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, p.o.) 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.

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion.

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam.

The pharmacokinetics and pharmacodynamics of the benzodiazepine alprazolam (1 mg, administered orally) were compared between eight patients with panic disorder and eight age- and sex-matched healthy volunteers. Subjects received orally administered placebo and alprazolam in a randomized, double-blind, single-dose crossover study. The elimination half-life, time of maximum plasma concentration, maximum concentration, volume of distribution, and clearance of alprazolam were similar for both groups. For each cohort, alprazolam treatment (vs. placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and impaired cognitive performance on the digit-symbol substitution test. For the panic disorder group only, there was a significant increase in the subjective rating of"contented" and a reduction in the rating of "easily irritated." For the healthy volunteer group, alprazolam produced increases in ratings of "fatigued" and "slowed thinking," but also increases in ratings of "relaxed." In each group, alprazolam significantly increased the electroencephalographic (EEG) measure of relative beta amplitude (range, 13-30 Hz) compared with placebo. Concentration-EEG response curves fit a sigmoid E(max) model, and there was greater sensitivity to EEG effects, as measured by a 28% reduction in the EC50 value, in the panic disorder group compared with healthy control subjects. After alprazolam treatment, there was increased sensitivity to EEG and mood effects and fewer aversive effects in the panic disorder group compared with healthy subjects. There were no differences in the pharmacodynamic measures of sedation and cognition or differences in pharmacokinetics between the two groups.

Comparison of the effects of pravastatin and lovastatin on sleep disturbance in hypercholesterolemic subjects.

We have studied the effects of two cholesterol-lowering medications, lovastatin and pravastatin, on different sleep parameters in hypercholesterolemic subjects. These medications are 3-hydroxy-methylglutaryl coenzyme A inhibitors. Only subjects who had complained of sleep disturbance while on previous treatment with lovastatin were enrolled. Sixteen subjects (11 men and 5 women) underwent a randomized, double-blind, three-way crossover treatment with lovastatin, pravastatin, and placebo. Each phase of the study lasted 4 weeks. A placebo wash-out period of 4 weeks separated each treatment phase. At the end of each treatment phase, subjects were admitted to the sleep laboratory for 2 consecutive nights. No statistical differences were detected during treatment with lovastatin, pravastatin, and placebo for sleep parameters such as total sleep time, total awake time, wake time after sleep onset, efficiency of sleep, and percent of different phases of sleep. Our study suggests that lovastatin and pravastatin do not have a significant effect on sleep parameters in hypercholesterolemic subjects that could explain their complaints of insomnia. Nevertheless, the subjects did have moderate sleep disturbances that could account for insomnia and most likely predate the use of HMG-CoA reductase inhibitors.

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.

Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo.

PURPOSE: This study evaluated the relationship of dose, plasma concentration, and time to the pharmacodynamics of zaleplon and zolpidem, 2 structurally distinct benzodiazepine receptor agonists. METHOD: Ten healthy male volunteers received single oral doses of placebo, 10 mg zaleplon, 20 mg zaleplon, 10 mg zolpidem, and 20 mg zolpidem in a double-blind, 5-condition crossover study, with 48 hours elapsing between trials. Plasma drug concentrations and pharmacodynamic effects were measured during the 8 to 24 hours after administration. RESULTS: Kinetics of zaleplon and zolpidem were not significantly related to dose. However, zaleplon had more rapid elimination (apparent elimination half-life [t1/2] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than zolpidem (t1/2, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min). Active treatments produced pharmacodynamic effects consistent with benzodiazepine agonist activity: self- and observer-rated sedation, impairment of digit symbol substitution test (DSST) performance, impaired memory, and increased electroencephalographic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 10 mg zolpidem < 20 mg zolpidem; on a number of measures, 20 mg zaleplon was comparable to 10 mg zolpidem. Quantitative effects of zolpidem 20 mg far exceeded those of other treatments. Dynamic effects of both drugs were significantly related to plasma concentration. CONCLUSIONS: Benzodiazepine agonist effects of zaleplon and zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of zolpidem exceeded those of zaleplon.

Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences.

BACKGROUND: 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. METHODS: In a double-blind, 5-way crossover study, healthy volunteers received (A) ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg ketoconazole twice a day plus 1.0 mg alprazolam, (C) ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. RESULTS: For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half-life (t1/2) prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8-hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit-symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t1/2 was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8-hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of ketoconazole. CONCLUSION: For triazolam, an intermediate-extraction compound, impaired clearance by ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound.

Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome.

OBJECTIVE: There is an increased risk of patients with obstructive sleep apnea syndrome (OSAS) to have stroke or cardiac infarcts. Besides hypertension, epinephrine-induced platelet activation could be a further reason for the increased cardiovascular morbidity and mortality in OSAS. METHODS: During a 4-month period (August 1994 to December 1994) we recruited prospectively 76 patients referred for polysomnograms because of a suspected sleep disorder such as OSAS. RESULTS: Fifty patients had no respiratory events during sleep (non-OSAS), 19 patients had more than five but less than 50 obstructive apneas or hypopneas per hour of total sleep time (mild-to-moderate OSAS group), and seven patients had an apnea hypopnea index of more than 50 per hour of total sleep time (severe OSAS group). Blood pressure, plasma epinephrine levels, and P-selectin expression (as a marker for platelet activation) were measured in every patient at 9 PM and 6 AM (before and after the polysomnogram). There was a significant correlation of the apnea hypopnea index with 9 PM and 6 AM systolic and diastolic blood pressure, with 9 PM platelet activation, and with 6 AM epinephrine levels mainly due to high values in the severe OSAS group. CONCLUSIONS: Our results suggest that platelet activation, epinephrine, and high blood pressure play a role in the high prevalence of cerebrovascular and cardiovascular events in patients with OSAS.

Single-dose pharmacokinetics and pharmacodynamics of alprazolam in elderly and young subjects.

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double-blind, single-dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half-life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam-placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit-symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13-30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly.

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.

Patient-based health status measurement in clinical practice: a study of its impact on epilepsy patients' care.

The objective was to assess the potential benefits of the routine use of the MOS SF-36 Health Survey (SF-36) in the care of ambulatory patients. The design was a longitudinal, prospective, randomized, controlled study set in the outpatient neurology clinic at the New England Medical Center. There were 163 consecutive patients with epilepsy who had 210 follow-up visits with one of two epileptologists. The patients completed the SF-36 before the patient-physician encounter and the forms were optically scanned. The SF-36 results of the intervention group patients were given to the physicians before the encounter and withheld for control group patients. For intervention group patients, the physicians completed a questionnaire assessing the impact of the SF-36 on the process of care. After the visit, all patients completed a satisfaction questionnaire. The main outcome measures were the physicians' responses to standardized questions about the usefulness of the SF-36 for communication with and management of epilepsy patients and the patients' responses to standardized questions about their satisfaction with care. The physicians indicated that the SF-36 provided new information in 63% of the intervention group encounters. A change in therapy was prompted in 13%. The physicians rated the SF-36 as at least moderately useful for communication in 14% of the encounters and to management in 8%. The lower (indicating worse health status) the patients' SF-36 scale scores, the more useful the SF-36 results were rated by the physicians for communication and management. It was concluded that the routine use of health status measures may enhance patients' care.

The health status of adults with epilepsy compared with that of people without chronic conditions.

STUDY OBJECTIVES: To examine the feasibility of administering and the psychometric properties of a general health status questionnaire in adults with epilepsy, and to assess the health status of these patients. DESIGN: Prospective, cross-sectional, observational study. SETTING: Neurology clinic of a tertiary care medical center. PATIENTS: One hundred forty-eight ambulatory adults with epilepsy. INTERVENTIONS: Patients completed the SF-36, a general health status questionnaire. Respondent burden and data quality as well as psychometric characteristics were evaluated. Patients' SF-36 scale scores, adjusted for comorbidities, were compared with those of 641 people without chronic conditions with the same sociodemographic characteristics. MEASUREMENTS AND MAIN RESULTS: Administering the SF-36 to adult outpatients with epilepsy is feasible and results are psychometrically sound. Compared with those who were not ill, patients had significantly (p < 0.001) lower (0 = worst, 100 = best) scores in six of the eight SF-36 domains: general health perceptions (57.7 vs 82.1), mental health (61.3 vs 79.6), vitality (53.5 vs 67.8), role limitations owing to physical (69.6 vs 95.0) and emotional problems (67.2 vs 88.4), and social functioning (75.2 vs 89.9). CONCLUSIONS: Lower SF-36 scores may reflect patients' assessments of the balance among epilepsy, seizures, and antiepileptic drug therapy-related effects. Incorporating health status information into therapeutic decision making may help to attain the ultimate goal of improving patients' health.

Comorbidity of migraine: the connection between migraine and epilepsy.

Although an association between migraine and epilepsy has long been discussed, it has rarely been studied systematically. According to the evidence from the large epidemiologic study reviewed in this article, individuals with epilepsy are 2.4 times more likely to develop migraine than their relatives without epilepsy. Risk of migraine is elevated in patients with partial-onset and generalized-onset seizures. The comorbidity of migraine and epilepsy may be explained by a state of neuronal hyperexcitability that increases the risk of both disorders. Clinical and EEG features useful in the differential diagnosis of migraine and epilepsy as well as in the diagnosis of both conditions when they occur concurrently are reviewed. When migraine and epilepsy occur together, therapy with agents effective for both conditions should be considered.

Restless legs syndrome in childhood and adolescence.

Restless legs syndrome (RLS) is believed to be a condition primarily of middle to older age. However, it can have its onset in childhood. Five illustrative case histories with an autosomal dominant mode of inheritance are described. A mother and her 3 children (age: 6 1/2, 4 and 1 1/2 years) as well as a 16-year-old patient from a second family have typical RLS signs of leg discomfort (paresthesias) and motor restlessness prevalent at night and at rest, with temporary relief by activity. Polysomnography or videotaping revealed periodic limb movements in sleep (PLMS) and, in some cases, involuntary jerking of the legs was present during wakefulness as well. Clinicians should be aware that RLS can occur in childhood and adolescence and may be more common than heretofore recognized. "Growing pains" and attention deficit hyperactivity disorder (ADHD) are in the differential diagnosis of RLS in childhood.

Lateralization of memory for the visual attributes of objects: evidence from the posterior cerebral artery amobarbital test.

We used the posterior cerebral artery amobarbital test to examine how each temporal lobe mediates memory for objects. Temporal lobectomy candidates were presented with four objects while one hemisphere was anesthetized. We assessed recall and recognition following recovery from the drug. Verbal recall was significantly better following object presentation to the left hemisphere when the left hemisphere was not the seizure focus. Recognition memory, tested with two identical objects, two objects that shared the same name but had different physical characteristics, and two foils, was superior following object presentation to the right hemisphere. Only the right hemisphere could discriminate identical objects from same-name foils. These data confirm that the left temporal lobe has an advantage in encoding the verbal representation of an object and suggest that the right temporal lobe is critical for memory of specific visual attributes of objects.

Migraine-related seizures in adults with epilepsy, with EEG correlation.

We studied the relationship between migraine and epilepsy in 395 adult seizure patients. Seventy-nine patients (20%) also had migraine syndrome, and 13 of these patients (3%) experienced seizures during or immediately following a migraine aura. Patients with catamenial epilepsy and patients with migraine with aura were at an increased risk for an association between these two disorders. In two patients, we recorded the entire sequence from migraine aura to partial seizure, and in both there were distinctive changes on the EEG during the migraine aura that preceded the onset of an electrographic complex partial seizure. Periodic lateralized epileptiform discharges were recorded in five other patients in close temporal relation to their migraine attacks. There was improved seizure control with combination antimigraine and antiepileptic drugs (AEDs) in six patients who failed to respond to AEDs alone.

Asymmetries of sleep spindles and beta activity in pediatric EEG.

Unilateral suppression of beta activity, unilateral suppression of sleep spindles, and unilateral delta slowing on EEG have not been previously compared regarding accompanying neuroradiological (NR) and clinical neurological (CN) findings in children. We studied EEGs in children under age 10 years with unilateral beta suppression (n = 80), spindle suppression (n = 51) or unilateral delta slowing (n = 49). There were no significant differences between the three groups of abnormal EEGs in their relationships with NR and CN. Unilateral suppression of sleep spindles and beta activity are at least as accurate as focal slowing in lateralizing NR and CN findings.