Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation.

This study evaluated the effects of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation. Patients with epilepsy and mental retardation having uncontrolled seizures despite treatment with other antiepileptic drugs were eligible (n=67). The open-label study comprised a Baseline Phase, an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted. Almost half (44%) of patients experienced a 50% reduction in seizure frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became seizure-free. A similar pattern of results was reported for the Optimization Phase. Investigator-rated clinical status was improved relative to baseline in 66 and 74% of patients at the end of the Maintenance and Optimization Phases, respectively. Most patients experienced improvements in seizure frequency, duration, and intensity during the Maintenance Phase (62 to 72%) and the Optimization Phase (65 to 74%). Many patients were rated as having improved social functioning during the Maintenance Phase (42%) and the Optimization Phase (46%). The Aberrant Behavior Checklist score for lethargy and the mean Habilitative Improvement Scale score were improved at the ends of the Maintenance and Optimization Phases relative to baseline (P< or =0.04). One limitation of this study is its open-label design, which limits the ability definitively to attribute the clinical improvements to lamotrigine. Adjunctive lamotrigine in patients with refractory epilepsy and mental retardation appears to decrease seizure frequency and improve behavior while permitting a reduction in dose of concomitant antiepileptic drugs.

Foot force direction in an isometric pushing task: prediction by kinematic and musculoskeletal models.

The abilities of a kinematic model and a muscle model of the human lower limb to predict the stereotyped direction of the muscular component of foot force produced by seated subjects in a static task were tested and compared. Human subjects ( n=11) performed a quasi-static, lower-limb pushing task against an instrumented bicycle pedal, free to rotate about its own axis, but with the crank fixed. Each pushing trial consisted of applying a force from the resting level to a force magnitude target with the right foot. Ten force target magnitudes were used (200, 250, ..., 650 N) along with 12 pedal positions. For each pushing effort, the muscular contribution to the measured foot force was determined from push onset to peak attained force. This segment was well characterized by a straight line across subjects, pedal positions, and force target magnitudes. The linear nature of the muscular component allowed a characteristic direction to be determined for each trial. A three-joint (hip, knee, and ankle) and a two-joint (hip and knee) net joint torque optimization was applied to a sagittal-plane kinematic model to predict the characteristic force direction. A musculoskeletal model was also used to create a feasible force space (FFS) for the lower limb. This FFS represents the range of possible forces the lower limb could theoretically produce. From this FFS, the direction of the maximum feasible foot force was determined and compared with the characteristic direction of subject performance. The muscle model proved to be the most effective in predicting subject force direction, followed by the three-joint and two-joint net joint torques optimizations. Similarities between the predictions of the kinematic and muscle model were also found.

Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.

OBJECTIVE: To compare the incidence and magnitude of change in body weight associated with lamotrigine or divalproex sodium monotherapy in patients with epilepsy. METHODS: A randomized, double-blind study with 8-week escalation phase and 24-week maintenance phase was conducted. Target maintenance dosage was 200 mg/day (lamotrigine) and 20 mg/kg/day (valproic acid), with adjustment from 100 to 500 mg/day (lamotrigine) and 10 to 60 mg/kg/day (valproate) based on investigators' judgment. Eligible patients were > or = 12 years old with new-onset or previously diagnosed partial or generalized seizures. Weight change was primary and seizure frequency and tolerance were secondary outcome measures. RESULTS: For the lamotrigine group, 65 patients (mean age 34.5 years) were investigated; for the valproate group, 68 patients (mean age 30.1 years) were investigated. Weight remained stable in lamotrigine-treated patients. Significant weight gain occurred in valproate-treated patients by the 10th week of treatment; weight continued to increase throughout the study. After 32 weeks of treatment, mean weight gain was significantly higher in valproate-treated (12.8 +/- 9.3 lb) than lamotrigine-treated (1.3 +/- 11.9 lb) patients. Similar proportions of patients in lamotrigine (29%) and valproate (26%) groups were seizure-free. Overall frequency of adverse events was similar between the two treatment groups. Mean time to withdrawal from the study due to adverse events was 103 +/- 70 days for the lamotrigine group and 79 +/- 48 days for the valproate group. CONCLUSION: Valproate monotherapy was associated with significantly greater weight gain than lamotrigine monotherapy. Weight gain associated with valproate was significant within 10 weeks after initiating therapy and continued throughout the study. Efficacy of lamotrigine was comparable with that of valproate; lamotrigine tended to be better tolerated.

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

Stable weight during lamotrigine therapy: a review of 32 studies.

A side effect associated with the use of some antiepileptic drugs (AEDs) is change in body weight. To evaluate the effect of lamotrigine on body weight in adult patients with epilepsy, we conducted a retrospective review of data from 463 patients treated with lamotrigine in 32 clinical trials. Mean daily dose was 259 (+/-155) mg and duration of therapy was 318 (+/-87) days. The mean change in body weight was 0.5 (+/-5) kg. Lamotrigine was associated with stable body weight in patients with epilepsy.

Digoxin toxicity: an evaluation in current clinical practice.

BACKGROUND: Serum digoxin concentrations (SDCs) are frequently sampled before completion of drug distribution. If elevated, these concentrations may be misinterpreted, potentially leading to a misdiagnosis of digoxin toxicity. OBJECTIVES: To determine the frequency of elevated SDCs (>2.6 nmol/L [>2.0 ng/mL]) obtained at appropriate postdosing intervals and to evaluate the frequency of clinically defined digoxin toxicity in patients with elevated SDCs. METHODS: The medical records of adult patients with SDCs assayed at 5 general hospitals in North Carolina during a 3-month period (May 1 through July 31, 1996) were prospectively evaluated. Data on SDC, inpatient or outpatient status, and medical or surgical service were collected for all patients. Data on patient demographics, serum chemistry values, indication for digoxin treatment, clinical evidence of digoxin toxicity, and timing of the blood sample relative to administration of the last dose of digoxin were collected for patients with SDCs higher than 2.6 nmol/L (>2.0 ng/mL). RESULTS: Of 3434 SDCs assayed in 2009 patients, 320 (9.3%) were higher than 2.6 nmol/L (>2.0 ng/mL). Fifty-one (15.9%) of the 320 SDCs were drawn at 6 hours or less following a digoxin dose. Sampling time relative to the digoxin dose could not be determined in 70 (21.9%) of the 320 elevated SDCs, leaving 199 (62.2%) of 320 SDCs in 138 patients evaluable for digoxin toxicity. Eighty-three of the 138 patients had clinical evidence of digoxin toxicity for an overall incidence of 4.1%. CONCLUSIONS: Digoxin toxicity occurs less frequently than historically reported. Continued emphasis needs to be placed on obtaining appropriately timed SDCs.

A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia.

BACKGROUND: Comparisons of the intubation conditions with mivacurium and rocuronium from previous reports are confounded by the use of varied induction regimens. The authors compared intubation conditions of mivacurium, rocuronium, and a placebo at 90 s and their recovery profiles during anesthesia with nitrous oxide, oxygen, and propofol. METHODS: After induction with midazolam, fentanyl, and propofol in a randomized blinded study, 100 patients received one of the following treatments: 0.25 mg/kg mivacurium in divided doses (0.15 mg/kg followed by 0.1 mg/kg 30 s later); 0.45, 0.6, 0.9, or 1.2 mg/kg rocuronium; or placebo. Evoked thumb adduction was measured throughout. Intubation was attempted 90 s after the initial dose of mivacurium and other treatment doses by a "blinded" physician. Intubating conditions were graded as excellent, good, poor, or not possible. Spontaneous recovery was studied until a 25% initial twitch height was reached. Mean arterial blood pressure and heart rate changes between groups were determined before induction through 6 min after administration of the study drugs. RESULTS: There were no important changes or intergroup differences in mean arterial blood pressure and heart rate. Intubation conditions were good or excellent for both mivacurium and rocuronium at the 0.9 mg/kg dose (93%) and at the 1.2 mg/kg dose (100%). Rocuronium at the 0.6 mg/kg dose was excellent in 27% of patients, whereas rocuronium at the 0.45 mg/kg dose had the least number of excellent conditions and the most poor or not possible assessments. Patients given placebo could not be intubated. Times to maximum blockade for 0.9 and 1.2 mg/kg rocuronium were the shortest. The times to 25% recovery for 0.6 mg/kg rocuronium (mean +/- SD = 27 +/- 8.6 min), 0.9 mg/kg (43.1 +/- 10.8), and 1.2 mg/kg (62.3 +/- 17.4 min) were significantly longer than were those for mivacurium (17.4 +/- 6.2 min). CONCLUSIONS: Mivacurium in a 0.25 mg/kg divided dose and rocuronium at 0.9 mg/kg and 1.2 mg/kg provide good or excellent intubation conditions at 90 s in most patients. Rocuronium was faster in onset at the higher doses (0.9 and 1.2 mg/kg) but had more prolonged recovery times to 25% single twitch height.