Implication of NGF and endocannabinoid signaling in the mechanism of action of sesamol: a multi-target natural compound with therapeutic potential.

RATIONALE: Sesamol, a natural compound with anti-inflammatory, antioxidant and neuroprotective properties, has shown promising antidepressant-like effects. However, its molecular target(s) have not been well defined, which merits further investigation. OBJECTIVES: Based on the interaction between the neurotrophin and endocannabinoid (eCB) systems and their contribution to emotional reactivity and antidepressant action, we aimed to investigate the involvement of nerve growth factor (NGF) and eCB signalling in the mechanism of action of sesamol. METHODS: Following acute and 4-week intraperitoneal (i.p.) administration of sesamol (40, 80 and 100 mg/kg), the classical antidepressant amitriptyline (2.5, 5 and 10 mg/kg) or the benzodiazepine flurazepam (5, 10 and 20 mg/kg), brain regional levels of NGF and eCB contents were quantified in rats by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In the case of any significant change, the cannabinoid CB1 and CB2 receptor antagonists (AM251 and SR144528) were administered i.p. 30 min prior to the injection of sesamol, amitriptyline or flurazepam. RESULTS: Following the chronic treatment, sesamol, similar to amitriptyline, resulted in the sustained elevation of NGF and eCB contents in dose-dependent and brain region-specific fashion. Neither acute nor chronic treatment with flurazepam altered brain NGF or eCB contents. Pretreatment with 3 mg/kg AM251, but not SR144528, prevented the elevation of NGF protein levels. AM251 exerted no effect by itself. CONCLUSIONS: Sesamol, similar to amitriptyline, is able to affect brain NGF and eCB signalling under the regulatory drive of the CB1 receptors.

Gender differences in highway driving performance after administration of sleep medication: a review of the literature.

OBJECTIVES: It is generally assumed that there are minimal gender differences in the safety and efficacy of central nervous system drugs, as is evidenced by men and women receiving the same drug dosage. There is, however, evidence that drugs may have a differential effect on performance in men and women, given reported differences in pharmacokinetics as well as the presence or absence and severity of adverse effects. It is especially important to verify whether gender differences in performance exist in case of activities that have potentially dangerous outcomes such as driving a car. This review summarizes the current scientific evidence on gender differences in driving performance after treatment with hypnotic drugs. METHODS: A literature search was conducted to obtain all studies that conducted on-road driving tests to examine the effects hypnotic drugs on driving. Cross-references were checked and technical reports and raw data were obtained, if possible. RESULTS: Fourteen studies were evaluated. Many studies did not allow analyses of gender effects because only women were included. Others did not report data on gender analyses. Technical reports and additional data analyses revealed significant gender differences in driving performance the morning following bedtime administration of flurazepam (30 mg) and after middle-of-the-night administration of zolpidem (10 mg). No significant gender differences were found for ramelteon (8 mg), lormetazepam (1 and 2 mg), zaleplon (10 and 20 mg), and zopiclone (7.5 mg). CONCLUSIONS: Although the available data are limited, the results show that significant gender differences have been found for some drugs but not others. Therefore, in the future more research is needed to reveal potential gender differences and to determine what mediates them.

Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports.

BACKGROUND: Constipation is an exceedingly common side effect of treatment with clozapine. In rare cases, this side effect has resulted in fatal complications. OBJECTIVE: The authors review the literature on fatal complications of clozapine-related constipation and bowel obstruction. METHOD: The authors provide two new case reports of patients who died of similar causes. RESULTS: There were seven reports of deaths from clozapine-related bowel obstruction in the literature, with the most common mechanisms of death being severe impaction leading either to feculent vomiting or bowel necrosis. DISCUSSION: The discussion outlines potential mechanisms and management of clozapine-related constipation.

Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects.

OBJECTIVE: To evaluate the next-day residual effects of the novel hypnotic, gaboxadol, following bedtime dosing in healthy elderly subjects. METHODS: Healthy women (N = 15) and men (N = 10) aged 65-79 years received a single bedtime (22:00 h) dose of gaboxadol 10 mg, flurazepam 30 mg (positive control), and placebo in a randomized, double-blind, crossover study. Measures of information processing and psychomotor performance (choice reaction time, critical flicker fusion, digit symbol substitution, compensatory tracking, body sway), memory (immediate and delayed word recall), and daytime sleepiness (Multiple Sleep Latency Test), as well as subjective ratings (line analog rating scales, Leeds Sleep Evaluation Questionnaire), were obtained starting at 07:00 h the following morning. Adverse events were recorded. RESULTS: Gaboxadol did not show next-day impairments versus placebo on any pharmacodynamic measures whereas the positive control, flurazepam, did show impairments versus placebo on most measures. Gaboxadol showed improvements versus placebo on some measures including subjective rating of next-day alertness/clumsiness on the Leeds Sleep Evaluation Questionnaire. Gaboxadol was generally well-tolerated; there were no serious adverse experiences and no subjects discontinued due to an adverse experience. CONCLUSIONS: A single oral bedtime dose of gaboxadol 10 mg did not have next-day residual effects in healthy elderly subjects, as measured by a range of pharmacodynamic assessments, in contrast to the clear impairments produced by flurazepam 30 mg.

Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries.

BACKGROUND AND OBJECTIVES: Accurate assessment of medication impact requires modeling cumulative effects of exposure duration and dose; however, postmarketing studies usually represent medication exposure by baseline or current use only. We propose new methods for modeling various aspects of medication use history and employment of them to assess the adverse effects of selected benzodiazepines. STUDY DESIGN AND SETTING: Time-dependent measures of cumulative dose or duration of use, with weighting of past exposures by recency, were proposed. These measures were then included in alternative versions of the multivariable Cox model to analyze the risk of fall related injuries among the elderly new users of three benzodiazepines (nitrazepam, temazepam, and flurazepam) in Quebec. Akaike's information criterion (AIC) was used to select the most predictive model for a given benzodiazepine. RESULTS: The best-fitting model included a combination of cumulative duration and current dose for temazepam, and cumulative dose for flurazepam and nitrazepam, with different weighting functions. The window of clinically relevant exposure was shorter for flurazepam than for the two other products. CONCLUSION: Careful modeling of the medication exposure history may enhance our understanding of the mechanisms underlying their adverse effects.

[Diagnostics and treatment of insomnia with concomitant arterial hypertension. Use of somnol as an adjuvant remedy]. / Diagnostika i lechenie insomnii pri arterial'noi gipertenzii. Primenenie Somnola kak ad'iuvantnogo sredstva.

Based upon the conception of "circular-type addiction" scientists mark out psychological (alexithimia), psychopathological (anxiety and depressive disorders), neurological (insomnia) and somatic (circulator disturbances) levels in pathogenesis of arterial hypertension. Sleep disorder have been noted to be a key symptom in phenomenology of arterial hypertension therefore it is recommended giving Somnol as an adjuvant remedy for treatment of arterial hypertension.

Role of protein kinase A in GABAA receptor dysfunction in CA1 pyramidal cells following chronic benzodiazepine treatment.

One-week treatment with the benzodiazepine (BZ) flurazepam (FZP), results in anticonvulsant tolerance, associated with reduced GABAA receptor (GABAR) subunit protein and miniature inhibitory post-synaptic current (mIPSC) amplitude in CA1 neurons of rat hippocampus. Because protein kinase A (PKA) has been shown to modulate GABAR function in CA1 pyramidal cells, the present study assessed whether GABAR dysfunction is associated with changes in PKA activity. Two days after 1-week FZP treatment, there were significant decreases in basal (- 30%) and total (- 25%) PKA activity, and a 40% reduction in PKA RIIbeta protein in the insoluble fraction of CA1 hippocampus. The soluble component of CA1 showed a significant increase in basal (100%) but not total PKA activity. Whole-cell recording in vitro showed a 50% reduction in mIPSC amplitude in CA1 pyramidal cells, with altered sensitivity to PKA modulators. Neurons from FZP-treated rats responded to 8-bromo-cAMP with a significant increase (31%) in mIPSC amplitude. Likewise, vasoactive intestinal polypeptide (VIP), an endogenous PKA activator, caused a significant 36% increase in mIPSC amplitude in FZP-treated cells. Neither agent had a significant effect on mIPSC amplitude in control cells. This study supports a role for PKA in GABAR dysfunction after chronic FZP treatment.

Effects of flurazepam and zolpidem on the perception of sleep in normal volunteers.

In previous studies we have reported that the benzodiazepine hypnotic triazolam and the nonbenzodiazepine zolpidem increase the likelihood that insomniacs will report having been asleep when awakened by an electronic tone of progressive intensity. It has not been known, however, whether this occurs with normal sleepers. In the present study we have administered placebo, flurazepam 30 mg and zolpidem 10 mg to 15 normal sleepers and awakened them with an electronic tone at five points across the night. In contrast to previous reports with insomniacs, both compounds made only modest improvements in sleep. When all time points were combined, subjects reported having been asleep in 40.3, 42.9 and 47.9% of the trials on placebo, flurazepam and zolpidem, respectively (ns). Subjects were accurate in their estimate of total time asleep, and this accuracy was not influenced by the drugs. Similarly, there were no effects on a variety of questions related to dreaming and other cognitive activity during sleep. These results suggest that the effects of these hypnotics, which have been described previously in insomniacs, are not found in normals. Further studies will be necessary to clarify whether such effects in insomniacs are related to the clinical efficacy of hypnotics.

Chronic benzodiazepine agonist treatment produces functional uncoupling of the gamma-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons.

We have investigated the effect of chronic flurazepam HCl treatment on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic flurazepam (1-5 microM, for 1-10 days) treatment did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H] Ro15-1788, and [3H]Ro15-4513 was also not altered after the chronic treatment. However, chronic flurazepam treatment produced uncoupling between GABA and pentobarbital sites and the [3H]flunitrazepam binding site. The EC50 values of GABA and pentobarbital were not significantly altered after chronic flurazepam treatment; however, their Emax values were decreased by approximately 50%. The effect of chronic flurazepam treatment on the observed uncoupling was both time and concentration dependent. Furthermore, the binding of [3H]GABA and t-butylbicyclophosphoro[35S]thionate was also not altered by chronic flurazepam treatment. The effect of GABA on 36Cl influx was not altered after chronic flurazepam treatment; however, treatment significantly attenuated the ability of diazepam to enhance GABA-induced 36Cl influx. Chronic flurazepam-induced uncoupling and decreased diazepam efficacy were reversed by the concomitant presence of the benzodiazepine antagonist Ro15-1788, suggesting that these events are mediated via the benzodiazepine receptor site. Taken together, these results suggest that chronic benzodiazepine treatment produces uncoupling of GABA and pentobarbital sites from the benzodiazepine site and decreased coupling between the benzodiazepine site and GABA receptor-gated Cl- channels. The uncoupling and decreased efficacy may be due to an alteration in the levels of various alpha subunits and may be responsible for the tolerance associated with chronic benzodiazepine agonist treatment.

Decreased expression of gamma-aminobutyric acid type A/benzodiazepine receptor beta subunit mRNAs in brain of flurazepam-tolerant rats.

The expression of GABAA/benzodiazepine beta subunit mRNAs was studied in cerebral cortex, hippocampus, and cerebellum of flurazepam-treated rats. Immediately following 4 wk of treatment, beta 2 and beta 3 subunit mRNAs were significantly reduced in cerebellum and hippocampus, whereas only beta 2 was decreased in cortex. These decreases had largely reversed 48 h following flurazepam treatment. After 2 wk of treatment, both beta 2 and beta 3 mRNAs were reduced in cerebellum, and beta 3 mRNA was reduced in hippocampus, but neither was changed in cortex. Four hours after an acute flurazepam treatment, the only change was a decrease in beta 3 mRNA in hippocampus. These results indicate that the expression of GABAA receptor beta subunit mRNAs in different brain regions is differentially regulated during chronic flurazepam treatment, and some changes occur within hours after a single large dose.

Characterization of substantia nigra pars reticulata neurons based on response to iontophoretically applied GABA and flurazepam.

Previous work had suggested that neurons in the pars reticulata of the substantia nigra (SNpr) might be differentiated based on responsiveness to GABA and benzodiazepines (BZs). To evaluate this possibility, multi-barreled glass capillary assemblies were used to examine the effects of GABA and a BZ, flurazepam (FZP), on the spontaneous activity of single SNpr neurons in chloral hydrate anesthetized rats. Both FZP and GABA, as a function of increasing ejection current, decreased the rate of neuronal discharge. SNpr neurons differed according to the maximum effect of each agent. For over half of the cells, the spontaneous discharge could be inhibited at least 90% by GABA, while the maximum FZP effect in the same cells ranged from 20 to 100% inhibition. Except for 3 neurons, the maximum inhibition produced by GABA was about the same or greater than that produced by FZP. No clear anatomical segregation according to BZ effect was found.

Oral benzodiazepines and conscious sedation: a review.

A large number of benzodiazepines have been studied for use as sedatives and for their anxiolytic potential as premedicants for outpatient surgery. Potent, new, orally-administered drugs with short half-lives, rapid onset, and minimal residual effects have been developed. Dose-dependent amnesia is also produced by some of these agents. Advances in understanding receptor physiology have shed light on specific pharmacologic activities and aided the discovery of benzodiazepine antagonists with antidote properties. While these drugs have relatively low toxicity, dose-related oversedation remains a risk in susceptible patients, especially when combined with other sedatives.

Diagnosis and treatment of outpatient insomnia by psychiatric and nonpsychiatric physicians.

Insomnia is commonly encountered in general medical practice, but little is known about how primary care physicians manage this problem. We reviewed medical records describing 536 patient encounters in which either triazolam (Halcion) or flurazepam (Dalmane) was prescribed for outpatient use. Only 12% of the progress notes written by internists or surgeons contained even a remote reference to sleep, whereas 74% of psychiatrist's notes contained at least some sleep symptom documentation. In a multivariate analysis including the number of medical and psychiatric diagnoses, patient age, and physician gender, only the prescriber department was independently associated with the presence of symptom documentation. We also found that 30% of the prescriptions written by internists or surgeons were for inappropriately large quantities of these drugs (180 or more doses) compared with 6% of the prescriptions written by psychiatrists. We conclude that the evaluation of insomnia by nonpsychiatrists is often incomplete and that hypnotic drugs may be inappropriately prescribed by these physicians. Further efforts are needed to improve the management of insomnia by primary care physicians in the outpatient setting.

Clinical uses and advantages of low doses of benzodiazepine hypnotics.

The most common adverse effects associated with the use of benzodiazepine hypnotics are residual daytime effects (daytime sedation and daytime performance decrements), anterograde amnesia, and rebound insomnia. Studies show that these adverse effects are related to dose. Hence, benzodiazepine hypnotics should be used in low doses so as to minimize or prevent these common adverse effects. It is now generally accepted that benzodiazepines should not be administered long-term for the treatment of chronic "idiopathic" insomnia. Two noncontinuous sleep disturbances, insomnia in the elderly and transient insomnia in young and middle-aged adults, are probably the most acceptable indications for the use of benzodiazepines. Low doses of short- and intermediate-acting benzodiazepines (triazolam and temazepam) are efficacious in the treatment of insomnia in the elderly, and preliminary evidence suggests that they are efficacious in the treatment of transient insomnia in young and middle-aged adults.

Insomnia in the elderly.

Insomnia is common in the elderly population. Difficulty in initiating and maintaining sleep affects nearly half of all patients over the age of 65, representing an increased prevalence in older versus younger patients. Nocturnal sleep time is decreased, frequent awakenings occur, and daytime napping is common. Age-related changes in sleep physiology correlate with the subjective complaints of disturbed sleep. Multiple etiologies for insomnia in the elderly have been described. Management strategies must include attention to both nonpharmacologic and pharmacologic aspects of care, especially with respect to the altered pharmacokinetics and pharmacodynamics associated with advanced age. Reassessing therapy is essential to promote the end goal of improvement of the elderly patient's quality of life.

Chronic benzodiazepine treatment of rats induces reduction of paired-pulse inhibition in CA1 region of in vitro hippocampus.

Paired-pulse inhibition was studied extracellularly in in vitro hippocampal slices from rats sacrificed 48 h or 7 days after 1 week flurazepam (FZP) treatment. Population spikes and field excitatory postsynaptic potentials (EPSPs) were recorded with NaCl-containing glass micropipettes in the stratum pyramidale and stratum radiatum, respectively, of the CA1 region. Conditioning pulses were delivered by stimulating Shaffer collaterals (orthodromic) or the alveus (antidromic). Orthodromic test pulses were delivered with interpulse intervals of 10-200 ms. There was a significant reduction in paired-pulse inhibition in slices from treated vs control rats in both the orthodromic-orthodromic and antidromic-orthodromic paradigms. Reduced inhibition was evident 48 h, but not 7 days, after the end of FZP treatment. Furthermore, there was a significant prolongation of the half decay time of the field EPSP, without a significant change in the initial slope or maximum amplitude. The results may suggest an impairment of endogenous gamma-aminobutyric acid function in the hippocampus after chronic benzodiazepine (BZ) treatment and may provide a basis for a mechanism of BZ tolerance.

Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Behavioral tolerance to flurazepam.

Rats were trained to earn 180 food pellets in daily, fixed-interval 1-min sessions. When performance had stabilized, a Before group was given a weekly 16 mg/kg flurazepam injection IP for 3 weeks immediately before the sessions, while an After group received their weekly injections immediately after the sessions. Then, the After group received 3 such weekly injections before the sessions. Behavioral tolerance developed by the 2nd flurazepam injection for the Before group, but for the After group, the 3 postsession flurazepam injections resulted in subsequent tolerance to presession flurazepam injection for session lever presses, but not for the time taken to earn 180 pellets. Dispositional tolerance to the serum elimination rate of flurazepam did not develop over the course of 3 injections. Behavioral suppression still evident in the initial portion of sessions with the 2nd and 3rd presession injection coincided with the duration of rising and high levels of serum flurazepam.