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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy, safety, and performance of triazolam was compared with those of other shorter-acting hypnotics acting on the gamma-aminobutyric acid (GABA) receptor--zopiclone, zolpidem, midazolam, brotizolam, temazepam, lormetazepam, and loprazolam. In all, 5506 patients participated in 38 clinical and epidemiologic studies, of whom 2462 were treated with triazolam in parallel-design and crossover studies. To provide clinically relevant comparisons, only studies using comparator agents in doses equipotent to the triazolam doses were included. Two general findings emerged. First, "serious" central nervous system side effects, such as excitement and violence, were not demonstrated for any of the hypnotic agents, including triazolam. Other central nervous system side effects, such as depression and irritability, were reported with equal frequencies for all the hypnotics reviewed. Rebound insomnia, reported intermittently with most of these agents, was short-lived and not clinically significant. So-called early morning insomnia was noted only once and does not appear to be a valid clinical entity. Daytime anxiety was not observed in large numbers of triazolam-treated subjects studied, which is contrary to claims that the drug is anxiogenic. Second, a remarkable similarity was found among all of these shorter-acting agents in terms of efficacy, side effects, and performance-related effects. This was particularly of note for zopiclone and zolpidem. Although claims have been made suggesting differences, evaluation of the studies herein showed that these nonbenzodiazepine hypnotics were indistinguishable from triazolam and other benzodiazepine hypnotics in their clinical and pharmacologic activity. Thus, different chemical structures did not a priori predict different clinical profiles when drugs share a similar mechanism of action.
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PMID:Comparative clinical profiles of triazolam versus other shorter-acting hypnotics. 133 76

In order to determine critical sites within the hypothalamus responsible for the induction and maintenance of wakefulness (W), we performed microinjections of muscimol, a potent gamma-aminobutyric acid (GABA) agonist, in various lateral hypothalamic regions of freely moving cats. We found that bilateral injections of a small amount of muscimol (0.1-1.0 micrograms/0.5 microliters) in the preoptic and anterior hypothalamus and rostral mesencephalic tegmentum resulted in increased vigilance and insomnia. In contrast, microinjections of muscimol in the middle and anterior parts of the posterior hypothalamus induced long-lasting behavioral and electroencephalographic signs of sleep with short latency. The hypersomnia was characterized by a significant increase in both light and deep slow wave sleep (SWS), and a nearly complete suppression of paradoxical sleep (PS). Animals with muscimol microinjections in the ventrolateral part of the posterior hypothalamus, however, exhibited increased SWS followed by a significant increase in PS. When injected into the posterior hypothalamus of insomniac cats pretreated with p-chlorophenylalanine (PCPA), muscimol induced not only SWS but also PS with short latency. The present data thus support the hypotheses that the posterior hypothalamus plays a critical role in the mechanisms of W and that sleep might result from functional blockade of the hypothalamic waking center.
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PMID:A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. 292 57

The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. Our major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of [3H]TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (Kd = 0.27 +/- 08 nM at 0 degree C; Kd = 1.96 +/- 0.85 nM at 37 degrees C) while the Bmax values remained unchanged (1220 +/- 176 fmoles/mg protein at 0 degree C and 1160 +/- 383 fmoles/mg protein at 37 degrees C). Saturation studies of [3H]TZ binding in the presence or absence of GABA (100 microM) showed a GABA-shift. At 0 degrees C the Kd values were (Kd = 0.24 +/- 0.03 nM/-GABA; Kd = 0.16 +/- 0.04/+GABA) and at 37 degrees C the Kd values were (Kd = 1.84 +/- 0.44 nM/-GABA; Kd = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, our findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists.
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PMID:Temperature dependence and GABA modulation of [3H]triazolam binding in the rat brain. 303 25

A first Japanese case of glutaric aciduria type I (GA-I) was described. She was a 7-month-old girl presenting with poor head control, irritability and sleeplessness. The profile of urinary organic acids by gas chromatography mass spectrometry (GC/MS) suggesting GA-I were confirmed by no activity of glutaryl-CoA dehydrogenase in the fibroblasts. The cerebral computer tomography (CT) showed marked changes such as large fluid collections on bilateral frontotemporal regions and a slight enlargement of bilateral ventricles. The amounts of urinary glutarate excretion decreased after restriction of lysine and tryptophan in her diet and administration of carnitine improved the carnitine levels in blood and urine, while these were less effective for the neurological symptoms. On the other hand, oral administration of lioresal, an analogue of gamma-aminobutyrate (GABA), cleared her symptoms such as ill temper, irritability and sleeplessness dramatically, and the abnormalities of the CT examinations were not more deteriorative until 2 years of her age at least. The neurological manifestations of GA-I seemed to be affected by the unusual metabolism of GABA in the central nervous system.
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PMID:A case of glutaric aciduria type I with unique abnormalities in the cerebral CT findings. 359 Jan 75

Between 5 and 20% of the adult population in Western countries suffer from insufficient and/or unsatisfying sleep, often associated with certain psychiatric disorders or with certain types of professional activities (for example, shift workers) and travel schedules (for example, jet lag). The benzodiazepines are at present the drug treatment of choice for the management of anxiety and stress-related conditions as well as insomnia. Benzodiazepines are thought to act by potentiating the action of the neurotransmitter gamma-aminobutyric acid (GABA), a widely distributed transmitter in the central nervous system. The circadian system has a key role in the regulation of the sleep-wake cycle, and at least some forms of insomnia may be the result of a disorder of the circadian sleep-wake rhythm. Similarly, at least some forms of depression may also involve disruption of normal circadian rhythmicity. A central pacemaker for the generation of many circadian rhythms in mammals, including the sleep-wake cycle, appears to be located in the suprachiasmatic nucleus, and recent research indicates that both cell bodies and axons containing GABA are present within the bilaterally paired suprachiasmatic nuclei. These findings raise the possibility that the benzodiazepines, commonly prescribed for sleep and mental disorders, may have an effect on the central circadian pacemaker. Here we report that the acute administration of triazolam, a short-acting benzodiazepine commonly prescribed for the treatment of insomnia, induces a phase-shift in the circadian rhythm of locomotor activity in golden hamsters. This suggests a role for GABA-containing neurones in the mammalian circadian system.
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PMID:A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock. 370 16

This article outlines some of the new developments in the field of insomnia. To obtain a better understanding of insomnia and avoid the diversities of impractical diagnosis, the medical profession must universally agree on the classification of insomnia. This knowledge has to be available to all levels of the medical community, especially general practitioners. The article reviews some new data about classification, diagnosis, and treatment of insomnia. It discusses the definition of insomnia and sets up the accepted criteria for the severity of its various forms. The policy of using hypnotics in Norway is fairly restrictive. Only three hypnotics are available, two benzodiazepins (nitrazepam and flunitrazepam) and the newly introduced cyclopyrrolone (zopiclone). The mechanisms of action of various hypnotics on the gamma-aminobutyric acid system are briefly discussed, and guidelines are given for use and choice of hypnotics, their indications and contraindications. In any modern society like Norway, there should be a clear awareness of the impact of insomnia on the quality of life and the seriousness of the effects it can have on the everyday activities of subjects suffering from this disorder.
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PMID:[Insomnia and hypnotics]. 772 91

Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia. Current developments in benzodiazepine receptor pharmacology, i.e. the advent of partial agonists and receptor subtype specific agonists (Fig. 1), however, might eventually overcome these limitations, thus greatly improving therapeutic prospects. The present study demonstrates that subchronic administration of alprazolam (a high-efficacy agonist) results in strong withdrawal reactions upon injection of a benzodiazepine receptor antagonist in mice and monkeys. The partial agonist bretazenil, as well as the benzodiazepine receptor type 1-preferring agonist zolpidem, however, are much less prone to producing such reactions. Neurochemical studies showed that subchronic infusion of lorazepam (a high-efficacy agonist), in contrast to betrazenil, led to benzodiazepine receptor downregulation in vivo and reduced potentiation of gamma-aminobutyric acid (GABA)-stimulated chloride flux by diazepam ex vivo. These findings indicate that partial and receptor subtype 1-selective agonists differ from full, non-selective agonists in their liability to induce drug dependence and tolerance upon chronic administration. It is hypothesized that the neurochemical basis of these adaptive phenomena may be receptor downregulation and/or reduced coupling between GABAA receptor/chloride channel gating and benzodiazepine receptor binding.
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PMID:Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence. 791 Jul 39

A critical mass of evidence now supports the existence of a novel class of neuroactive steroids. These steroids are devoid of any known steroid hormone activity and have high specificity for the gamma-aminobutyric acidA receptor complex (GRC), which is a ligand-gated chloride channel that mediates the inhibitory action of the neurotransmitter gamma-aminobutyric acid (GABA). The action of these steroids at the GRC is to allosterically potentiate the effect of GABA on chloride channel conductance through a unique site on the GRC. These neuroactive steroids have been termed the epalons, a shortened form of epiallopregnanolone, an endogenous metabolite of progesterone with potent actions at the GRC. Putative epalon receptors may be unique sites on the GRC that mediate the effects of epalons on GABA-gated channel function. The pharmacological profile of the epalons is consistent with those of other positive modulators of GABA action (e.g., the clinically useful benzodiazepines (BZs) and barbiturates). These neuroactive steroids have anxiolytic, anticonvulsant, and sedative-hypnotic properties. Based upon some of the unique characteristics of the epalons relative to barbiturates and the BZs, it is plausible that the epalons can be developed into a novel class of therapeutic agents for the treatment of anxiety, epilepsy, and insomnia.
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PMID:A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons. 858 84

Antiepileptic drugs (AEDs) have various mechanisms of actions and therefore have diverse anticonvulsant, psychiatric, and adverse effect profiles. Two global categories of AEDs are identified on the basis of their predominant psychotropic profiles. One group has "sedating" effects in association with fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects. These actions may be related to a predominance of potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission induced by drugs such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The other group is associated with predominant attenuation of glutamate excitatory neurotransmission and has "activating" effects, with activation, weight loss, and possibly anxiogenic and antidepressant effects. This group includes agents such as felbamate and lamotrigine. Agents such as topiramate, with both GABAergic and antiglutamatergic actions, may have "mixed" profiles. Mechanisms of actions, activity in animal models of anxiety and depression, and clinical psychotropic effects of AEDs in psychiatric and epilepsy patients are reviewed in relationship to this proposed categorization. These considerations suggest the testable hypothesis that better psychiatric outcomes in seizure disorder patients could be achieved by treating patients with baseline "activated" profiles (insomnia, agitation, anxiety, racing thoughts, weight loss) with "sedating" predominantly GABAergic drugs, and conversely those with baseline "sedated" or anergic profiles (hypersomnia, fatigue, apathy, depression, sluggish cognition, weight gain) with "activating" predominantly antiglutamatergic agents. Systematic clinical investigation of more precise relationships of discrete mechanisms of actions to psychotropic profiles of AEDs is needed to assess the utility of this general proposition and define exceptions to this broad principle.
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PMID:Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. 1049 35

Zopiclone is a cyclopyrrolone hypnosedative that is chemically unrelated to the benzodiazepines but nevertheless potentiates gamma-aminobutyric acid-mediated neuronal inhibition, and has demonstrated proven efficacy and good tolerability in the treatment of insomnia over 15 years of use. Zopiclone is indicated for short term use, and should not be prescribed for more than 4 weeks. This review compares the efficacy of zopiclone with that of a number of commonly used short-, medium- and long-acting benzodiazepines. Zopiclone at dosages of 7.5 mg/day has demonstrated efficacy equivalent and in some cases greater to that of flurazepam 30 mg/day, nitrazepam 5 mg/day, flunitrazepam 1 to 2 mg/day, temazepam 20 mg/day, triazolam 0.125 to 0.5 mg/day and midazolam 15 mg/day. Zopiclone-treated patients reported themselves to be less impaired by daytime sedation than patients treated with the medium- and long-acting hypnosedatives flurazepam, nitrazepam and flunitrazepam. Zopiclone and temazepam showed similar effects on daytime behaviour while zopiclone appeared to have somewhat better effects on daytime well-being than the short-acting triazolam and midazolam. There has been no clinical comparison with the frequently used medium-acting benzodiazepines lormetazepam and brotizolam and the imidazopyridine hypnosedative zolpidem. Data from clinical trials, pooled analyses and postmarketing surveillance including over 30,000 patients showed that with the exception of bitter taste (reported by <10% of zopiclone recipients), the tolerability profile of zopiclone is similar to that of placebo. Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.
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PMID:A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience. 1061 70


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