[The clinical relevance of serial determinations of plasma concentrations of carbamazepine and sodium valproate]. / Relevancia clínica de las determinaciones seriadas de concentraciones séricas de carbamacepina y valproato sódico.

INTRODUCTION: Serum concentrations of valproate (VPA) and carbamazepine (CBZ) were monitored in 66 epileptic out patients to determine then pharmacokinetic profiles. PATIENTS AND METHODS: Thirty-eight patients were receiving monotherapy, 17 with CBZ and 28 with VPA, and 28 patients were receiving VPA and CBZ. All were receiving standard (not controlled-release) CBZ or VPA preparations. Blood samples were obtained 2, 4, and 6 hours after the last dose. Serum concentrations were determined by gas chromatography. RESULTS: Mean serum concentrations of patients receiving CBZ were 8.2, 7.3 and 6.4 micrograms/ml for the 2, 4 and 6 hours samples, respectively. Mean serum concentrations of CBZ in the group receiving CBZ + VAP were 7.8, 8.4 and 7.8 micrograms/ml, respectively. Patients receiving VPA had mean serum concentrations of 92.8, 97.8 micrograms/ml, respectively. Those receiving CBZ + VPA had serum concentrations of 69.1, 70.6 and 55.8 micrograms/ml, respectively. Mean variation in the CBZ serum concentrations was 45% (range 7-91%) in patients receiving monotherapy and 31% (range 8-93%) in patients receiving CBZ + VPA. Mean variation in VPA serum levels of the patients receiving CBZ + VPA (56%) was greater than those of patients receiving CPA alone (38%). Subtherapeutic serum levels of either drug were detected in 35% of the patients. CONCLUSIONS: The large inter- and intraindividual variability of serum concentrations showed that a single measurement does not reflect the reality or CBZ and VPA clinical kinetics. The results confirm that three samples collected at 2, 4, and 6 hours after the last dose determine a clinically useful kinetic profile.

Serum levels of clomipramine and desmethylclomipramine and clinical improvement in panic disorder.

Several placebo-controlled trials have shown the efficacy of clomipramine (CMI) in panic disorder. However, none has investigated the relationship between CMI, and desmethylclomipramine (DCMI) plasma levels, and outcome. In this trial, 41 patients meeting the DSM-III-R criteria for panic disorder with/without agoraphobia received 50-200 mg of CMI daily in a single-blind, flexible dose regimen for 14 weeks. At the end of treatment, 97% of the patients were free of panic attacks. Patients were classified into two groups of improvement according to the panic symptom items of the 'Patient-Rated Anxiety Scale'. A repeated-measures analysis of variance suggested a significant association between outcome and serum DCMI level/daily dose ratio as well as total serum level/daily dose. Patients with intense improvement showed DCMI and total serum levels lower than those with moderate improvement. The results indicate the importance of monitoring clomipramine and desmethylclomipramine serum levels in this disorder.

Nitric oxide modulates Na+, K+-ATPase activity through cyclic GMP pathway in proximal rat trachea.

The present work demonstrated that nitric oxide (NO) modulates Na+, K+-ATPase activity in the proximal rat trachea. Sodium nitroprusside induced concentration-dependent (10-100 microM) stimulation in proximal trachea Na+, K+-ATPase activity. The effect was specific for Na+, K+-ATPase since Mg-ATPase activity was unaffected. This NO-donor changed neither Na+, K+-ATPase nor Mg-ATPase activity in the distal segment. The modulatory action on Na+, K+-ATPase induced by sodium nitroprusside was linked to an increase in nitrates/nitrites and cyclic GMP levels in proximal segments. Modulation of proximal Na+, K+-ATPase activity by sodium nitroprusside was mimicked by S-nitroso-N-acetylpenicillamine (100 microM) and 8-bromo-cyclic GMP (100 microM). Both sodium nitroprusside and 8-bromo-cyclic GMP effects on Na+, K+-ATPase activity of proximal segments of trachea were blocked by 2 microM of KT 5823 (a cyclic GMP-dependent protein kinase inhibitor), but not by 0.5 microM of KT 5720 (a cyclic AMP-dependent protein kinase inhibitor). Both kinase inhibitors decreased proximal Na+, K+-ATPase activity, but did not change Mg-ATPase activity. Okadaic acid (1 microM), a phosphatase-1 inhibitor, increased proximal Na+, K+-ATPase but not Mg-ATPase activity. The effect of okadaic acid was non-additive with that of 8-bromo-cGMP on Na+, K+-ATPase activity. Our results suggest that NO modulates proximal rat trachea Na+, K+-ATPase activity through cyclic GMP and cyclic GMP-dependent protein kinase.

Impairment of performance associated with long-term use of benzodiazepines.

The long-term effects of benzodiazepines (BDZ) on psychomotor and cognitive functions were assessed in 28 out patients, users of low therapeutic doses of diazepam (13.6 ± 4.9 mg/day, range: 5-20 mg/day) for 5-20 years (10.1 ± 5.0 years). These patients' performance was compared with two control groups: 53 BDZ-free anxious out patients and 56 healthy volunteers. The three groups were similar in sex, age and education. BDZ chronic users were tested before and after short-term (3 weeks) and long-term discontinuation (at an average of 10 months). Performance of chronic users of BDZ was consistently worse than those of the control groups, suggesting an impairment in these patients on both psychomotor and cognitive functions. These were not related to either dose or cumulative exposure to BDZ, and were also independent of diagnosis and levels of anxiety and depression. Moreover, these deficits were persistent as their performance failed to improve after drug discontinuation.

[Quantitative clinical and EEG measures of epileptogenesis in temporal lobe epilepsy]. / Medidas quantitativas clínicas e electrencefalográficas de epileptogênese na epilepsia do lobo temporal.

In this controlled, prospective and partially blind study two groups of patients with temporal lobe epilepsy were evaluated, respectively with good and bad prognosis. Measurements of epileptogenesis were based on frequency of seizures, and on epiletogenic electroencephalographic abnormalities obtained from scalp electrodes over the temporal lobes. The results were analysed by non-parametric analysis of variance, comparison of groups and analysis of correlation. The results indicated the temporal lobe groups were similar to at least one of the control groups in age, sex, educational and social level, therapeutic regime, age at onset and length of history of epilepsy. The quantitative measurements showed a global difference between the group of temporal lobe with bad and good prognosis, reaching statistical significance in clinical epileptogenesis, and a trend towards greater epileptogenesis on the electroencephalogram, in the same group of patients. The results indicate the experimental usefulness of some of the original measurements used in the study, but also their problems. A review of the literature is carried out.

Medidas quantitativas clínicas eletrencefalográficas de epileptogênese na epilepsia do lobo temporal / Quantitative clinical and EEG measures of epileptogenesis in temporal lobe epilepsy

Neste estudo controlado, prospectivo e parcialmente cego foram avaliados dois grupos de 10 portadores de epilepsia do lobo temporal, respectivamente de bom e mau prognóstico. Foram definidas medidas de epileptogênese baseadas nas frequências de crises e na qualificaçäo de atividade epileptogênica nas derivaçöes eletrencefalográficas de lobo temporal. Os grupos de estudo foram semelhantes a no mínimo um dos grupos de controle em idade, sexo, nível educacional e social, regime terapêutico, idade de início e tempo de evoluçäo da epilepsia. Houve uma diferença global do grupo de epilepsia do lobo temporal com mau prognóstico das outras populaçöes, atingindo significado estatística em epileptogênese clínica, e uma tendência dos dados sugerindo maior epileptogênese eletrencefalográfia na mesma populaçäo. Os resultados indicam a utilidade experimental de algumas das medidas introduzidas, mas também seus problemas. Revisäo da literatura pertinente é realizada

Vigabatrin: clinical evidence supporting rational polytherapy in management of uncontrolled seizures.

Monotherapy is the policy for management of patients with epilepsy. With increasing knowledge of the biology of epilepsy and of the modes of action of antiepileptic drugs (AEDs), this concept must be reevaluated. When monotherapy fails to control seizures, subsequent treatment should be based on "rational pharmacology," taking into consideration the mode of action of the drugs, to provide improved efficacy with maintained tolerance and ease of administration. Introduction of vigabatrin (VGB) as a new AED calls for just such a reevaluation. VGB is an enzyme-activated irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase that increases brain and cerebrospinal (CSF) GABA concentrations in animals and humans. It has limited efficacy in the classic animal seizure screening tests, but in many clinical studies has halved the incidence of seizures in approximately 50% of patients, especially those with partial epilepsies. We evaluated the efficacy of VGB in "socially integrated and active outpatients" as a likely subset to demonstrate any advantage of rational polytherapy. The criteria for this evaluation included the effects on seizure frequency, patient tolerability, and cognitive performance in a battery of psychometric tests. Fourteen of the 19 patients (73%) completing the study had > 50% reduction in seizure frequency, and 10 of 19 (52%) had > 70% reduction in seizure frequency. Tolerability appeared good; somnolence was the most frequent adverse event. Three patients complained of a worsening of their seizures, 1 with an increase in frequency and 2 with development of myoclonic jerks not previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbamazepine and phenytoin in epilepsies refractory to barbiturates: efficacy, toxicity and mental function.

A group of 51 patients with chronic cryptogenic or symptomatic localized epilepsy refractory to therapy with barbiturates underwent progressive substitution with phenytoin or carbamazepine, in standardized and randomized fashion. After drug changes were completed two thirds of the patients remained seizure free during a period of 6 months. A clearer effect of phenytoin and carbamazepine was seen on secondary generalized than on partial seizures. The frequency of severe side effects decreased after the change to phenytoin and carbamazepine. The group on carbamazepine improved in immediate and late recall, and in immediate and late recognition of pictures. The group on phenytoin improved significantly in the Stroop test. Patients changed to phenytoin, but not those changed to carbamazepine, became significantly more aggressive, anxious and depressive than when on phenobarbital, as measured by subjective scales. The results indicate that patients should not be considered refractory to antiepileptic drug therapy while on barbiturates. Cognitive dysfunction and mood changes observed in epilepsy may be temporary and dependent on the presence of seizures and/or on use of barbiturates.

Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects.

The present reference drugs for the treatment of panic disorder and agoraphobia are imipramine and alprazolam. The latter decreases performance and cognitive functioning. No study of such functions in panic/agoraphobia is available. Fifty four out-patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia (PAG), taking part in a parallel groups controlled trial of imipramine (mean dose ±SEM 114±9 mg), clomipramine (50±4 mg) and propanteline (active placebo) over 8 weeks, were studied. A test battery of psychomotor and memory tests was administered at baseline, and after 1, 4 and 8 weeks of treatment. Their results were compared (at baseline and at the end of the trial) with those of a control group of 57 normal untreated subjects. There was no difference between treatments, and no drug effect on any test at any time. No consistent difference between patients and controls was detected. Given its apparently higher potency, and the absence of deleterious effects on cognitive measures known to be affected by benzodiazepines, we conclude that clomipramine is better than imipramine or alprazolam as a reference drug for panic/agoraphobia.

Cognitive functions, epileptic syndromes and antiepileptic drugs.

Cognitive function of patients on monotherapy specific for their epileptic syndrome has been studied infrequently. We evaluated 7 patients with symptomatic localised epilepsies (SEL) on phenytoin aged 30 +/- 12 (mean +/- standard deviation) years, 8 with idiopathic generalised epilepsies on sodium valproate aged 18 +/- 4 years, 16 with SEL on carbamazepine aged 28 +/- 11 years, and 35 healthy controls aged 27 +/- 11 years. All subjects were of normal intelligence, educated appropriately to age, and led productive lives in the community. Two of the patients on carbamazepine and one on valproate had less than five partial, absence or myoclonic seizures monthly, the remaining were controlled. Carbamazepine serum concentrations were 12 +/- 5 micrograms/ml, phenytoin were 23 +/- 7, and valproate were 62 +/- 23 (mean +/- sd). Tests included immediate recall and recognition for pictures, Stroop test, delayed recall and recognition of pictures. Patients on phenytoin and valproate performed significantly worse than controls on immediate recall, and patients on carbamazepine performed significantly worse than controls in Stroop test (p < 0.01). The results indicate relatively minor effects of the epileptic syndromes and of phenytoin, carbamazepine and valproate on cognition of patients with controlled epilepsy leading productive lives in the community. We conclude that the cognitive deficit found in chronic epileptic patients on poly-therapeutic drug regimen must be multifactorial, and that future studies need to control for all possible variables in order to achieve meaningful results.

Cognitive functions of epileptic patients on monotherapy with phenobarbitone and healthy controls.

Quantitative measurements have indicated that heredity, cerebral damage, psycho-social aspects, ictal and inter-ictal phenomena and antiepileptic drugs may interfere in the cognitive dysfunction of epileptic patients. In the present study objective methods included immediate and late recall and recognition of pictures, Stroop test and auditory selection. Twenty patients with symptomatic localized epilepsy aged 17-52 years (27 +/- 10, mean +/- sd) were compared to age and socially matched healthy controls. Patients were on therapeutic serum concentrations (25 +/- 12 mu/ml) of phenobarbitone and had active epilepsy with 1.94 generalized tonic-clonic, 0.85 simple partial and 6.28 complex partial seizures monthly (means). Patients performed worse than controls in all 6 tests (p less than 0.05 to p less than 0.001), indicating a generalized cognitive deficit related to seizures and/or barbiturate therapy. We suggest further studies should be carried out in populations with uniform monotherapeutic regimens and epileptic syndromes in order to isolate factors related to the cognitive dysfunction of epileptic patients.