7 vs 119 +/- 10 microg ml(-1) h respectively, means +/- s.e. mean, P < 0.05), whereas 10-OH-CZ half-lives were only marginally shorter (17 +/- 1 h vs 20 +/- 2 h, NS). These data indicate that the biotransformation of OXC and 10-OH-CZ may be accelerated by concomitant treatment with phenobarbitone but that the magnitude of this effect is unlikely to be of great clinical significance.

Administration, Oral↗
PubMed1993

Vigabatrin-induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability.

The possibility that vigabatrin (VGB) decreases serum phenytoin (PHT) concentration by lowering the oral bioavailability of PHT was investigated in 21 patients with epilepsy. Each patient was switched from oral to intravenous PHT for 5 days before and after combined treatment with VGB. After VGB (2-3.5 g day(-1) for at least 5 weeks), serum PHT concentrations decreased slightly from 87 +/- 25 to 76 +/- 31 micromol l(-1) (means +/- s.d., P < 0.05), but in a subgroup of seven patients the decrease was more prominent (from 72 +/- 22 to 49 +/- 17 micromol l(-1), P < 0.005). At baseline (before VGB), serum PHT remained unaffected (85 +/- 30 micromol l(-1)) after switching PHT dosage to the intravenous route, indicating that the oral availability of the drug was virtually complete. During VGB treatment, serum PHT was also unchanged (74 +/- 34 micromol l(-1)) after switching from oral to intravenous therapy, and this was also true for the subgroup of patients showing a prominent interaction (48 +/- 18 micromol l(-1)). The urinary recoveries of PHT and its metabolites pHPPH and mHPPH remained constant throughout the study. It is concluded that the oral availability of PHT is unaffected by VGB and that the VBG-induced decrease in serum PHT is mediated by alternative mechanisms.

Adolescent↗
PubMed1993

Drug interactions with nimesulide.

Nimesulide is a recently developed analgesic, antipyretic and anti-inflammatory agent that differs from conventional nonsteroidal anti-inflammatory drugs both in structure and pharmacological profile. Since nimesulide may be prescribed for patients receiving concomitant medication, the propensity for drug interactions exists. Investigations have been conducted to assess the potential for pharmacokinetic and pharmacodynamic interaction. With regard to absorption, there is some evidence that nimesulide may decrease the oral bioavailability of furosemide (frusemide). Nimesulide is extensively bound to plasma proteins and may be displaced from binding sites by concurrently administered drugs such as fenofibrate, salicylic acid and tolbutamide. In addition, nimesulide may displace salicylic acid and furosemide (but not warfarin) from plasma proteins. Major interactions involving interference with drug metabolism have not been described with nimesulide. A marginal decrease in plasma theophylline levels (without changes in respiratory function tests) has been described after addition of nimesulide to chronic theophylline therapy. Despite earlier suggestions that nimesulide may increase the hypoglycaemic effect of glibenclamide, a formal study excluded any influence of the drug on fasting blood sugar and glucose tolerance in diabetic patients treated with various sulfonylureas. Although nimesulide does not usually affect the response to warfarin, a few patients may show some increase in anticoagulant effect; therefore, it would seem prudent to monitor coagulation status when the 2 drugs are administered together. Finally, nimesulide may reduce the natriuretic response to furosemide and potentiate the furosemide-induced reduction in glomerular filtration rate and renal blood flow, through a pharmacodynamic interaction which is likely to involve inhibition of renal cyclo-oxygenase. These results suggest that caution should be exercised when nimesulide is used in combination with drugs that are known to adversely affect renal haemodynamics.

Anti-Inflammatory Agents, Non-Steroidal↗