Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers.

OBJECTIVE: To determine whether lacosamide prolongs the corrected QT interval (QTc). MATERIALS AND METHODS: In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. RESULTS: The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. CONCLUSIONS: Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures.

Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures.

OBJECTIVE: To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS). METHODS: Post-randomization changes from baseline for electrocardiographic (ECG) measurements, diagnostic findings, and relevant adverse events (AEs) were compared for pooled data from three randomized, placebo-controlled trials of adjunctive lacosamide for the treatment of POS. RESULTS: Lacosamide did not prolong the QTc interval or affect heart rate as determined by an analysis of data from patients randomized to lacosamide 200, 400, or 600 mg/day (n = 944) compared with placebo (n = 364). After 12-week maintenance treatment, mean changes from baseline for QRS duration were similar between the placebo and lacosamide 200 and 400 mg/day groups (0.0, -0.2, and 0.4 ms), but slightly increased for lacosamide 600 mg/day (2.3 ms). A small, dose-related mean increase in PR interval was observed (-0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively). First-degree atrioventricular (AV) block was reported as a non-serious AE in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the same respective groups. Second- or higher degree AV block was not observed. There was no evidence of a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine. CONCLUSIONS: Evaluation of the pooled cardiac safety data from patients with POS showed that adjunctive lacosamide at the maximum recommended dose (400 mg/day) was not clearly associated with any cardiac effect other than a small, dose-related increase in PR interval that had no evident symptomatic consequence.

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.

BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.

An active-control trial of lamotrigine monotherapy for partial seizures.

OBJECTIVE: We report the results of a double-blind, double-dummy, active-control study designed to evaluate the efficacy and safety of lamotrigine (LTG) administered as monotherapy to adult outpatients with partial seizures. BACKGROUND: The effectiveness of LTG as add-on therapy for partial seizures in adults has previously been established. METHODS: After an 8-week baseline during which patients continued their baseline antiepileptic drug (carbamazepine or phenytoin monotherapy), 156 patients were randomly assigned to receive increasing doses of LTG (target 250 mg b.i.d.) or valproic acid (VPA; target low dose of 500 mg b.i.d.) during the first 4 weeks of an 8-week transition period. Carbamazepine or phenytoin was withdrawn over the next 4 weeks; then patients entered a 12-week monotherapy period. Study drug treatment was discontinued in patients who met predetermined escape criteria for seizure worsening. RESULTS: More patients receiving LTG were successfully maintained on monotherapy compared with patients receiving VPA (56% versus 20%; p < 0.001). The time to meet the escape criteria was also significantly longer in LTG-treated patients (median = 168 days) than in VPA-treated patients (median = 57 days; p = 0.001). The incidence of adverse events during the monotherapy period was lower than during the transition period. Four LTG patients and five VPA patients reported serious adverse events. Two of those patients experienced a rash that led to withdrawal soon after adding LTG to carbamazepine. CONCLUSIONS: We conclude that LTG is effective and well tolerated when administered as monotherapy in adult patients with partial seizures.

Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group.

We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.

Dose-response relationships of doxacurium chloride in humans during anesthesia with nitrous oxide and fentanyl, enflurane, isoflurane, or halothane.

In a two-part study, the dose-response relationships of doxacurium chloride (BW A938U) were evaluated during general anesthesia maintained with commonly used anesthetic techniques. In part 1, cumulative dose-response methodology was used to establish the ED95 of doxacurium in 36 patients receiving 70% nitrous oxide and fentanyl, or 50% nitrous oxide and either 1.26% enflurane, 0.84% isoflurane, or 0.57% halothane anesthesia. Mechanomyographic response to train-of-four stimulation was used to monitor neuromuscular blockade. The peak effect of doxacurium following each 5 micrograms/kg incremental dose was noted and a log-probit dose-response curve was constructed for each individual patient. The median ED50s were 11 micrograms/kg, 6 micrograms/kg, 8 micrograms/kg, and 8 micrograms/kg for patients receiving fentanyl, enflurane, isoflurane, or halothane anesthesia, respectively. The median ED95s were 24 micrograms/kg, 14 micrograms/kg, 16 micrograms/kg, and 19 micrograms/kg for patients receiving fentanyl, enflurane, isoflurane, and halothane anesthesia, respectively. In part 2, 72 additional patients received a rapid single injection of the ED95 (n = 36) or 2 X ED95 (n = 36) of doxacurium appropriate for the administered anesthetic as estimated from part one of the study. Peak effects of the ED95 given as single injections correlated well with the results in part 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxacurium chloride for neuromuscular blockade before tracheal intubation and surgery during nitrous oxide-oxygen-narcotic-enflurane anesthesia.

The neuromuscular effects of doxacurium (BW A938U) were studied in 36 patients, divided into four groups of 9 patients each, given doxacurium either 50 micrograms/kg (2 x ED95) 5 or 4 minutes or 80 micrograms/kg (3 x ED95) 4 or 3 minutes before tracheal intubation. Adequate neuromuscular relaxation permitted successful intubation at 5 minutes for doxacurium 50 micrograms/kg and at 4 minutes for 80 micrograms/kg. Time to 90% blockade was 5.4 +/- 1.5 minutes for doxacurium 50 micrograms/kg and 3.5 +/- 1.2 minutes for 80 micrograms/kg. Time to 25% spontaneous recovery was 84.7 +/- 54.3 minutes for doxacurium 50 micrograms/kg and 164.4 +/- 85.2 minutes for 80 micrograms/kg. Either neostigmine 45 micrograms/kg, neostigmine 60 micrograms/kg, or edrophonium 1000 micrograms/kg was given for reversal when T1 had spontaneously recovered to 25% of baseline level, T1 being the first response to repetitive train-of-four (TOF) stimuli (2 Hz for 2 seconds at 10-second intervals) expressed as percent of baseline level. The T4:T1 ratio is the amplitude of the fourth twitch relative to the first twitch in a TOF stimulus expressed as a ratio. T1 rapidly achieved 90% of baseline in 5-10 minutes after reversal of neuromuscular blockade. In contrast, the T4:T1 ratio lagged, recovering to a mean of 0.6 at 20 minutes when T1 was over 90% of baseline. Recovery patterns were not statistically significantly different (unpaired t-test) among the three reversal regimens. Therefore, the reversal data were pooled. No clinically significant hemodynamic effects occurred in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide narcotic anesthesia.

The purpose of this study was to evaluate neuromuscular and cardiovascular effects of doxacurium chloride, a new long-acting neuromuscular blocking agent, during a stable state of nitrous oxide and narcotic anesthesia. Ninety-three ASA physical status I or II patients were studied after informed written consent had been obtained. Eighty-one patients (group A) received doxacurium. The 81 patients were divided into nine subgroups according to the dose of doxacurium administered (0.01-0.06 mg.kg-1). Patients in a control group (group B) (n = 12) received pancuronium. To assess neuromuscular responses, a force displacement transducer recorded the twitch response of the adductor pollicis muscle following ulnar nerve stimulation. The ED50 and ED95 for doxacurium were estimated to be 0.013 mg.kg-1 and 0.023 mg.kg-1, respectively. The time to maximum twitch suppression following a dose of 1.0 (ED95) and 1.7 (ED95) was 10.3 +/- 1.3 min and 7.6 +/- 0.8 min, respectively. After an ED95 dose of doxacurium the time to spontaneous recovery to 95% of control twitch height was 73.7 +/- 8.7 min. With larger doses of doxacurium, 0.04 mg.kg-1 (1.7 X ED95) and 0.05 mg.kg-1 (2.2 X ED95), the time to spontaneous recovery to 95% of control twitch height was 125.8 +/- 24.8 and 204.0 +/- 21.2 minutes, respectively. When 25% twitch height recovery or more was present the reversal of doxacurium induced neuromuscular blockade was prompt.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant.

Doxacurium chloride (BW A938U) is a bis-quaternary benzylisoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 micrograms/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 micrograms/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 micrograms/kg. At 1.3 times the ED95 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 +/- 4.1 (n = 23 of 26) and 75.7 +/- 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 +/- 10.3 (n = 8 of 8) and 83.0 +/- 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 micrograms/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED95. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.

Clinical pharmacology of doxacurium chloride (BW A938U) in children.

The neuromuscular effects of doxacurium were studied in 26 children during halothane-nitrous oxide-oxygen anesthesia. Neuromuscular blockade was measured using electromyographic activity of the adductor pollicis muscle after supramaximal stimulation of the ulnar nerve at 2 Hz for 2 seconds at 10-second intervals. To estimate the cumulative dose-response relation, nine patients received incremental doses of doxacurium (2.5-10 micrograms/kg); nine patients received 27.5 micrograms/kg (the estimated ED95); eight patients received 50 micrograms/kg (1.8 X ED95). The ED25, ED50, ED75, and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 11.5, 14.8, 19.0, and 27.3 micrograms/kg, respectively. Clinical duration (T25) was 27.8 +/- 10.3 (mean +/- SD) minutes at 1 X ED95 and 50.6 +/- 15.6 minutes at 1.8 X ED95. Time to recovery of the train-of-four ratio to 0.75 was 63.1 +/- 32.9 minutes at 1 X ED95 and 108.5 +/- 25.7 minutes at 1.8 X ED95. There were no significant changes in heart rate or mean arterial pressure after bolus administration of any dose of doxacurium.

Continuous infusion of atracurium in children.

Atracurium infusion requirements were determined in 28 children anesthetized with N2O:O2 narcotic, N2O:O2 halothane (1% inspired), and N2O:O2 enflurane (2% inspired). When the patient was recovering from a bolus dose of 0.4 mg/kg atracurium, a continuous infusion of atracurium was started and the rate was adjusted to maintain 90-99% muscle twitch depression. Patients receiving enflurane anesthesia required atracurium at an infusion rate of 4.9 +/- 0.3 micrograms X kg-1 X min-1 which was a significantly lower rate (P = 0.0001) than those anesthetized with halothane (8.3 +/- 0.4 micrograms X kg-1 X min-1) or with N2O:O2 and narcotic (9.3 +/- 0.5 micrograms X kg-1 X min-1). At the onset of neuromuscular blockade, the twitch response disappeared faster after train-of-four stimulation repeated every 10 s than after single twitch rates of stimulation at 0.1 Hz. In children, during halothane anesthesia after 0.4 mg/kg atracurium, the response of the adductor of the thumb was ablated in 2.0 +/- 0.3 min with train-of-four stimulation, and in 3.7 +/- 0.4 min with single twitch stimulation. The authors recommend the use of a nerve stimulator during continuous infusion of atracurium because of the marked interpatient differences in infusion-rate requirements.

Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia.

We were interested in determining the dose-response relationship of atracurium in children (2-10 yr) during nitrous oxide-isoflurane anesthesia (1%) and the atracurium infusion rate required to maintain about 95% neuromuscular blockade during nitrous oxide-halothane (0.8%), nitrous oxide-isoflurane (1%), or nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation at the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five children received 80, 100, 150 micrograms/kg atracurium, respectively. During isoflurane anesthesia, the neuromuscular block produced by 80 micrograms/kg was 23.6% +/- 6.5 (mean +/- SEM), by 100 micrograms/kg was 45% +/- 7.2, and by 150 micrograms/kg was 64% +/- 8.7. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 120 micrograms/kg and 280 micrograms/kg, respectively. At equipotent concentrations, halothane and isoflurane augment atracurium neuromuscular block to the same extent, compared to narcotic anesthesia. Atracurium steady-state infusion requirements averaged 6.3 +/- 0.6 micrograms . kg-1 . min-1 during halothane or isoflurane anesthesia; the requirements during balanced anesthesia were 9.3 +/- 0.8 micrograms . kg-1 . min-1 (P less than 0.05). There was no evidence of cumulation during prolonged atracurium infusion.

Clinical pharmacology of atracurium in infants.

The neuromuscular effects of atracurium were studied in 25 infants anesthetized with 1.0% end-tidal halothane and N2O-O2. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five infants received 60, 80, and 100 micrograms/kg atracurium, respectively; another ten infants received 300 micrograms/kg (2 X ED95). The neuromuscular block produced by 60 micrograms/kg was 27% +/- 10.9 (SEM), by 80 micrograms/kg was 34% +/- 8.0 and from 100 micrograms/kg was 70% +/- 8.3. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 85 micrograms/kg and 150 micrograms/kg, respectively. Neuromuscular blockade lasted 23 +/- 1.6 min at 1 X ED95 and 32.5 +/- 5.2 min at 2 X ED95. Changes in heart rate and mean arterial pressure were clinically insignificant.

Clinical pharmacology of atracurium in paediatric patients.

The potency of atracurium was determined in adolescents and children during nitrous oxide-halothane and nitrous oxide-thiopentone-fentanyl anaesthesia using single dose-response curves. Dose-response curves were parallel. The effective doses producing 95% twitch depression (ED95) (mg kg-1) during nitrous oxide-halothane were larger in younger children than in the adolescents. Halothane (0.8% end-tidal) did not significantly potentiate atracurium when compared with thiopentone-fentanyl. On a microgram m-2 basis there was no difference in the ED95 between patients of different age or those anaesthetized with different techniques. At approximately 95% twitch depression intubating conditions were excellent in all groups. Minimal cardiovascular effects were noted at several multiples of the ED95.

Intubation conditions after atracurium and suxamethonium.

Conditions for endotracheal intubation provided by different dose regimens of atracurium 0.4 mg kg-1 and 0.5 mg kg-1 were studied and compared with each other and with suxamethonium 1.0 mg kg-1. Intubation was attempted at 2.5, 2 min and 1.5 min following a bolus dose of atracurium, and 1 min following suxamethonium. Ease of intubation was rated excellent in 90-100% of all patients studied. Atracurium, when administered 5 min following recovery from a suxamethonium-induced block, had a significantly faster onset of neuromuscular blockade (P less than 0.01) than the onset observed following atracurium alone. Administration of atracurium 0.42 mg kg-1 3 min after an initial dose of 0.08 mg kg-1 of the drug produced a significantly more rapid onset of block when compared with a bolus dose of 0.5 mg kg-1 (P less than 0.02).

In vitro evaluation of liquid antacid products.

The in vitro neutralizing capacities, sodium content, and cost of 21 nonprescription antacid products were compared. A 5-ml sample of each antacid product was placed in a beaker using a pipette. The pipette was rinsed three times wtih purified water 5 ml, and the mixture was stirred with a magnetic stirring rod. After one minute, 1.0 N hydrochloride acid 30 ml was added to the mixture and stirring was continued for 15 minutes. The pH was then measured. Using a burette, sufficient 0.5 N sodium hydroxide was added to the mixture to raise the pH stable value to 3.5. Samples were tested in duplicate. Manufacturers were requested to provide sodium content for the antacid products, and costs were obtained based on wholesale prices. Neutralizing capacity of the antacids ranged from 1.3 to 8.7 meq/ml. Of the 21 products, 17 contained at least 90% of the claimed neutralizing capacity, as required by FDA. One product did not qualify as an antacid by FDA standards. Sodium content has been reduced in may preparations and may no longer be a factor in choosing an antacid. Chronic therapy with antacids can be expensive, and it costs more to deliver a given amount of neutralizing capacity with less concentrated antacids.

Prevention of acetaminophen-induced hepatic necrosis by cimetidine in mice.

A preliminary trial was conducted to determine if cimetidine would prevent acetaminophen-induced hepatic necrosis. When administered to mice after experimental acetaminophen overdose, cimetidine generally prevented the development of centrilobular necrosis, but did not prevent loss of glycogen or appearance of fat in the hepatocytes. The efficacy of cimetidine in preventing acetaminophen-induced hepatic necrosis should be further studied.