Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The indications for the benzodiazepines include anxiety, insomnia, muscle spasm and epilepsy and each disorder has a variety of biological substrates. Limbic structures and the neurotransmitters noradrenaline, 5-HT and GABA have all been implicated. Benzodiazepines act on allosteric receptor sites and potentiate the actions of GABA in modulating chloride ionophores across nerve membranes. These effects can be blocked by the benzodiazepine antagonist, flumazenil. The molecular pharmacology of the benzodiazepine-GABA-chloride receptor is complex, with a wide range of different subunits. Animal models of dependence have suggested that the changes associated with long-term benzodiazepine use are related more to receptor-effector coupling than to the receptor characteristics themselves. Thus, benzodiazepine agonists on long-term use lose their efficacy, antagonists become partial inverse antagonists, and inverse agonists increase in efficacy. Various clinical implications are explored, including the use of flumazenil to prevent and to treat benzodiazepine withdrawal syndromes.
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PMID:Biological processes in benzodiazepine dependence. 784 50

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.
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PMID:Antiepileptic drugs in development: prospects for the near future. 817 17

The results of stimulating human subjects with the LISS Cranial Stimulator (LCS) and the LISS Body Stimulator (LBS) include an increase or decrease in the activities of certain neurotransmitters and neurohormones and the reduction of associated pain, insomnia, depression, and spasticity. The effects were documented in human subjects with measurements of the serum concentration of the various agents and assessments of the symptoms being performed before and after stimulation. The stimulators had a carrier frequency of 15,000 hz, which utilizes the bulk capacitance of the body, and a 15 hz modulating bioactive frequency. The second modulating frequency presently used, 500 hz, reduces the energy input to the patient by half. Significant increases in levels of CSF serotonin and beta endorphin were recorded post stimulation. There were also elevations in the levels of plasma serotonin, beta endorphin, GABA and DHEA together with diminished levels of cortisol and tryptophan. Concomitant with these changes were significant improvements in the symptoms of pain, insomnia, spasticity, depression, and headache.
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PMID:Physiological and therapeutic effects of high frequency electrical pulses. 880 93

Zopiclone is a new short half-life cyclopyrrolone hypnotic agent acting at the GABA-benzodiazepine receptor complex. In order to characterize its pharmacological profile, the effects of 7.5 mg zopiclone on nocturnal melatonin secretion were investigated under polysomnographic control in 11 healthy subjects following acute and subchronic administration as well as after abrupt discontinuation of the drug. No effect of zopiclone on the melatonin plasma levels could be observed. Regarding both total melatonin production and the temporal pattern of melatonin secretion during the night, there was no difference between placebo baseline condition, acute and subchronic administration, and discontinuation. In contrast, the sleep EEG data demonstrated the hypnotic efficacy of zopiclone under acute administration and indicated a rebound insomnia after abrupt discontinuation. Moreover, alterations of sleep architecture were found under treatment as well as after discontinuation. Whereas, with regard to sleep EEG parameters, zopiclone appears to be comparable with some short-acting benzodiazepines, a discrepancy between the missing effect of zopiclone on pineal function and the suppressing influence of benzodiazepines known from the literature becomes obvious. The fact that zopiclone does not interfere with nocturnal melatonin secretion at pharmacologically active doses as indicated by alterations in sleep EEG parameters might possibly point to a pharmacodynamic difference between the two drug classes.
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PMID:Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion. 888 74

Hypericum perforatum L. Hypericaceae (St. John's wort), has been used since the time of ancient Greece for its many medicinal properties. Modern usage is still quite diverse and includes wound healing, kidney and lung ailments, insomnia and depression. This plant has been known to contain a red pigment, hypericin, and similar compounds, which have been assumed to be the primary active constituent(s) in this plant genus. A crude Hypericum extract was tested in a battery of 39 in vitro receptor assays, and two enzyme assays. A sample of pure hypericin was also tested. Hypericin had affinity only for NMDA receptors while the crude extract had significant receptor affinity for adenosine (nonspecific), GABAA, GABAB, benzodiazepine, inositol triphosphate, and monoamine oxidase (MAO) A and B. With the exception of GABAA and GABAB, the concentrations of Hypericum exact required for these in vitro activities are unlikely to be attained after oral administration in whole animals or humans. These data are consistent with recent pharmacologic evidence suggesting that other constituents of this plant may be of greater importance for the reported psychotherapeutic activity. Alternative pharmacologic mechanisms for Hypericum's antidepressant activity are critically reviewed and the possible importance of GABA receptor binding in the pharmacology of Hypericum is highlighted. Some of these results have been previously reported.
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PMID:In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. 934 70

The present article reviews direct and indirect evidence of the effects of sex steroids on different aspects of sleep. It begins with a review of what is known about the effects of steroid hormones on sleep and on central nervous system processes related to sleep, such as the GABA-ergic system, in animals. It continues with a review of the effects of exogenous hormones on human sleep and a review of studies comparing sleep during hypogonadal states secondary to surgical or natural menopause. The article proceeds to review the data on the effects of the menstrual cycle on both subjective and objective aspects of sleep and circadian temperature and melatonin rhythms in samples of healthy women, women with premenstrual dysphoric disorder, and women with primary insomnia. Then, the article reviews gender differences in sleep during depression and raises the possibility that sex steroids moderate these differences. Finally, the article concludes with a discussion of the implications of the data reviewed for basic clinical, and methodological aspects of sleep research.
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PMID:Sex, steroids, and sleep: a review. 1045 May 90

Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.
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PMID:gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. 1086 13

Insomnia is a frequent complaint in the elderly population. Hypnotic agents, including benzodiazepines, with longer pharmacological half-lives have been associated with side effects, including residual sedation, memory impairment, and discontinuation effects. Zaleplon is a short-acting (elimination half-life of 1 hour), non-benzodiazepine hypnotic that acts on the benzodiazepine type 1 site of the gamma-aminobutyric acid type A (GABA(A)) receptor complex. The pharmacology and pharmacokinetics of Zaleplon suggest a safety profile that is improved over other hypnotics. The objective of this placebo-controlled study was to evaluate the efficacy and safety of Zaleplon (5 and 10 mg) in elderly (> or =65 years) outpatients with primary insomnia. This was a multicenter, double-blind, randomised, placebo-controlled 2-week outpatient study. Postsleep questionnaires were used to record subjective sleep variables: sleep latency, sleep duration, number of awakenings, and sleep quality. Zaleplon significantly reduced subjective sleep latency during both weeks of the study with both 5- and 10-mg doses. Subjective sleep quality was improved for significantly more patients treated with zaleplon 10 mg than those treated with placebo during both weeks of treatment. There was a weak indication of rebound insomnia after discontinuation of treatment with the 10-mg dose, but no significant difference in common treatment-emergent adverse events across treatment groups. Zaleplon is an effective and safe hypnotic for the treatment of insomnia in the elderly.
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PMID:Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group. 1096 Aug 82

Restricted electrolytic lesions of the lateral hypothalamus (LH) evoke sleeplessness in the rat. The present study was aimed to analyze a possible anatomical substrate of the LH hyposomnia within the hypothalamus. In a group of electrolytically lesioned LH rats the intensity of sleep disturbances, assessed on the basis of EEG records from the neocortex and the hippocampus, was confronted with the localization and the extent of destruction of the LH area and with the topography of known fiber systems of the medical forebrain bundle (MFB). In separate experiments the effects of the destruction of LH cell bodies by means of bilateral ibotenic acid (IBO) injections and inhibition of LH neuronal elements by bilateral muscimol (MUSC) administration were also tested. It was found that pronounced hyposomnia follows electrolytic but not IBO lesions of the LH/MFB area. The effective LH damage might have been localized at every level of its antero-posterior axis, from the preoptic area up to the posterior hypothalamus, suggesting involvement of fiber system(s) rather than a localized group of neuronal pericaria. The most effective lesions transsected projections descending from the preoptic/anterior hypothalamic area, olfactory structures, ventral striatum and the central amygdaloid nucleus as well as fibers connecting LH with the brainstem reticular formation, many of them using GABA as a neurotransmitter. Bilateral MUSC injections caused a dose-dependent, bicuculline-reversible, increase in waking time, most pronounced at a dose of 50 ng, which ressembled the effect of the electrolytic lesion. These results indicate that LH hyposomnia is not attributable to the damage to the intrahypothalamic neurons and suggest the participation of GABA-ergic transmission in LH in waking-sleep regulation.
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PMID:Anatomical correlates of the lateral hypothalamic influence on waking-sleep relationship in the rat. 1101 73

Sleep is an active process consisting of macro- and microarchitectural rhythms, chronobiology, and neurochemical changes. Disruptions in sleep chronobiology, which may occur in shift workers and the elderly or due to jet lag, often respond to exogenous melatonin. Insomnia requires careful evaluation to determine contributions of comorbid medical conditions and drug effects. Treatment options include sleep hygiene principles and sedative hypnotic therapy. Zaleplon and zolpidem, short-acting benzodiazepines selective for omega-1 GABA receptors, are effective first-line agents for initiating sleep.
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PMID:Sleep disorders: assisting patients to a good night's sleep. 1102 66


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