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.

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.

Efficacy and interactions of oxandrolone, halo-fenate and clofibrate in a factorial study on experimental acute nephrotic hyperlipidemia.

Nephrotic mixed hyperlipidemia may be associated with accelerated coronary artery disease. To investigate the response of experimental nephrotic hyperlipidemia to therapy, a 2(4) factorial study of sodium clofibrate and beta-benzalbutyrate, halofenate and oxandrolone (250, 150, 100 and 10 mg/kg/day, respectively) was carried out. Nephrotic syndrome was induced by a single i.p. injection of puromycin aminonucleoside (90 mg/kg) in 80 female white rats of average weight 160 g. Oxandrolone proved to be significantly hypotriglyceridemic in combined therapy (average fall, 38%; P less than .05), and also lowered serum total cholesterol and phospholipid concentrations (23% and 21% falls, P less than .01) and less than .05), due largely to synergistic interactions with clofibrate-like drugs. Hypocholesteremic effects (23 and 22% average falls) were also significant for halofenate (P less than .01) and clofibrate (P less than .05) . Serum triglyceride levels actually rose significantly (P less than .05) with drug combinations containing beta-benzalbutyrate. Clofibrate and its analogs (halofenate and beta-benzalbutyrate) produced significant hepatomegaly (mean responses of +18, +18 and +10%, respectively) whereas oxandrolone produced significant hepatic shrinkage (-10%)(P less than .05). Secondary effects (drug interactions) were also found; hypotriglyceridemic synergism (effects more than additive) occurred between oxandrolone and clofibrate or its analogs (P less than .05), whereas antagonism (effects less than additive) was observed within the clofibrate-like group (P less than .01 or less .05).

Survey of cardiac failure therapy in Australian medical practice: dependence on digoxin level for diagnosis of toxicity.

A questionnaire was mailed to 3000 medical practitioners throughout Australia to assess attitudes to cardiac failure therapy. The proportion of responses suitable for analysis was 31%. There was a preference for initiating treatment with a diuretic rather than digoxin and for commencing digoxin in daily maintenance dosage rather than with a loading dose. Two-thirds of the doctors surveyed regulated glycoside therapy by monitoring blood digoxin levels. The answer pattern suggested digoxin level measurement had influenced diagnosis of toxicity.

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'.

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.

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.

Potassium-sparing effect of amiloride in a diuretic factorial study in man.

1. The effects of amiloride (M, 20 mg/day), chlorothiazide (C, 1000 mg/day), ethacrynic acid (E, 100 MG/day) and frusemide (F, furosemide 80 mg/day, given alone and in combination, were investigated in eight patients in a 2(4) factorial study. Effects between blocks of four treatments in each sixteen-treatment replicate were confounded with higher interactions to allow for differences between early and late diuresis. 2. All patients exhibited marked diuresis, with significant mean increases in daily urinary sodium excretion (P smaller than 0.05) and urinary volume (P smaller than 0.01) induced by chlorothiazide, frusemide and ethacrynic acid (68, 69 and 38%; and 35, 40 and 34%, respectively). Amiloride appeared to be half to one-third as potent as the other diuretics. 3. Amiloride produced a significant potassium-sparing effect (P smaller than 0.01), reducing urinary potassium excretion by 30%, compared to significant urinary potassium wasting with frusemide (increase of 33%, P smaller than 0.01) and chlorothiazide (increase of 31%, P smaller than 0.05). 4. No adverse reactions occurred, but serum potassium levels twice rose to 6 mmol/l and subsided without additional therapy, and on one occasion fell to 2.5 mmol/l, requiring a potassium supplement for 4 days. 5. It was concluded from these factorial studies that amiloride is a mild diuretic and potent potassium-sparing agent acting independently and additively in combination with chlorothiazide, ethacrynic acid or frusemide. For the three latter diuretics, all two-drug interactions were simply additive also, without evidence of synergism or antagonism between drugs.

A study of serum and myocardial digitoxin concentrations in man during cardiac arrest.

In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 (+/- 1.86, range 0.6-8.2) ng/ml, significantly higher (P less than 0.001) than the "eudigitalized" concentration (1.3 +/- 0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ng/ml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 +/- 2.66 v. 1 +/- 0.26 mg/dl for non-toxic subjects, P less than 0.001), partly due to a higher mean daily digoxin dose (0.40 v 0.31 mg/day, P less than 0.05) and frequently associated with potent diuretic therapy (73 v 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (14%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 (+/- 63.3, range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration (r=0.8107, P less than 0.01) or serum creatinine concentration (r=0.4637, P less than 0.001).

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.

Interaction between phenytoin and valproate.

Displacement of phenytoin from plasma proteins by valproate causes a reduction in total serum phenytoin levels. However, no adjustment of phenytoin dosage is warranted, unless clinically indicated, since the free phenytoin levels remain unchanged.

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.

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.

Individualized patient assessment in the treatment of epilepsy with sodium valproate.

This study records a comprehensive clinical protocol developed to assess seizure control and unwanted effects in 19 patients treated with sodium valproate (VPA). The assessment is based on six parameters individually ranked: seizure frequency, seizure duration, EEG comparisons, intellectual and cognitive function tests, sociological profile, and unwanted effects. Each parameter was ranked from one to five, and the mean was used to assess the overall patient state. Using this technique, this study assesses the therapeutic efficacy of VPA and the benefits of individualization of therapy as predicted by the use of pharmacokinetic parameters in a controlled trial.

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.

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.