Bruce L. Ehrenberg

An Algorithm for the Management of Restless Legs Syndrome

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Dose‐Dependent Pharmacokinetics and Psychomotor Effects of Caffeine in Humans

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double‐blind, single‐dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half‐life prolonged at the 500‐mg compared to the 250‐mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500‐mg dose exceeded those of the 250‐mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high‐dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration‐dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8–11 Hz) and beta (12–30 Hz) ranges; however, effects were not dose‐dependent. While favorable subjective and performance‐enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1‐minute infusion in a double‐blind, three‐way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast‐Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepams half‐life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and + 21.3%, respectively).

Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences

Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles.

Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo

This study evaluated the relationship of dose, plasma concentration, and time to the pharmaco‐dynamics of zaleplon and zolpidem, 2 structurally distinct benzodiazepine receptor agonists.

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees

Restless legs syndrome (RLS) can occur with an autosomal‐dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One‐factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal‐dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p < 0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Treatment of Migraine

This invention relates to a method for treating classical migraine headaches. Pursuant to this method, a therapeutic amount of β-adrenergic-blocking agent is administered to a person suffering a migraine attack promptly upon onset of aura. The invention further relates to a method wherein the blocking agent is nasally administered.

Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid

Abstract.We aimed to compare the efficacy of valproic acid (VPA) on paresthesias and sleep in RLS to that of levodopa (LD). Twenty patients with idiopathic restless legs syndrome (RLS) were treated with 600 mg slow-release VPA and 200 mg slow-release LD+50mg benserazid in a randomized, placebo-controlled, cross-over, double-blind setting with polysomography (PSG) at the end of each 3-week treatment periods. There was no major difference between the efficacy of valproic acid or LD. Periodic leg movements in sleep (PLMS) and PLM arousal index (PLMAI) significantly decreased with LD (p ≤ 0.005). However, LD, but not VPA, significantly increased arousals not associated with PLMS (p = 0.002). Decrease of intensity and duration of RLS symptoms were more pronounced with VPA (p ≤ 0.022) than with LD (NS). We conclude that slow-release VPA provides a treatment alternative for RLS.

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A‐selective inhibitor ketoconazole. Lymphoblast‐expressed CYPs were used to study amitriptyline N‐demethylation and E‐10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N‐demethylation and E‐10 hydroxylation). Assuming no extrahepatic metabolism, the model‐predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, PO) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%‐42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%‐40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.

Valproate for sleep consolidation in periodic limb movement disorder.

In this study, open-label valproate (VPA) was administered to patients as a treatment for periodic limb movement disorder (PLMD). Six patients aged 28 to 62 years with complaints of sleep disturbance and at least five periodic limb movements (PLMs) per hour of sleep underwent polysomnograms (PSGs) with and without low-dose VPA treatment (125-600 mg at bedtime). After a baseline PSG, patients received VPA therapy from 2 weeks to 14 months, until the time of the follow-up PSG on VPA (median, 5 months; mean, 6 months). All six patients experienced subjective improvement in daytime alertness. Sleep efficiency was improved from 76% to 88% (p = 0.003), stage 1 (light) sleep decreased from 26% to 13% (p = 0.04), stage 3 and 4 (deep) sleep increased from 19% to 30% (p = 0.01), and rapid eye movement sleep was unchanged. There was a trend toward a reduction in the number of PLMs per hour of sleep and in the percentage of arousals associated with PLMs. All of the patients continued taking VPA after the PSGs were completed. One patient discontinued VPA 1 month after completion of the last PSG because of short-term side effects, and one patient stopped VPA 22 months after the last PSG because of weight gain. Thus, these data indicate that VPA has a long-term beneficial effect on sleep consolidation in patients with PLMD.