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.

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.