AUStralian study of titration to effect profile of safety (AUS-STEPS): high-dose gabapentin (neurontin) in partial seizures.

PURPOSE: To evaluate the safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin; GBP) as adjunctive therapy in patients with refractory partial seizures. METHODS: AUS-STEPS was an open-label, multicenter, prospective study in patients experiencing partial seizures who were inadequately controlled with one to three concurrent antiepileptic drugs (AEDs). GBP treatment was titrated to a maximum of 4,800 mg/day, over a treatment period of 24 weeks, to achieve an efficacious and tolerable dosage. Efficacy was assessed by seizure-frequency data. Quality of life was evaluated by using the QOLIE-10 questionnaire, and safety was assessed by adverse-event reports and clinical laboratory findings. RESULTS: A total of 176 patients received treatment with GBP, with 174 evaluable for intention-to-treat (ITT) efficacy analysis. A reduction of >50% in overall seizure frequency was observed in 93 patients (53%). There was a small (4.6%) overall improvement in QOLIE-10 score. The most frequent adverse events were dizziness (31%), fatigue (29%), somnolence (27%), headache (21%), and ataxia (20%), with no major increase seen in adverse events necessitating discontinuation as the dose of GBP was titrated upward. CONCLUSIONS: This study indicates that patients with partial epilepsy may be effectively treated with GBP at dosages of < or =4,800 mg/day, without altering the safety profile of the drug.

Relation between dosage of carbamazepine and concentration in hair and plasma samples from a compliant inpatient epileptic population.

Compliance is a problem in all areas of therapeutic medicine. Methods for its assessment are classified as either indirect or direct. Indirect assessment is based on criteria such as pill counts, questionnaires, and self-reporting; direct methods involve the analytic measurement of the drugs in biologic fluids such as plasma or urine. Drugs taken either therapeutically or recreationally become incorporated into hair. This prospective study investigated the relation between the daily intake of the antiepileptic drug carbamazepine and both its trough plasma and hair concentrations in a highly supervised inpatient population of patients with epilepsy during a period of 6 months. Results showed that although there was a significant variation between patients resulting from the substantial range in the daily intake of carbamazepine (800-2400 mg/day), the intrapatient variation in both trough plasma and hair concentrations during the 6-month period were not significantly different. The mean intrapatient percentage coefficient of variation in total plasma and hair concentrations of carbamazepine was 11.5 +/- 4.7 and 15.0 +/- 5.2, respectively, both of which were independent of the daily dosage. This relatively small intrapatient variation in hair concentration over time and its close relation to the plasma concentration suggests that hair analysis may be a complementary and useful technique in monitoring drug-taking behavior.

A survey of lamotrigine and vigabatrin treatment in children with severe epilepsy.

A retrospective survey was carried out of add-on treatment with lamotrigine (LTG) and vigabatrin (GVG) in 109 children with severe epilepsy, treated between 1987 and 1994, identified from a total population of 300 patients seen annually, in a tertiary referral outpatient clinic in Cardiff, Wales. Of 79 patient treatments with LTG and 86 with GVG, 42 patients were treated with add-on LTG, 52 with add-on GVG and 20 with both drugs simultaneously. A Kaplan-Meier curve, applied to each of the two index drugs, indicated that 71 and 62% of patients would be expected to continue taking LTG or GVG, respectively after 40 months. Improved seizure control (> or = 50%) at the time of audit was seen in 65% of LTG and 58% of GVG patient treatments for all epilepsy syndromes, but there was a higher proportion of patients with generalized epilepsy improved by LTG (28/41, 68%) than that improved by GVG (8/20, 40%), and only those with generalized epilepsy treated with LTG became seizure free (8/38, 21%). Similar proportions of patients discontinued LTG (16%) and GVG (15%) due to an adverse experience, but a higher proportion discontinued GVG (18%) compared with LTG (6%) because of lack of efficacy. This study supports the relative clinical effectiveness of LTG and GVG in the real world, where children with severe epilepsy are treated in clinical practice and serves to generate hypotheses to enable design of prospectively controlled trials, which should enable more rational use of these two drugs in the paediatric population with epilepsy.

A survey comparing lamotrigine and vigabatrin in everyday clinical practice.

The objective of this study was to compare the efficacy and tolerability of two new antiepileptic drugs, lamotrigine (LTG) and vigabatrin (GVG) in everyday clinical practice. A comprehensive retrospective survey of a computerized data base and hospital case notes was carried out at the Mersey Regional Epilepsy Clinic (MREC), Liverpool, which services a population of 3 million in the North West of England. The study comprised 333 out-patients with refractory epilepsy exposed to LTG and GVG forming a subset in a total population of 2250 patients with epilepsy held on a comprehensive database. The main outcome measures were duration of treatment with each drug described by a Kaplan-Meier survival curve, seizure control determined by a 50% decrease in seizure frequency and freedom from seizures, and incidence of adverse drug effects leading to discontinuation. The Kaplan-Meier curve indicated a 57% probability of patients continuing to take LTG and 43% GVG after 40 months. A 50% improvement in seizure control followed the addition of LTG in 45% of patients, with 10% seizure free, compared with 32% and 6%, respectively after the addition of GVG. LTG was discontinued because of adverse events (most frequently skin rash) in 15% of patients compared to GVG in 25% (particularly because of personality disturbance and psychiatric disorder). Both LTG and GVG are effective new AEDs in patients with refractory epilepsy, treated in a tertiary referral out-patient setting. LTG has a broader spectrum of antiepileptic efficacy for patients with both partial and idiopathic generalized seizures, whereas GVG should be reserved for patients with partial seizures at low risk of psychiatric disorder.

A double-blind, placebo-controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures.

The efficacy and tolerability of vigabatrin as add-on therapy was assessed in patients with uncontrolled partial seizures. Ninety-seven patients entered this seven-centre, double-blind, placebo-crossover study. Vigabatrin (2 g or 3 g) or placebo was administered daily. Vigabatrin was well-tolerated and did not cause clinically significant adverse drug effects when added to established anticonvulsant therapy. No significant differences were observed between dose groups for the overall incidence of adverse events, although drowsiness and visual disturbances (diplopia, ataxia, visual abnormalities) showed a dose-related increase with vigabatrin treatment. The results of this study indicate that vigabatrin, given in a daily dose of either 2 g or 3 g is significantly more effective than placebo in reducing seizure frequency among patients with partial seizures.

Tiagabine and non-convulsive status epilepticus.

Three patients who developed clinical evidence of non-convulsive status epilepticus while on high doses of the investigational antiepileptic drug, tiagabine are reported. This apparently paradoxical phenomenon developed when the tiagabine dose was increased to 48 mg/day in one patient, and to 60 mg/day in two other patients, in combination with other antiepileptic drugs. Seizure control improved following reduction in tiagabine dose in one patient and discontinuation of tiagabine in the two others. The observation raises the possibility of a clinically relevant paradoxical epileptogenic effect of GABA-ergic drugs such as tiagabine.

Combination vigabatrin and lamotrigine therapy for intractable epilepsy.

Vigabatrin (GVG) and lamotrigine (LTG) are new antiepileptic drugs (AEDs) individually effective as add-on therapy for refractory seizures. The efficacy of GVG and LTG in combination was evaluated in a prospective audit of 42 patients with intractable epilepsy. There was a statistically significant median reduction of 62% (P < 0.025) from a median baseline monthly seizure frequency (MSF) of 29 (mean 59, 95% CI 22, 96) to a median MSF of 11 (mean 23, 95% CI 8, 38) during a median treatment period of eight months, with a greater than 50% reduction in MSF in 29 patients (69%) treated with the add-on combination of GVG and LTG. The additional MSF reduction achieved by the combination amounted to 21% (18% when GVG was added to LTG and 24% when LTG was added to GVG). The median trough plasma lamotrigine concentration was 9.9 mg/l (range 3.4-19.6 mg/l). The average daily dose of LTG was 517 mg (range, 175-800 mg) and GVG 2400 mg (range, 1500-3500 mg). Adverse events requiring alteration of therapy occurred in 24 patients (57%) with a drop-out rate of 12%. The combination of GVG and LTG should be considered as a therapeutic option in patients with intractable epilepsy. The results of the present study support the need to confirm additive efficacy of GVG and LTG by conducting controlled trials of this combination therapy.

Melatonin response in active epilepsy.

Urinary excretion of 6-sulfatoxymelatonin (aMT.6S), the hepatic metabolite of melatonin, was measured for three consecutive 8-h intervals, beginning at 0600 h, in 30 patients with untreated active epilepsy and in 19 healthy subjects. Excretion of aMT.6S in a 24-h period in patients with active epilepsy was 77.3 +/- 55 nmol (median 68.0, range 8.7-280 nmol), significantly higher (p < 0.05) than that of healthy subjects (49.1 +/- 14 nmol, median 49.0, range 19.7-68.0 nmol). Sequential 8-h urinary aMT.6S excretion rates in patients with active epilepsy were 2.45 +/- 2.8 nmol/h (0600-1400 h), 0.83 +/- 0.5 nmol (1400-2200 h) and 6.38 +/- 5.0 nmol/h (2200-0600 h) as compared with 1.43 +/- 0.8, 1.10 +/- 0.8 and 3.81 +/- 1.3 nmol/h, respectively, in healthy subjects. Analysis of variance (ANOVA) indicated that the difference in total output resulted from greater nocturnal excretion (F = 5.58, p = 0.018). Melatonin production in untreated patients with active epilepsy is increased and has a circadian pattern with a phase difference as compared with that of normal subjects.

Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures.

The results of a multicentre, randomised, double-blind, placebo controlled, crossover trial of lamotrigine as add-on therapy in patients with partial seizures poorly controlled by established antiepileptic drugs (AEDs) are presented. The study consisted of two 12 week treatment periods each followed by a four week washout period. During the lamotrigine treatment phase, patients received 150 mg or 300 mg daily dose depending on their concomitant AEDs to achieve concentrations in the range 1-3 mg/L. Forty one patients were entered at four centres and all patients entered completed the study. There was a highly significant (p < 0.001) decrease in total seizure counts on lamotrigine compared with placebo. Overall, 22% of patients experienced at least a 50% reduction in the total numbers of all seizures types on lamotrigine, compared with none on placebo. When the total numbers of partial seizures (simple and complex partial) were analysed there was also a significant (p < 0.05) reduction in seizure counts on lamotrigine compared with placebo. When total numbers of secondarily generalised seizures were compared the trend for a reduction in this seizure type did not achieve significance (0.05 < p < 0.1). Concomitant AED plasma concentrations were virtually unchanged. It is concluded that lamotrigine is an effective AED in the treatment of therapy-resistant partial seizures.

Video-audio/EEG monitoring in epilepsy--the Queen Elizabeth Hospital experience.

Our experience of using video-audio/EEG monitoring in the diagnosis and management of epilepsy at The Queen Elizabeth Hospital Comprehensive Epilepsy Service from March 1987 to December 1990 is described. We performed 75 long term monitoring studies on a total of 66 patients. Following monitoring, a change in seizure diagnosis was made in 21 of 66 patients (32%). Pseudoseizures were diagnosed in 17 patients. A change in management as a consequence of monitoring occurred in 53 of the 66 patients (80%). The referring neurologists considered that 56 of the 75 studies (75%) were successful. The investigational technique is effective and is particularly useful for the diagnosis of pseudoseizures.

Cutaneous vasculitis due to cyclophosphamide therapy for chronic lymphocytic leukemia.

A 55-year-old male with chronic lymphocytic leukemia developed a skin eruption after receiving oral cyclophosphamide. Subsequent rechallenge with parenteral cyclophosphamide led to recurrence of the skin lesions, which on biopsy were shown to be vasculitic in nature.

Phenytoin and phenobarbital assayed by the ACCULEVEL method compared with EMIT in an outpatient clinic setting.

The ACCULEVEL (Syntex) therapeutic drug assay technique was evaluated for phenytoin and phenobarbital in 30 patients with epilepsy who attended a neurology outpatient clinic. This finger-prick whole blood method is calibrated by the manufacturer to give assay results equivalent to plasma drug concentration. The results were compared with EMIT (Syva) technique measurements on the plasma from venous blood drawn simultaneously. The results presented show regression lines of y = 0.91x + 10.8, (r2 = 0.92) and y = 0.97x + 5.01, (r2 = 0.77) for phenytoin and phenobarbital (microM), respectively, when the ACCULEVEL finger-prick blood assay was compared with the EMIT venous plasma assay. Acceptable precision and accuracy data are presented for replicated ACCULEVEL assays. The ACCULEVEL method was found to be reliable when performed by a laboratory technician and provides a very convenient quantitative drug assay that could easily be performed by a variety of individuals at a site remote from laboratory facilities.

Hyperammonaemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs.

Erythrocyte (ENH3) and plasma (PNH3) ammonia levels, liver function tests and plasma valproate concentration were measured in 81 epileptic patients, comprising three therapeutic groups: Group 1 (23 patients) received sodium valproate (VPA) monotherapy, group 2 (33 patients) received sodium valproate combined with phenytoin, carbamazepine, phenobarbitone and/or primidone and group 3 (25 patients) received one or more of these anti-epileptic drugs without sodium valproate. The mean ENH3 and PNH3 of patients in group 1 (41.1 +/- 30.7 mumol l-1 and 37.1 +/- 31.8 mumol l-1, respectively) and group 2 (44.5 +/- 21.3 and 37.6 +/- 21.4 mumol l-1, respectively) were significantly (P less than 0.01) higher than those in group 3 (28.7 +/- 10.6 and 21.5 +/- 7.8 mumol l-1, respectively) and the reference range (30.1 +/- 7.9 and 20.8 +/- 5.7 mumol l-1, respectively). Hyperammonaemia was more prevalent amongst patients in group 2, for both ENH3 (45.5%) and PNH3 (54.6%), than amongst patients in group 1 (30.4% and 52.2%, respectively) and group 3 (8% and 8%, respectively). There was a significant (P less than 0.05) positive correlation between plasma VPA and total bilirubin concentrations. Chronic VPA therapy was also associated with an increase in bilirubin concentrations measured on average four months apart.

Effect of 5-aminosalicylic acid (5-ASA) and other salicylates on short-chain fat metabolism in the colonic mucosa. Pharmacological implications for ulcerative colitis.

5-Aminosalicylic acid (5-ASA) suppressed nitrite-stimulated oxidation of the fatty acid n-butyrate in a dose-dependent manner in isolated human and rat colonic epithelial cells. 4-ASA had one-sixth of the capacity of 5-ASA and sulphapyridine (SP) little of the capacity of 5-ASA to suppress fatty acid oxidation in human colonic epithelial cells. Sulphasalazine (SASP), azodisalicylic acid (ADS), acetyl-5-ASA and acetyl salicylic acid (ASA) did not suppress fatty acid oxidation in rat colonocytes. The suppression index of fatty acid oxidation (SIFO) of respective salicylic acids correlated with the reported clinical effectiveness of each drug against ulcerative colitis (UC). The capacity of 5-ASA to affect nitrite-stimulated oxidation of fat in the colonic mucosa suggests that nitrite ions and control of fatty acid oxidation play a central role in the development and therapy of active UC.

The effect of a single oral dose of prazosin on venous reflex response, blood pressure and pulse rate in normal volunteers.

1 A single 500 micrograms oral dose of prazosin was associated with significant suppression of sympathetically mediated venoconstriction, as measured by the venous reflex response in six healthy volunteers. 2 The impaired venous reflex response consistently preceded orthostatic hypotension and tachycardia, which were associated with faintness and other unpleasant symptoms. 3 The plasma prazosin concentration, which was measured by a sensitive, specific h.p.l.c. assay, varied appreciably both between and within individual subjects. 4 There was no precise relationship between the plasma prazosin concentration and the symptomatic haemodynamic effects observed. 5 It was concluded that reduced venous return to the heart, due to significant suppression of sympathetically mediated venoconstriction by small initial oral dosage of prazosin, contributes to the pathophysiology of the orthostatic hypotension and faintness, described as the 'first-dose phenomenon'.

The predictive value of the serum digoxin concentration in the management of hospitalized patients.

Serum digoxin concentration (SDC) was compared with clinical and ancillary predictors as a guide to adjustment of digoxin dose and as a test for digitalis toxicity in a total of 76 hospitalized patients during a period of 9 months. The mean SDC (3.6 +/- 2.5 nmoles/liter) associated with unexpected discontinuation of therapy was significantly higher (p less than 0.001) than that (1.1 +/- 0.6 nmoles/liter) associated with unaltered digoxin dose, while the mean SDC (0.6 +/- 0.4 nmole/liter) associated with unexpected dose increase was significantly lower (p less than 0.05). There was no significant association between other pharmacokinetic or pharmacodynamic predictors and therapeutic intention. There was a 13% incidence of confirmed digitalis intoxication. The mean SDC (3.6 +/- 1.9 nmoles/liter) of patients presenting and confirmed as digitalis toxic was significantly higher (p less than 0.001) than that (1.4 +/- 0.6 nmoles/liter) involving a situation in which digitalis toxicity could not initially be excluded by other means. The predictive value of an SDC greater than or equal to 2.6 nmoles/liter for toxicity was 80%, and its efficiency for diagnosing both toxicity and nontoxicity was 95%. The SDC was thus shown to be a valid test of digitalis toxicity and to provide extraordinary information enabling the clinician to modulate digoxin therapy precisely.