Psychostimulants and epilepsy.

PURPOSE: The aim of this article is to review the literature on the effects of psychostimulants in epileptic subjects in order to reach a consensus statement regarding the use or abuse of these substances. METHODS: Psychostimulant substances have been considered the drugs that share the ability to produce excitation of the CNS leading to convulsions. The stimulation may be at cortical, brainstem, or spinal levels. In this article, the following cortical stimulants are analyzed and discussed: cocaine, amphetamine and related agents, caffeine, cannabinoids, and psychedelic drugs. This review is based on research done using pharmacological textbooks and Medline. RESULTS: The use of cocaine is associated with the occurrence of seizures. The reported frequency varies from 1% to 40% of addicted subjects, based on the typology of the considered study. Amphetamines and related drugs rarely induce epileptic seizures at therapeutic doses, but seizures may occur after the first dosing. Caffeine at high doses may induce epileptic seizures because of its adenosine receptor-antagonizing properties. Marijuana, at variance with other psychostimulants, owing to its serotonin-mediated anticonvulsant action, could have a medical use for the treatment of epilepsy. Psychedelic compounds rarely induce epileptic seizures, but the most common clinical CNS complication after ingestion of ecstasy is the occurrence of seizures. CONCLUSIONS: The use of psychostimulants, except for marijuana, can induce single or multiple seizures in healthy subjects.

Allopurinol as add-on therapy in refractory epilepsy: a double-blind placebo-controlled randomized study.

The antiepileptic effect of allopurinol was assessed in a double-blind, randomized, placebo-controlled, cross-over trial in 84 patients with epileptic seizures refractory to standard antiepileptic drugs (AEDs). During a retrospective baseline period, patients experienced at least four seizures of any type per month. The effects of allopurinol and matching placebo were examined for 4-month periods. Allopurinol dosage was 150 mg daily for children weighing < 20 kg and 300 mg daily for other patients. Efficacy analysis based on the Wilcoxon rank-sum test was conducted for the 80 patients who completed the study. No significant period effect or treatment-period interaction was noted. Allopurinol significantly reduced total seizures (p = 0.005), and secondarily generalized seizures (p = 0.0015). Median seizure reduction for total seizures was 10.5 and 27.9% for secondarily generalized seizures. Subjective preferences by clinicians evaluated blindly significantly favored allopurinol. No significant change occurred in the plasma concentration of concomitant AEDs between treatment periods, but serum urate decreased by 32% during allopurinol treatment. No clinically relevant side effects or changes in routine laboratory clinical chemistry or hematology were ascribed to allopurinol.

[Evaluation of the efficacy and tolerability of fluoxetine in major depression, Multicenter clinical study]. / Valutazione dell'efficacia e della tollerabilità della fluoxetina nella depressione maggiore. Studio clinico multicentrico.

In an Italian multicenter study, 296 patients (115 males, 181 females) affected with major depression diagnosed according to the criteria of the DSM III-R, were treated for 8 weeks with 20 mg/die fluoxetine (Fluoxeren-Menarini s.r.l.). At the end of the therapy the mean scores on the Hamilton Depression Scale had improved considerably, going down from 27.42 to 10.05. 69.6% of the patients had improved by at least in the 50% in the HAM-D scores (responders). At the CGI the overall improvement was evaluated with a mean score of 2.05 (marked improvement), while the patients assessed themselves at the end of treatment as being from "improved" to "greatly improved". No significant differences in efficacy were found to depend on age, type of depression or response to previous treatment, though younger patients (18-40 years), and those with single or recurring episodes, with atypical depression and good response to other antidepressants, showed a more marked improvement. The tolerability of the drug was found to be good. The laboratory tests, ECG and body weight stayed within normal limits.

Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy.

A retrospective study was conducted in 282 patients with epilepsy to assess the predictive performance of pharmacokinetic methods for individualizing dosage of phenytoin. Two population-based dosing methods (population clearance method and bayesian feedback method) and one individual-based method (the so-called linearized Michaelis-Menten method) were evaluated, when applicable, for single-point and/or 2-point dose predictions of phenytoin. In single-point predictions, we found a generally low percentage of dose calculations falling inside the +/- 10% range (48.9% and 51.1% for the population clearance and the bayesian methods, respectively). In 2-point predictions, the bayesian method was 'accurate' (dose within the +/- 10% range) in approximately 54.3% or 55.0% of cases (depending on the particular method of implementation adopted). An even worse percentage of 'accurate' dose predictions (38.3%) was obtained by using the linearized Michaelis-Menten method. Our data do not confirm results from previous studies indicating a generally good performance of pharmacokinetic methods for predicting phenytoin dosage.

Single photon emission computed tomography with 99mTc HM-PAO in the study of focal epilepsy.

We used 99mTc HM-PAO SPECT to study 50 patients with partial epilepsy: 47 interictally and 3 during a seizure. All 3 patients studied during a seizure presented an area of increased tracer uptake. Of those in whom recordings were taken during seizure-free intervals 35 (74%) showed perfusion asymmetries: 27 (57%) with decreased and 8 (17%) with increased uptake. We discuss the findings and compare them with those of similar studies using SPECT and positron emission tomography.

Quantitative EEG effects and plasma concentration of sodium valproate: acute and long-term administration to epileptic patients.

The quantitative background EEG effects (power spectral analysis) and plasma concentration of sodium valproate were studied after acute single-dose administration and during long-term single-drug treatment, in 10 previously untreated epileptic patients with generalized nonconvulsive seizures. A transient decrease of the signal amplitude (preponderant on anterior scalp areas) and of the 12.5 to 45.0-Hz relative power (limited to the posterior electrode derivations) was observed during the first weeks of chronic treatment. These EEG effects were not correlated with the drug plasma concentration levels or with the occurrence of behavioral side effects (e.g. drowsiness), while being concomitant with the reduction of specific epileptic EEG phenomena. Opposite trends of variation were observed after single-dose acute administration, though with limited statistical significance across subjects.

Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double-blind, placebo-controlled study.

A multicentre, double-blind, between-patient study was carried out to evaluate the efficacy and tolerability of oxiracetam (800-mg tablets), in comparison with placebo, each given twice daily for 12 weeks to patients suffering from primary degenerative, multi-infarct or mixed forms of dementia. Efficacy was assessed by the Inventory of Psychic and Somatic Complaints in the Elderly (IPSC-E), administered at entry and after 4, 8 and 12 weeks of treatment, and by the Blessed Dementia Scale and the Newcastle Memory, Information and Concentration Scale (NMICS), administered at the beginning and at the end of the study. Three hundred and seven patients were enrolled, 18 of whom were excluded from the analysis because of violation of the protocol. Two hundred and eighty-nine patients were analyzed (145 m, 144 f, mean age 73 years) and 272 completed the study; 3 patients in each treatment group were withdrawn because of poor tolerability, 10 because of poor compliance and 1 patient because of the occurrence of a cerebral stroke. A significantly (p less than 0.01) different effect, in favor of oxiracetam, was observed in the three main efficacy criteria (i.e. IPSC-E, Blessed Dementia Scale and NMIC total scores), and confirmed by descriptive analyses carried out on some subitems of the scales used. Thirty-one patients on oxiracetam and 27 on placebo complained of a total of 35 and 32 minor unwanted effects, respectively. No clinically or statistically significant changes were observed on routine laboratory examinations.

Allopurinol in severe epilepsy. A preliminary report.

We have studied 64 epileptic subjects aged 2-54 years. The subjects were not hyperuricemic and presented daily or weekly severe seizures not controlled by optimal therapy with antiepileptic drugs maintained at 'therapeutic' plasma concentrations. Allopurinol at doses ranging from 150 to 300 mg daily was added to a preexisting antiepileptic drug treatment which was never modified throughout a study period of 1 year. After about 1 month of therapy, a progressive decrease of the seizure frequency was observed in two thirds of the patients. At the end of follow-up, seizures; were completely controlled in 18.75% of the patients; in 34.37% seizure frequency was reduced by more than 75%; in 15.62% of the subjects, a reduction of the seizure frequency superior to 50% was observed, while 25% of the population studied was unaffected by the treatment and 7.81% worsened.

Allopurinol and severe epilepsy.

Forty-one epileptic and not hyperuricemic subjects, aged 2 to 54 years, had epileptic seizures, ranging from 1 to 220 weekly (mean = 21.3). All seizure types were represented. They were already medicated with two or three antiepileptic drugs with plasma drug concentrations maintained in therapeutic range. They were treated with allopurinol in doses ranging from 150 to 300 mg daily. After 20 to 35 days of this regimen, a progressive decrease of the weekly seizure frequency was observed in two-thirds of the cases. After a follow-up of 3 to 9 months, seizures disappeared completely (22%) or decreased more than 50% (47%). Twenty-five percent of subjects continued to have the same seizure frequency, while about 6% were worse than before.

Sulphinpyrazone dose schedule in hyperuricemic patients with cardiovascular diseases: tolerability assessment.

Renal tolerability of four different dose schedule of sulphinpyrazone (S) was evaluated in a bi-centre, 2-week long open study performed in fifty-six cardiovascular patients of both sexes (47 males, 9 females; mean age 64 yrs) at different risk as regards serum uric acid levels. Each patient was allocated, according to his/her baseline values of serum uric acid or serum creatinine to four different sulphinpyrazone incremental dosage schedules. Renal function and other biochemical assessments (liver function; blood lipids; blood glucose) were assessed at the entry, after the 1st and the 2nd week. Reported signs and symptoms were collected at the 1st and the 2nd week, too. Renal function did not show any statistically and clinically significant impairment during the whole trial. General tolerability, both objective and subjective was particularly good. Only one patient was withdrawn because of reasons unrelated to the ongoing treatment. Sulphinpyrazone can be safely administered also in patients at risk as regards uric acid levels if the proposed therapeutic program is adopted.

[Frequency of risk factors in cerebrovascular disease and their effect on the course and outcome. Study on 423 hospitalized patients]. / Frequenza dei fattori di rischio nella malattia cerebro-vascolare e loro influenza su decorso ed esito. Studio su 423 pazienti ospedalizzati.

In a group of 423 patients with cerebrovascular accident (CVA) the so-called risk factors have been studied and correlated with course and outcome of the disease. High levels of glycemia, seric lipids and uric acids, high blood pressure and cardiopathy are the most often observed abnormalities, but age is anyhow strictly correlated with the frequency of the disease and in old patients with diabetes bad outcome of the cerebrovascular accident is to be expected. The EEG, often a valid tool to evaluate the gravity of the cerebral lesion, can give clear information about the prognosis: bioelectrical signs of diffuse suffering of the brain are supporting a bad prognosis. The nature (ischaemic and haemorrhagic) of the CVA remains the most important factor influencing the course of the disease and death is very predictable in haemorrhagic accidents of diabetic patients.

[Plasma levels of anti-epileptic drugs. Evaluation of determinations carried out in the years 1978-1979]. / Il dosaggio plasmatico dei farmaci antiepilettici. Valutazione delle determinazioni eseguite negli anni 1978-1979.

The results of 701 determinations of antiepileptic drug plasma concentrations administered to 190 patients are described. It has been possible to reduce the number of prescribed drugs to 1.55 per patient, so that only 8.1% of subjects takes three or more drugs while 53% is on monotherapy. The use of the measurement of AEDs plasma concentrations resulted very useful: a) when Phenytoin (PHT) is prescribed; b) in epileptic children; c) when the patient takes two or more drugs; d) to evaluate the compliance. A significant increase (p less than 0.01) of the level/dose ratio of Phenobarbital (PB) when PHT is in, or over, the therapeutic range was observed, while at plasma concentrations of PHT below 10 micrograms/ml it does not influence the metabolism of PB.

Antiepileptic drug therapy and plasma levels in 2500 patients from Northern Italy.

The antiepileptic drug therapy of 1912 patients coming from various neurological clinics of Northern Italy has been evaluated in a collaborative survey. The following epidemiological data have been analysed: incidence of the various seizures types, according to the International Classification (Gastaut, 1969), in relation to the age; drug choice and therapeutic schedules in relation to the seizure type and to the age; number of drugs administered in various age and seizure groups; side effects in relation to type, number and plasma concentrations of the administered drugs. The analysis of the drug plasma level determinations, carried out either with gas-chromatographic methods or with the EMIT system, was effected in order to evaluate the number of patients who were under, in or over the suggested therapeutic ranges, the influence of age on drug disposition and the modifications of the drug plasma levels due to drug interactions.

Plasma levels of di-no-propylacetate and clonazepam in epileptic patients.

Plasma levels of DPA and CNP and associated antiepileptic drugs were measured in groups of respectively 106 and 30 epileptic patients aged from 3 to 49 years. A poor correlation between daily oral dose and plasma levels of both drug was observed when the whole group of patients was considered. A better correlation was seen in a group of adult patients who received DPA and PB. Children below 10 years of age disposed both drugs faster than adults and the difference was significant (p less than 0.01) in groups receiving PB as associated drug. Patients medicated with PB and DPA or CNP showed lower plasma levels of both drugs; on the other hand DPA appeared to cause a decrease of PB clearance which was more marked in children. The clinical significance of the fluctuations of daily plasma levels of both drugs are discussed in relationship to the schedule of administration and plasma sampling. Observations on the therapeutic ranges and adverse effect of the drugs are reported.