The safety and tolerability of zolpidem--an update.

Zolpidem belongs to a new class of hypnotic agents, chemically distinct from the pre-existing ones, and has a unique neuropharmacological profile. It induces sedative/hypnotic effects in rodents at doses much lower than those for anticonvulsant and myorelaxant activities. Clinically, zolpidem is indicated for the short term treatment of insomnia. It has a short half-life (2.4h), with no active metabolite, and does not accumulate during repeated administration. The pharmacokinetic profile associated with the absence of active metabolites is consistent with the short duration of action and absence of residual effects that have been observed. Polysomnographic experience indicates that zolpidem induces a sleep pattern which is similar to that of physiological sleep, and which produces either no or only minimal effects on sleep architecture after abrupt discontinuation. Aspects of the general safety of zolpidem have been studied in data obtained from healthy volunteers and patients, both adult and elderly, during its clinical development and in post-marketing experience. Zolpidem appears to be well-tolerated in adults and in the elderly, when administered in accordance with prescribing instructions. The available data indicate that, in these circumstances, the risk of abuse or dependence is minimal.

Comparison of continuous versus intermittent administration of zolpidem in chronic insomniacs: a double-blind, randomized pilot study.

The subjective efficacy and safety of intermittent administration of a hypnotic for insomnia was assessed, since such a regime may provide a potential means of reducing the risk of habituation and dependence. A total of 160 adult patients (mean 45 years) with chronic insomnia were treated for 2 weeks with zolpidem, 10 mg, either continuously or intermittently (five nights zolpidem, two consecutive nights placebo per week) in this multicentre, out-patient, pilot study. At the end of the 2-week treatment, patients subjectively estimated their nightly total sleep time as 6.96 +/- 1.19 h (from 6.07 +/- 1.25 h at baseline) and 6.94 +/- 1.30 h (from 5.72 +/- 1.46 h) after the continuous and intermittent treatments, respectively. Patients' reports did not indicate any differences between the two groups in global evaluation of impairment, sleep quality, or the incidence of adverse events. These results suggest that the efficacy and safety of zolpidem, 10 mg, are comparable whether the drug is administered every night or intermittently. Further studies with a broader well-defined patient base, are needed to confirm these data.

[Contribution of zolpidem in the management of sleep disorders]. / Apport du zolpidem dans la prise en charge des troubles du sommeil.

Zolpidem is a nonbenzodiazepine hypnotic agent belonging to a new class of psychotropic drugs the imidazopyridines which enhance the GABAA receptor function by interacting with a specific receptor population. Zolpidem binds selectively to the Omega-1 receptor subtype and from a pharmacological point of view differs from benzodiazepines (BZD) by producing a strong sedative and hypnotic profile which predominates over the anticonvulsivant and anxiolytic activity and moreover appears practically devoid of myorelaxant properties. From a pharmacodynamic point of view, these results suggest that zolpidem facilitates more selectively than BZD, GABAA function and produces a selective hypnotic effect. Though if the role played by receptors in tolerance and dependence has not been yet fully elucidated, it could be described as an adaptative process to sustained stimulation of GABA function. Animal data obtained with zolpidem differs substantially from that of the BZD and indicates that repeated zolpidem administration may not lead to phenomena of tolerance and withdrawal syndrome after abrupt drug discontinuation. In human following oral intake, zolpidem is very rapidly (Tmax: 30-40 min) absorbed. The clearance is essentially metabolic and less than 1% is recovered in urine. The apparent plasma half-life is of 2.0-2.5 hours in most adult subjects and metabolites are totally inactive. The hypnotic activity of zolpidem and its effects on sleep architecture have been assessed in polysomnographic studies: 11 studies in 579 healthy volunteers and 12 studies in 202 insomniac patients. From all the patient studies, it emerges clearly that zolpidem at the dose of 10 mg significantly decreases sleep onset latency, the number and the duration of nocturnal awakenings, and concomitantly increases total sleep time. Furthermore, at variance with what observed with reference benzodiazepine hypnotics, zolpidem does not alter patient sleep architecture: it increases only moderately stage 2, it increases, when reduced, stages 3 and 4 (slow wave sleep) and it does not decrease REM sleep. Clinical studies conducted on more than 4,000 insomniac patients have clearly shown that at the dose of 10-20 mg, zolpidem induces from the first night a definite hypnotic effect in all types of insomnia. In elderly subjects an initial dose of 5 mg should be considered. The possible presence of residual effects during the day following administration of zolpidem has been assessed in 535 healthy volunteers and in 133 insomniac patients according to a double blind (versus placebo and/or benzodiazepine) controlled design.(ABSTRACT TRUNCATED AT 400 WORDS)

Behavioral indices of beta receptor subsensitivity after chronic treatment with viloxazine in the mouse.

The aim of the experiments was to determine whether chronic pretreatment with viloxazine decreased the sensitivity of mice to the sedative effects of a beta agonist clenbuterol. Mice were subjected to chronic oral treatment with viloxazine (128 mg/kg twice daily) and then given a single administration of 32 mg/kg PO followed by clenbuterol (0.125 mg/kg IP) before being tested in a standard photocell activity meter. Imipramine, administered at the same doses in the same experimental conditions, was used as a comparison compound. The results showed that chronic but not acute viloxazine decreased the hypoactivity induced by clenbuterol, suggesting the induction of beta receptor subsensitivity. With imipramine the results were in the same direction but less clear. The findings are discussed in terms of the eventual specificity of the viloxazine effect to subsensitivity in beta-2 receptors.

[Clinical pharmacokinetics of viloxazine chlorhydrate. Practical implications]. / Pharmacocinétique clinique du chlorhydrate de viloxazine. Implications pratiques.

Pharmacokinetic data of an antidepressant agent: Apparent half-life (T1/2 elim), time of peak plasma concentration (Tmax), bioavailability, have a major contribution to determine optimal dosage in accordance with a low modification of steady-state levels. Viloxazine is a second generation antidepressant drug with a short apparent half-life (T1/2 elim: 2 to 5 h (3.4 h), which requires once a day 3 h i.v. infusion or three intakes of 100 mg oral standard formulation. The recent development of a new 300 mg slow-release form seems justified by a best compliance. Pharmacokinetic properties [Tmax = 3 to 9 h (5.2 h), T1/2 term = 6 to 7 h], suggest once a day dosage without risk of accumulation in chronic treatment. The relationships between plasma levels and the clinical improvement were not clear in literature. The recent therapeutic use of a 300 mg slow-release tablet has not permitted to change precedent findings.

A study of the interaction of viloxazine with theophylline.

The effect of viloxazine on the pharmacokinetics of theophylline was studied in eight healthy volunteers. Theophylline 200 mg/day (théophylline Bruneau 100 mg tablets) was administered on day 1; after a 3-day washout period, viloxazine 300 mg/day (Vivalan 100 mg tablets) was administered orally from days 5 to 7. On day 8, theophylline 200 mg and viloxazine 100 mg were concomitantly administered. The pharmacokinetic parameters of theophylline alone and after coadministration of viloxazine were determined. Viloxazine significantly increased the plasma concentrations (p less than 0.01) and the area-under-the-curve values (p less than 0.01) of theophylline and decreased its body clearance (p less than 0.05). Our results suggest that the dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is prescribed.