Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

263 records · Page 15Linked to original sources

PubMedDate not supplied

Interaction of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, with valproate: a pharmacokinetic study.

The mechanism responsible for the valproate (VPA)-induced elevation of serum carbamazepine-10,11-epoxide (CBZ-E) levels was investigated in 6 normal subjects who received single oral doses of CBZ-E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d.)]. VPA caused a significant prolongation of CBZ-E terminal half-life (t1/2 from 6.3 +/- 1.2 to 9.0 +/- 2.0 h, mean values +/- SD) and decreased CBZ-E clearance (from 90.6 +/- 18.8 to 63.2 +/- 16.1 ml h-1 kg-1, mean values +/- SD) without affecting CBZ-E apparent volume of distribution (from 0.82 +/- 0.19 to 0.81 +/- 0.24 l kg-1, mean values +/- SD). These findings indicate that VPA impairs the elimination of CBZ-E, presumably by inhibiting its metabolism.

Absorption↗

PubMedDate not supplied

Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation.

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.

Adult↗

PubMedDate not supplied

Clinically relevant anti-epileptic drug interactions.

Anti-epileptic drugs frequently interact due to pharmacokinetic features (induction or inhibition of metabolism, production of active metabolites, low therapeutic indices) and the need for prolonged treatment with possible addition of other drugs to treat concomitant diseases. The most important pharmacokinetic interactions are those that inhibit phenytoin, carbamazepine and phenobarbitone metabolism and thus increase their toxicity. Drugs inhibiting metabolism include antibiotic macrolides, chloramphenicol, isoniazide, some sulphonamides, propoxyphene, cimetidine, valproic acid and sulthiame. Anti-epileptic drugs can induce hepatic microsomal enzymes and, therefore, may increase metabolism of corticosteroids, oral contraceptives, oral anticoagulants, cardiovascular agents, antibiotics, chemotherapeutic agents, psychotropic drugs and non-opiate analgesics, thereby reducing their efficacy. Advantageous pharmacodynamic interactions include synergism of ethosuximide plus valproic acid and of carbamazepine plus valproic acid. A pharmacodynamic mechanism may be responsible for the reduced sensitivity of chronically treated epileptics to some neuromuscular blockers.

Anticonvulsants↗

PubMedDate not supplied

Effect of dose increments on serum carbamazepine concentration in epileptic patients.

The effect of progressive dose increments on the steady-state serum concentration of carbamazepine has been investigated prospectively in 20 adult institutionalised epileptic patients receiving long term therapy with the drug. In all but 1 subject, a strong positive correlation between the serum carbamazepine concentration and the prescribed daily dose was found. The relationship appeared to be linear over the dosage range examined (600 to 1400mg in most patients). In some patients, a trend was observed for the extrapolated regression lines to yield positive y-axis intercepts. The latter were significantly different from zero in 3 patients. Although these findings suggest that the relationship between serum carbamazepine concentration and dose may be curvilinear over the lower range of doses, further studies are required to clarify this point.

Adult↗

PubMedDate not supplied

Pharmacokinetic interactions with antiepileptic drugs.

A large number of pharmacokinetic interactions with antiepileptic drugs have been reported in recent years. Among the interactions affecting the disposition of anticonvulsants, the most important are probably those resulting in inhibition of the metabolism of phenytoin, phenobarbitone and carbamazepine. Drugs which have been shown to inhibit the metabolism of these anticonvulsants and to precipitate clinical signs of intoxication in epileptic patients include sulthiame, valproic acid, chloramphenicol, certain sulphonamides, phenylbutazone, isoniazid and propoxyphene. Interactions affecting the plasma protein binding of antiepileptic drugs are less likely to cause long-lasting alterations in response, but they are important because they change the relationship between serum drug concentrations and clinical effect. Anticonvulsant agents may induce important alterations in the pharmacokinetics of other drugs. Phenytoin and phenobarbitone may decrease the gastrointestinal absorption of frusemide and griseofulvin, respectively. Many of the drugs used in the treatment of the adult epilepsies, including phenytoin, phenobarbitone, primidone and carbamazepine, are potent inducers of the hepatic microsomal enzymes. This results in an increased rate of metabolism and decreased clinical efficacy of a number of drugs, including dicoumarol, steroid oral contraceptives, metyrapone, glucocorticoid agents, doxycycline, quinidine and vitamin D.

Anticonvulsants↗

PubMedDate not supplied

Plasma protein binding of drugs in pregnancy.

The degree of binding to plasma proteins is an important determinant of drug disposition and response. Normal human pregnancy is associated with concentration of plasma proteins, free fatty acids and possibly other endogenous substances interfering with drug binding. The possibility of an associated change in plasma binding capacity therefore needs to be taken into consideration. Experimental studies conducted mostly in vitro have shown that the plasma protein binding of many (but not all) drugs is decreased during pregnancy, particularly during the last trimester. This phenomenon should be taken into account when interpreting serum concentrations of total (free + protein-bound) drug in clinical practice. Notable examples of drugs whose unbound fraction increases during pregnancy include diazepam, valproic acid, phenytoin, phenobarbitone, salicylic acid, pethidine, lignocaine, dexamethasone, sulphafurazole and propranolol. For many drugs, important differences have been demonstrated in the degree of protein binding between maternal and cord plasma. In some cases, this may provide an explanation for the finding of marked differences in total drug concentration between maternal and fetal plasma at the time of delivery.

Adrenal Cortex Hormones↗

PubMedDate not supplied

Interpretation of drug levels in acute and chronic disease states.

Serum drug concentration monitoring can be an invaluable aid to patient management, particularly in certain pathological conditions when individualisation of dosage is particularly critical. To be clinically useful, however, drug levels must be interpreted in the context of all factors that could influence the correlation between the concentration of the drug in plasma and the intensity of action. Several such factors may be operating in acute and chronic disease states. For example, a number of pathological conditions are associated with marked changes in the fraction of free, pharmacologically active drug in plasma and this will result in disruption of the normal relationship between total serum drug level and effect, as seen for phenytoin in uraemia. An altered response to a given serum drug level in disease states may also be caused by changes in tissue distribution, by abnormal accumulation of pharmacologically active metabolites in plasma or by changes in end-organ responsiveness. The latter are best illustrated by the altered sensitivity to digoxin in patients with various conditions, including hypokalaemia and thyroid disease. In addition to the factors listed above, consideration should also be given to potential interactions with concomitantly used drugs and to the possibility of analytical errors, especially in view of the evidence that the performance of otherwise reliable drug assays may be grossly impaired in certain diseases (e.g. uraemia), due to abnormal plasma composition and/or accumulation of interfering metabolites. In view of these complexities, a correct interpretation of serum drug levels requires a good knowledge of clinical pharmacology and a close collaboration between physician and laboratory. In any case, serum drug concentrations, like other laboratory tests, are not a substitute for careful patient observation, and any decision about drug treatment should be primarily based upon evaluation of the clinical state and, whenever possible, direct measurement of drug effects.

Acute Disease↗

PubMedDate not supplied

Free concentration of carbamazepine and carbamazepine-10,11-epoxide in children and adults. Influence of age and phenobarbitone co-medication.

Total and free plasma concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) were determined in 39 children (aged 3 to 10 years) and 79 adults (aged 15 to 65 years) receiving long term treatment with CBZ alone or in combination with phenobarbitone (PB). Compared with the corresponding age groups treated with CBZ alone, adults and children receiving PB co-medication showed lower total and free CBZ concentrations, similar CBZ-E concentrations and higher CBZ-E/CBZ ratios. Among patients on CBZ alone, children had at any given dose lower total and free CBZ and CBZ-E concentrations than adults. Lower CBZ levels in children than in adults were also found among patients receiving phenobarbitone in combination. CBZ-E/CBZ ratios did not differ significantly between children and adults. These data provide evidence that children show an elevated free CBZ clearance with a metabolic pattern different from that observed during phenobarbitone induction.

Adult↗

PubMedDate not supplied

[Epidemiological observations on plasma levels of diphenylhydantoin in 130 patients on prolonged treatment (author's tranls)].

Plasma levels of diphenylhydantoin have been measured in 130 epileptic patients undergoing long-term anticonvulsant therapy. Only in a small percentage of the patients (15,38%) plasma levels were found to lie within the therapeutic range. Most patients (75,38%) exhibited subtherapeutic values, while in a few cases (9,24%) the upper limit of therapeutic range was exceeded. Although plasma concentrations significantly correlate with the administered dose, predictability of plasma levels in the individual patients given fixed dosage schedules is strongly limited by large interindividual variability. Sex, age and simultaneous administration of other drugs seem not to affect significantly DPH plasma levels. Our observations carried out in a meaningful sample of epileptic patients suggest that at present the practice of monitoring diphenylhydantoin plasma levels is still an essential tool for the management of epilepsy when a safe and effective therapeutic regimen is required.

Epilepsy↗

PubMedDate not supplied

[Malformations in the offspring of pregnant women with epilepsy. Presentation of an international registry of antiepileptic drugs and pregnancy (EURAP)].

The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Alcohol interactions with typical and atypical antidepressants.

Selected parameters of central nervous system function have been examined in rabbits and mice given ethyl alcohol (ET) in combination with antidepressant drugs with different pharmacological profiles. A significant prolongation of the ET-induced loss of righting reflex was observed in mice treated with amitriptyline, 3 mg/kg, or trazodone, 8 mg/kg, injected intraperitoneally. The same drugs failed to cause narcosis when given alone to mice at doses up to 40 (amitriptyline) and 100 (trazodone) mg/kg. Rabbits given single 5 mg/kg IV doses of amitriptyline or trazodone exhibited a synchronous EEG pattern with an increase in spectrum total power that became more pronounced after IV injection of a low dose of ET (0.2 g/kg). The increase in the spectrum total power after ET was significantly greater in rabbits given trazodone than in those given amitriptyline. No significant interactive effects were observed in animals receiving combinations of ET with viloxazine, bupropion or fluvoxamine.

Animals↗