Monotherapy Trials of New Antiepileptic Drugs

A number of clinical trials that test the efficacy and safety of the newer antiepileptic drugs (AEDs) have recently been concluded. Two dose-response trials in inpatients with refractory partial seizures and outpatients with newly diagnosed partial epilepsy established the efficacy of gabapentin as monotherapy. Lamotrigine was found to have efficacy similar to that of phenytoin and carbamazepine (CBZ) and to be better tolerated than CBZ in patients with newly diagnosed epilepsy. It was also shown to have efficacy as monotherapy in partial seizures, based on the results of an active controlled trial, and in the treatment of absence seizures, based on the results of a responder-enriched study. Topiramate as monotherapy was found to be efficacious for treatment of partial-onset seizures, based on the results of a single-center dose-response trial. A dose-response trial that tested the efficacy of tiagabine monotherapy in patients with refractory partial epilepsy was uninformative. Oxcarbazepine was found to be safe and efficacious in four comparative trials in patients with newly diagnosed epilepsy as well as in one placebo-controlled inpatient trial in patients with refractory partial seizures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65625/1/j.1528-1157.1997.tb05201.x.pd

Atrial arrhythmogenesis in wild-type and Scn5a+/Δ murine hearts modelling LQT3 syndrome

Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Δ (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher’s exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD90), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD90 in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD90 in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD90 over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD90 reduced such CI values and produced the opposite effect

Thermal plasticity of skeletal muscle phenotype in ectothermic vertebrates and its significance for locomotory behaviour

Seasonal cooling can modify the thermal preferenda of ectothermic vertebrates and elicit a variety of physiological responses ranging from winter dormancy to an acclimation response that partially compensates for the effects of low temperature on activity. Partial compensation of activity levels is particularly common in aquatic species for which seasonal temperature changes provide a stable cue for initiating the response. Thermal plasticity of locomotory performance has evolved independently on numerous occasions, and there is considerable phylogenetic diversity with respect to the mechanisms at the physiological and molecular levels. In teleosts, neuromuscular variables that can be modified include the duration of motor nerve stimulation, muscle activation and relaxation times, maximum force and unloaded shortening velocity (V-max), although not all are modified in every species. Thermal plasticity in Vmax has been associated with changes in myosin ATPase activity and myosin heavy chain (MyHC) composition and/or with a change in the ratio of myosin light chain isoforms. In common carp (Cyprinus carpio), there are continuous changes in phenotype with acclimation temperature at lower levels of organisation, such as MyHC composition and Vmax, but a distinct threshold for an effect in terms of locomotory performance. Thus, there is no simple relationship between whole-animal performance and muscle phenotype. The nature and magnitude of temperature acclimation responses also vary during ontogeny. For example, common carp acquire the ability to modify MyHC composition with changes in acclimation temperature during the juvenile stage. In contrast, the thermal plasticity of swimming performance observed in tadpoles of the frog Limnodynastes peronii is lost in the terrestrial adult stage. Although it is often assumed that the adjustments in locomotory performance associated with temperature acclimation enhance fitness, this has rarely been tested experimentally. Truly integrative studies of temperature acclimation are scarce, and few studies have considered both sensory and motor function in evaluating behavioural responses. Developmental plasticity is a special case of a temperature acclimation response that can lead to temporary or permanent changes in morphology and/or physiological characteristics that affect locomotory performance.</p

Thermal plasticity of skeletal muscle phenotype in ectothermic vertebrates and its significance for locomotory behaviour

Seasonal cooling can modify the thermal preferenda of ectothermic vertebrates and elicit a variety of physiological responses ranging from winter dormancy to an acclimation response that partially compensates for the effects of low temperature on activity. Partial compensation of activity levels is particularly common in aquatic species for which seasonal temperature changes provide a stable cue for initiating the response. Thermal plasticity of locomotory performance has evolved independently on numerous occasions, and there is considerable phylogenetic diversity with respect to the mechanisms at the physiological and molecular levels. In teleosts, neuromuscular variables that can be modified include the duration of motor nerve stimulation, muscle activation and relaxation times, maximum force and unloaded shortening velocity (V-max), although not all are modified in every species. Thermal plasticity in Vmax has been associated with changes in myosin ATPase activity and myosin heavy chain (MyHC) composition and/or with a change in the ratio of myosin light chain isoforms. In common carp (Cyprinus carpio), there are continuous changes in phenotype with acclimation temperature at lower levels of organisation, such as MyHC composition and Vmax, but a distinct threshold for an effect in terms of locomotory performance. Thus, there is no simple relationship between whole-animal performance and muscle phenotype. The nature and magnitude of temperature acclimation responses also vary during ontogeny. For example, common carp acquire the ability to modify MyHC composition with changes in acclimation temperature during the juvenile stage. In contrast, the thermal plasticity of swimming performance observed in tadpoles of the frog Limnodynastes peronii is lost in the terrestrial adult stage. Although it is often assumed that the adjustments in locomotory performance associated with temperature acclimation enhance fitness, this has rarely been tested experimentally. Truly integrative studies of temperature acclimation are scarce, and few studies have considered both sensory and motor function in evaluating behavioural responses. Developmental plasticity is a special case of a temperature acclimation response that can lead to temporary or permanent changes in morphology and/or physiological characteristics that affect locomotory performance.</p