Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v. and p.o. administration of 2.63 mg.kg-1 of [14C]zolpidem (dose expressed as the base). Autoradiography was used to examine the regional distribution of the compound and the metabolic profile of zolpidem in the plasma and brain was also investigated. The pharmacokinetic data were related to electrocorticogram power spectral analysis. After i.v. administration, the disappearance of zolpidem from plasma fitted a biexponential model with a rapid phase of 0.2 to 0.3 hr and a slower phase of 1.3 to 1.5 hr. After p.o. dosing, peak plasma concentrations where already attained at 15 min (first sampling time). Independent of the route of administration, the concentrations of zolpidem in the brain at shorter times were 30 to 50% those of the plasma values. Furthermore, up to 1 hr, zolpidem accounted for 80 to 90% of brain radioactivity. The rate of disappearance from brain paralleled that from plasma. Autoradiographic studies confirmed the rapid absorption and elimination of zolpidem as well as the relatively homogenous distribution throughout the brain. Electrocorticogram analysis in immobilized rats after i.v. administration of zolpidem showed a rapid onset and a short-acting sedative effect compatible with the kinetic profile of the parent compound. Metabolites of zolpidem displayed a poor penetration into the brain and no significant hypnotic activity. At the dose of zolpidem used, no alteration of the sleep pattern was observed.     

Pharmacokinetics of rizatriptan tablets during and between migraine attacks

Gastric stasis during migraine attacks results in delayed absorption of several orally administered antimigraine agents. This study, as part of a larger trial, was conducted to examine the pharmacokinetics of rizatriptan tablets during and between migraine attacks. Participating patients met IHS criteria for migraine with or without aura, and suffered between one and eight migraines per month for the previous 6 months. In part 1 of the study, 21 patients were randomized to receive a single 5-mg tablet of rizatriptan or placebo in the migraine-free state. In part 2, the same patients were treated during migraine with rizatriptan 5-mg tablets (n=18) or placebo (n=3). Blood samples were obtained before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration profile (ie, AUC_(0-∞), C_max, T_max) of rizatriptan 5-mg tablets administered during and between migraine attacks were comparable. The median T_max for rizatriptan between and during attacks was 1 hour, indicating rapid absorption even during a migraine attack. Rizatriptan 5 mg was well tolerated and 67% of the patients experienced headache relief 2 hours postdose.     

A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia

summary .  The objective of this study was to further explore the safety of Hemospan^® (Sangart Inc., San Diego, CA, USA), an oxygen-carrying plasma expander. The aim of this study was to determine if Hemospan is well tolerated in orthopaedic surgery patients with spinal anaesthesia in doses up to 1 L. Hemospan was previously found to be well tolerated in normal volunteers and orthopaedic surgery patients with spinal anaesthesia in doses up to 500 mL. Five cohorts of six orthopaedic surgery patients, American Society of Anesthesiologists (ASA) I and II, were studied. In each cohort, four patients received Hemospan in doses ranging from 200 to 1000 mL, and two received Ringer's lactate immediately prior to induction of spinal anaesthesia. There were no serious adverse events (SAEs). Iohexol clearance measured before and 24 h after dosing was unaffected. There were 14 adverse events (AEs) in the 10 control patients (1·4 per patient) and 30 in the 20 patients receiving Hemospan (1·5 per patient). One patient in the group receiving 200 mL Hemospan had elevated mean arterial pressure after dosing, but there were no elevations in any of the other patients. The peak plasma Hemospan concentration in the 1000 mL group was 1·3 g dL⁻¹, with a dose-dependent clearance ( T _1/2) ranging from 14·1 to 23·0 h. Plasma methaemoglobin levels were independent of dose, reaching a maximum at 40 h after dosing and never exceeded 0·125 g dL⁻¹. Troponin T was transiently elevated in two patients receiving Hemospan without symptoms or electrocardiographic abnormalities or elevation of myocardial creatinine kinase isoenzyme. Hemospan was well tolerated in this group of patients at doses up to 1000 mL.     

Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal.

This study examined in baboons various behavioral effects of zolpidem, a short-acting imidazopyridine hypnotic which has selectivity for subtypes of the benzodiazepine receptor. Intravenous drug self-injection was studied under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after each injection. Maximal rates of self-injection maintained by zolpidem (0.01-1 mg/kg) were consistently higher than those maintained by vehicle and the benzodiazepine hypnotic triazolam. Substitution of vehicle after about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a time-limited suppression of food pellet intake, indicating a drug withdrawal effect. In a drug discrimination study, baboons were trained to discriminate either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam- and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced ataxia and sedation that progressively decreased over 7 consecutive days of administration. The withdrawal, discriminative stimulus effects and tolerance shown with zolpidem were similar to those shown previously with benzodiazepines under similar conditions. The rates of self-injection of zolpidem were similar to those maintained by intermediate duration barbiturates (e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines studied previously under similar conditions. Further research on the reinforcing effects of zolpidem may provide useful insights into mechanisms underlying the maintenance of behavior by compounds acting through the benzodiazepine receptor.     

A double-blind comparative study of zolpidem versus zopiclone in the treatment of chronic primary insomnia

Zolpidem (10 mg/day) and zopiclone (7.5 mg/day), administered at night, were compared in a 14-day, double-blind, equivalence trial on 479 chronic primary insomniacs (zolpidem, 231; zopiclone, 248) throughout Japan, with a 1-week follow-up to assess rebound. The primary endpoint was the investigators' rating of global improvement of sleep disorders. A total of 32 patients in the zolpidem group (13.9%) and 45 patients in the zopiclone group (18.1%) withdrew from the study before the end of the treatment. In the zolpidem group, 67.9% (142/209) of patients were rated at least 'moderately improved' versus 61.6% (135/219) with zopiclone, zolpidem being at least as effective as zopiclone (90% confidence interval: -1.7, 14.3). With zolpidem, sleep onset latency improved in significantly more patients (85.8% versus 77.5%) and significantly fewer patients showed aggravated sleep onset latency relative to baseline at follow-up (4.5% versus 15.4%). Significantly fewer patients receiving zolpidem experienced drug-related adverse events (31.3% versus 45.3%), with bitter taste representing 5.8% (six of 104) of such complaints with zolpidem compared with 39.9% (69/173) with zopiclone. In conclusion, zolpidem was at least as effective as zopiclone, showed significantly less rebound on discontinuation and was better tolerated.     

Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability

Zolpidem, which is currently marketed in Europe as a hypnotic, is a short-duration imidazopyridine whose actions are mediated at the gamma-aminobutyric acid benzodiazepine receptor complex. However, zolpidem produces a variety of biochemical differences from classic benzodiazepine agonists including showing selectivity for the central BZ1 (omega 1) receptor subtype as well as showing a different pattern of distribution of binding sites. This study compared zolpidem to the benzodiazepine hypnotic triazolam in 15 healthy male volunteers with histories of sedative drug abuse. Placebo, zolpidem (15, 30 and 45 mg) and triazolam (0.25, 0.5 and 0.75 mg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. The onset time with zolpidem was faster than with triazolam, with peak effects of both drugs occurring at 1 to 2 hr after administration. Both zolpidem and triazolam produced dose-related decrements in performance on various performance tasks including circular lights, reaction time, balance, number recall and the digit symbol substitution test. Both drugs also produced similar dose-related changes on various observer ratings including overall strength of drug effect. Triazolam, but not zolpidem, increased subject- and observer-rated sleepiness and produced greater impairment on a picture memory task. Zolpidem, but not triazolam, produced increases in subject ratings of various somatic symptoms (e.g., dizzy, anxious and queasy) and there were 9 days on which subjects vomited after zolpidem, but none after triazolam. Although the highest dose of both drugs was identified by subjects as being active, the highest dose of triazolam was identified as being barbiturate, benzodiazepine or alcohol, almost twice as often as the highest dose of zolpidem. Overall, this study shows that although zolpidem produces many effects in common with triazolam, it also has a unique profile of effects distinguishable from classic benzodiazepine agonists. The mechanism(s) underlying these differences is unclear, but may be related to the atypical biochemical profile of zolpidem.     

A Novel Clinical Pattern of Visual Hallucination After Zolpidem Use

Abstract

Background:?Zolpidem is a new hypnotic that is supposed to have fewer side effects than traditional benzodiazepines. Some psychotic reactions, such as visual or hypnagogic hallucinations, have been reported to be associated with zolpidem use. Case Report:?A young female experienced three episodes of hallucination associated with the use of zolpidem. The visual or hypnagogic hallucination happened after she had stopped zolpidem and then restarted it 2 days later. Conclusion:?We postulate that hypnagogic or visual hallucinations associated with zolpidem use may be related to rapid withdrawal and restarting of zolpidem. The possible mechanism may be associated with the changes in the GABA_A receptor. Avoiding “as needed” use of zolpidem and using the lowest effective dose may prevent these adverse effects.     

In vivo interaction of zolpidem with central benzodiazepine (BZD) binding sites (as labeled by [3H]Ro 15-1788) in the mouse brain. Preferential affinity of zolpidem for the omega 1 (BZD1) subtype

Zolpidem is a novel hypnotic drug which possesses preferential affinity, under in vitro conditions, for the omega 1 (BZD1) subtype of BZD binding sites. In the present study the in vivo interaction of zolpidem with mouse brain BZD binding sites, as labeled by i.v. injection of [3H]Ro 15-1788, has been investigated. Intraperitoneal administration of zolpidem (30 min before sacrifice) decreased in a dose-dependent manner, the retention of [3H]Ro 15-1788 in the cerebral cortex (ED50 = 8.9 mg/kg i.p.); the inhibition by zolpidem was maximal (70%) at 5 to 10 min postinjection and of only 10% 1 hr later. These kinetics are in agreement with its short lasting hypnotic properties. CGS 9896, CL 218,872 and flunitrazepam also prevented the cortical accumulation of [3H]Ro 15-1788 with ED50 values of 12.5, 24 and 0.17 mg/kg i.p., respectively. Zolpidem, like flunitrazepam, diminishes exploratory activity and possesses anticonvulsant and myorelaxant effects in the mouse. However, in contrast to flunitrazepam, the sedative action of zolpidem can be evidenced at a much lower recognition site occupancy (35%) than that needed for myorelaxant or anticonvulsant effects (50-56%). The regional selectivity of zolpidem as an inhibitor of [3H]Ro 15-1788 in vitro and in vivo binding in the mouse brain has been assessed by quantitative autoradiography.(ABSTRACT TRUNCATED AT 250 WORDS)     

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.     

One rare side effect of zolpidem--sleepwalking: a case report

Zolpidem is an imidazopyridine agent indicated for the short-term treatment of insomnia. Sleepwalking is a rare side effect of zolpidem. A review of the literature produced only 2 cases. We report a case of a male rehabilitation inpatient in his mid fifties with a history of alcoholism and traumatic brain injury who had undergone a right hip hemiarthroplasty. He had no history of somnambulism or insomnia but walked in his sleep on 2 nonconsecutive nights after taking zolpidem. He had exhibited no such behavior before taking zolpidem, on the intervening night that was he was not given medication, and after the medication was discontinued. We conclude that zolpidem can cause sleepwalking, and patients who have suffered a brain injury may be more susceptible to this side effect. Here we describe the clinical presentation and review the relevant literature on zolpidem and sleepwalking.     

Pharmacokinetics of sparfloxacin in patients with renal impairment.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.     

Does once-daily dosing of aminoglycosides affect neuromuscular function?

Objective: Aminoglycosides have been reported to produce a curare-like neuromuscular blockade in animals at serum concentrations higher than those obtained with traditional dosing (1–2 mg/kg every 8 h) in humans. Aminoglycoside-induced neuromuscular blockade is rarely, if ever, seen in humans with traditional dosing. The recent adoption of once-daily dosing of aminoglycosides has raised concerns about increased potential for this adverse effect because higher serum concentrations are produced. The objective of this study was to determine if once-daily dosing of aminoglycosides inhibits respiratory muscle function.
Method: Nine mechanically ventilated ICU patients on once-daily dosing of gentamicin 6 mg/ kg/day were assessed for respiratory muscle strength by measuring maximum inspiratory pressure (MIP). MIP is a measurement of the maximal negative pressure generated by repeated inhalations against an occluded airway over 20 s. This was measured within 1 hour before (MIP_pre) and within 1 hour after each aminoglycoside dose (MIP_post).
Results: Mean values for MIP_pre and MIP_post were −26.7 cm H₂O and − 26.5 cm H₂O, respectively. The mean difference between MIP_pre and MIP_post was − 0.2 cm H₂O, which was not statistically significant ( P >0.05).
Conclusion: The effect of gentamicin (6 mg/kg/day) on respiratory muscle function was not statistically, nor clinically significant, and weaning from mechanical ventilation does not seem to be inhibited by once-daily dosing of aminoglycosides as detectable by measurement of MIP.     

Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.     

Dose-response study of metoclopramide in gastroesophageal reflux in infancy

Summary— Twenty-four infants, 1 to 18 months-old, who were referred to four centers for suspected gastroesophageal reflux and whose esophageal pH after a standard formula meal given at 9 to 10 am (Ho-day 1) fulfilled the criterion of being < 4 for more than 5% of the time between H₁ and H₆, entered a double-blind placebo-controlled dose-response trial of metoclopramide (M). Twenty-four hours later (day 2), patients were randomly assigned to receive either placebo or a single 0.1, 0.2, or 0.4 mg/kg dose of metoclopramide, 30 min before the formula meal ( n = 6/group) and the procedure was repeated. Metoclopramide plasma concentration was measured 1 h after dosing (C_1h). On day 1, the time during which the esophageal pH was < 4 (time pH < 4), and five other parameters, were not significantly different in the treatment groups. On day 2, time pH < 4 (m(SD)) decreased from 33(13) to 30(33), 39(27), to 36(47), 42(15) to 18(13) and 48(25) to 31(46) min in the placebo, 0.1, 0.2, and 0.4 mg/kg metoclopramide groups, respectively. Possibly due to the large interindividual variability, no significant differences in parameters were observed between the different groups. None of the parameters correlated with the metoclopramide dose. Time pH < 4 expressed as the difference between day 1 and day 2, relative to day 1, decreased significantly as a function of C_1h. No side effects were observed. A similar study should be performed after repeated dosing regimen.     

Changes of EEG and Pulmonary Venous Admixture During a Protein Load in Patients With Cirrhosis

Abstract. 21 patients with cirrhosis of the liver and 24 control patients were studied before and after a protein load (120 g protein per day during one week). An EEG was recorded and a visual assessment of frequency pattern was performed. Venous admixture was estimated during hyperoxia. According to the EEG frequency pattern the patient group with cirrhosis was subdivided into those with EEG slowing after the protein load (n = 7) and those without (n = 14). The following results were obtained: 1) Resting arterial blood gases did not change in either group. 2) There was a significant increase of the AaDO₂ (difference between alveolar pO₂ and peripheral arterial pO₂) in cirrhotics and controls. 3) The increase in AaDO₂ was significantly larger in those cirrhotics showing EEG slowing compared to those without EEG - slowing or to the controls. 4) Fractional venous admixture increased significantly in those cirrhotics showing EEG slowing. There was no significant change in those patients who did not show EEG changes or in the controls.     

Effect of Altitude on Erythropoiesis and Oxygen Affinity in Anaemic Patients on Maintenance Dialysis

Abstract. Six anaemic patients with terminal renal failure on maintenance haemodialysis and three healthy control subjects were exposed to altitude hypoxia at Jungfraujoch (3450 m above sea-level). In normal subjects plasma erythropoietin (ESF) as determined by the exhypoxie mouse assay exhibited the expected rise after 24 h (from 0.25 to 3.09%⁶*Fe incorporation). In the patients a smaller but still significant rise was demonstrable (from 0.39 to 2.18%^MFe incorporation), indicating that even severely damaged kidneys with negligible exocrine function retain a definite endocrine reserve for ESF production. For this reason bilateral nephrectomy should be avoided in these patients if possible. 2,3-DPG and P₅₀ (as corrected to pH 7.4) as well as blood pH increased within 24 h after altitude exposure in the control subjects, as described previously. In the patients the two parameters were already elevated under baseline conditions. Upon hypoxic stimulation they rose further (from 44.7 to 56.5 (junoles/10¹¹ Ec. and from 28.6 to 30.1 mmHg respectively), while a definite fall in whole blood pH occurred. High altitude exposure was tolerated remarkably well by the dialyzed patients in spite of the presence of anaemia and severe renal failure.     

Zolpidem, a novel nonbenzodiazepine hypnotic. II. Effects on cerebellar cyclic GMP levels and cerebral monoamines

The effect of zolpidem, a novel nonbenzodiazepine short-acting hypnotic, on cerebellar cyclic GMP (cGMP) and biochemical indices of cerebral norepinephrine, serotonin and dopamine metabolism has been investigated in the rat and mouse. Zolpidem diminished the levels of cerebellar cGMP in the rat markedly (ED50 = 0.7 mg/kg i.p.). This effect was antagonized, in a competitive manner, by the benzodiazepine antagonist Ro 15-1788. The zolpidem-induced decrease of cerebellar cGMP levels was rapid in onset and of short duration (less than 1 hr). When given in combination with muscimol (in a dose which by itself did not alter cerebellar cGMP content) zolpidem potentiated the diminution of the cyclic nucleotide levels induced by the gamma-aminobutyric acid mimetic. Zolpidem (up to 30 mg/kg i.p.) failed to alter the rate of utilization of norepinephrine or the levels of total 3,4-dihydroxyphenylethyleneglycol or 3-methoxy, 4-hydroxyphenylethyleneglycol sulfate in the rat brain. However, the compound (10-30 mg/kg) diminished serotonin synthesis in the hippocampus, striatum and frontal cortex. At high doses (30-100 mg/kg i.p.), zolpidem also decreased the rate of utilization of dopamine and 3,4-dihydroxyphenylacetic acid levels in the rat striatum. Moreover, zolpidem (10 mg/kg i.p.) prevented partially the haloperidol-induced increase in 3,4-dihydroxyphenylacetic acid concentrations in both striatum and frontal cortex. Finally, zolpidem prevented the increase in 3,4-dihydroxyphenylacetic acid levels in the frontal cortex induced by electric footshock stress in rats (ED50 = 2 mg/kg i.p.) and BALB/C mice. This effect was antagonized by coadministration of Ro 15-1788.     

Transient reversal of anoxic brain injury-related minimally conscious state after zolpidem administration: a case report

Shames JL, Ring H. Transient reversal of anoxic brain injury-related minimally conscious state after zolpidem administration: a case report.Zolpidem is a unique nonbenzodiazepine sedative hypnotic drug that selectively binds to omega-1 γ-aminobutyric acid receptors in the brain. Although used for years in Israel and abroad for insomnia, there have been periodic reports of unusual or remarkable neurologic effects in patients with various brain pathologies. Here, we report on a 50-year-old woman 18 months after severe anoxic brain injury in a minimally conscious state. Residual deficits included mutism, athetoid movements of the extremities, and complete dependence for all personal care. After the administration of 5 to 10mg of zolpidem, within 45 minutes, the patient’s condition improved markedly, including the cessation of athetoid movements, regained speaking ability, and ability to perform various tasks including self-feeding. These effects lasted 3 to 4 hours, after which the patient returned to her former state. This effect was repeatable on a daily basis. Existing evidence and possible mechanisms to explain zolpidem’s effects in brain injury are described.     

Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects

Summary— A double-blind study comparing the effect of zolpidem 10 mg, and placebo, on sleep architecture, nocturnal ventilation, cardiovascular parameters (heart rate, systolic, diastolic and mean blood pressures) was carried out. Ten healthy middle-aged males took part in the study. No significant differences were found between zolpidem and placebo in relation to sleep architecture. Mean respiratory disturbance index (RDI) and SaO₂ values (mean SaO₂, time spent with SaO₂ < 90%) were similar under both conditions. The diastolic and mean blood pressure readings taken from REM periods which occurred during the first third of the night were significantly higher with zolpidem. No changes in systolic blood pressure or heart rate were found with zolpidem in comparison to placebo.     

Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects

Eslicarbazepine acetate (ESL) is a new-generation voltage-gated sodium channel blocker, which has been demonstrated to be effective and well tolerated in the treatment of epilepsy. The primary objective of this study was to investigate the effect of ESL on the pharmacokinetics of digoxin. This study was a randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy subjects (six men and six women). The study included two 8-day treatment periods with a washout of ≥10 days. In each period, subjects received either ESL 1200 mg once-daily or placebo, concomitantly with a loading oral dose of digoxin 0.5 mg on days 1 and 2, followed by a once-daily maintenance dose of 0.25 mg on days 3–8. Maximum serum digoxin plasma concentrations ( C _max) were reached ( t _max) at 0.5–2.0 h post-dose (median = 1.0 h) and at 0.5–4.0 h post-dose (median = 1.0 h) with Reference (digoxin plus placebo) and Test (digoxin plus ESL) treatments, respectively. The Test/Reference digoxin geometric mean ratios and 90% confidence intervals (90% CI) were 0.96 and 0.90–1.03 for the area under the plasma concentration–time curve over the dosing interval (AUC_0–24) and 0.85 and 0.68–1.07 for C _max. The 90% CI was within the bioequivalence range (0.80–1.25) for AUC_0–24, thus demonstrating bioequivalence. The 90% CI was outside the 0.80–1.25 range for digoxin C _max, but it appeared to be caused by a higher variability in digoxin C _max following co-administration of digoxin with placebo than with ESL. Co-administration of ESL and digoxin was well tolerated. Concomitant administration of ESL has no clinically relevant effect in the systemic exposure to digoxin.