Effect of Suan Zao Ren (Semen Ziziphi Spinosae) Extract on the TXNIP/NLRP3 Pathway in Insomniac Rats

Objectives This study aimed to investigate the therapeutic effects of Suan Zao Ren(Semen Ziziphi Spinosae,SZS)extract on insomnia induced by p-chlorophenylalanine(PCPA)in rats and its influence on the thioredoxin-interacting protein(TXNIP)/nucleotide-binding domain Leucine-rich repeat and pyrin domain-containing receptor 3(NLRP3)inflammasome pathway,and to preliminarily explore themechanism by which SZS extract improves insomnia.Methods Fifty male Sprague–Dawley(SD)rats were used,with 8 rats in the blank group and 42 rats in the modeling group.The modeling group was induced by intraperitoneal injection of PCPA at a dose of 500mg·kg1 for six consecutive days,with daily cage exchange.After 6 days,40 successfully modeled rats were randomly divided into five groups:themodel group(equal volume of distilled water),the positive group(0.75 mg·kg1),and low-,medium-,and high-dose SZS extract groups(1.5,3,and 6 g·kg1,respectively),with 8 rats in each group.Treatments were administered for seven consecutive days.Enzyme-linked immunosorbent assay was used to measure levels of 5-hydroxytryptamine(5-HT)and gamma-aminobutyric acid(GABA)in the rat cerebral cortex.The thiobarbituric acid(TBA)method was used to determine malondialdehyde(MDA)levels,and the hydroxylamine method was used to determine superoxide dismutase(SOD)levels.The 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)method was used to measure total antioxidant capacity(TAOC)in the cerebral cortex.Pathological changes in the cerebral cortex were observed,and Western blot was used to detect the protein expressions of TXNIP,NLRP3,apoptosis-associated speck-like protein containing a Caspase activation and recruitment domain(CARD),and cysteine–aspartate-specific protease 1(Caspase-1)in the cerebral cortex.Results Compared with the blank group,the model group showed a significantly prolonged sleep latency(p<0.001)and a significantly shortened sleep duration(p<0.001).There were no changes in serum MDA and SOD levels.MDA levels in the cerebral cortex were significantly increased(p<0.001),while SOD and TAOC levels were significantly decreased(p<0.001).The 5-HT level was increased(p<0.05),and the GABA level was significantly decreased(p<0.001).SZS extract improved these conditions to varying degrees.Light microscopy showed no significant changes in cortical neurons but transmission electron microscopy revealed intact mitochondrial structures in the blank group,while the model group showed swollen and unclear mitochondria with reduced organelles.After 7 days of treatment,these conditions improved in the SZS extract groups.Compared with the blank group,the expressions of the four proteins in the model group were increased,and the expressions of these proteins were decreased in the SZS extract groups compared with the model group.Conclusion SZS extract may exert an antioxidant effect to treat insomnia by downregulating the expression of TXNIP/NLRP3 proteins and regulating oxidative stress levels in the cerebral cortex.

An Explanation of the Powers of Franz Mesmer

In his lifetime Franz Anton Mesmer was branded a charlatan by the scientific community on account of his claim of being able to cure many sickness and medical problems though animal magnetism.Notwithstanding this,although his specific claim to possess the power of animal magnetism has been discounted,his methods have had a vast influence in every branch of mental healing and spiritual healing and healing thru hypnotism as well as New Age techniques that involve not only―the power of suggestion‖but also the physical―laying on of hands.‖This article reviews Mesmer‘s techniques,and gives a broad overview of all the other branches of mental and spiritual healing where his methods are still used in one way or another,and presents recent scientific research that completely vindicates Mesmer‘s original claim to possess the power of being able to manipulate the―magnetic fluid‖in the living organism.It is now known from radiogenetics that the ferritin in our bodies can be manipulated not only by electromagnetic radiation(radio waves)but also by magnetic fields.

Synthesis of Sedative-hypnotic Zopiclone Analogues

Eight new cyclopyrrolone compounds were synthesized according to the structure activity relationship and action mechanism of Zopiclone, a cyclopyrrolone hypnotic. Their preliminary pharmacodynamics are under investigation.

Investigation of the usefulness of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function

Background:Military operation personnel often suffer from sleep difficulty because of their work requirements.In this study,we investigated the efficacy of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function; we subsequently established the optimal dosage regimen for military operation personnel.Methods:Twenty-two healthy young male volunteers were recruited for the study.Eight subjects took 10 mg or 15 mg of zaleplon and placebo alternately and then were exposed to noise.Changes in polysomnography(PSG) indices,including sleep latency(SL),sleep efficiency(SE) and sleep structure,were recorded after drug administration.After awakening,the volunteers' subjective judgments of sleep quality and sleepiness were measured.Eight volunteers underwent 3 psychomotor performance tests at a one-week interval,and the psychomotor performance tests were conducted before and after taking zaleplon and placebo.Six volunteers participated in the vestibular function test session,and parameters,including optokinetic nystagmus(OKN),vestibular ocular reflex(VOR),visualvestibular ocular reflex(VVOR) and vestibular ocular reflex fixation suppression(VOR-Fix),were detected by the same experimental design as described above.The data of sleep observations were subjected to one-way variance analysis.Results:Compared with the placebo group,SL was shortened significantly,and the scores of subjective sleep quality and sleep depth were clearly increased in the zaleplon 10 mg group(P<0.05).Moreover,the SE and the percent of REM(rapid eye movement) sleep were increased remarkably in the zaleplon 15 mg group(P<0.01).Furthermore,the SE,percent of REM sleep and scores of subjective sleep depth in the zaleplon 15 mg group were significantly higher than in the zaleplon 10 mg group(P<0.05).The psychomotor performance did not change significantly after ingestion of 10 mg or 15 mg of zaleplon,whereas the OKN and VOR gains were lower in the two dose groups of zaleplon(P<0.05) and restored to normal 3h after drug ingestion.Conclusion:Zaleplon is an ideal hypnotic for military personnel,and its hypnotic efficiency is dose-related under noise interference; a 15 mg dose of zaleplon could provide significantly better sleep than a 10 mg dose of zaleplon.

Advances in Researches on Chemical Composition and Functions of Hemerocallis Plants

The genus Hemerocallis is a kind of perennial herbaceous plants of Liliaceae and consists of about 15 species in the world,11 of which can be found in China. Some species of Hemerocallis are widely cultivated for medicinal,edible and ornamental application. Considerable progress had been made in researches on chemical composition and functions of Hemerocallis plants. Previous phytochemical studies on Hemerocallis plants have demonstrated the presence of flavonoids,anthraquinones,alkaloids,terpenoids,triterpenes and triterpenoid saponins,caffeoylquinic acid derivatives,naphthalene glycosides,steroid and steroidal saponins,phenylethanoid glycosides,and lignans. Functional activities of Hemerocallis plants are mainly manifested in sedative hypnotic,antidepressant,antioxidant,anti-tumor,hepatoprotective,antibacterial and insecticidal activities. Chemical composition of Hemerocallis plants is various,and structural type is rich,and has a variety of significant functional activities,so it is worth further study.

Sedation in gastrointestinal endoscopy: Where are we at in 2014?

Gastrointestinal endoscopies are invasive and unpleasant procedures that are increasingly being used worldwide. The importance of high quality procedures(especially in colorectal cancer screening), the increasing patient awareness and the expectation of painless examination, increase the need for procedural sedation. The best single sedation agent for endoscopy is propofol which, due to its' pharmacokinetic/dynamic profile allows for a higher patient satisfaction and procedural quality and lower induction and recovery times, while ma-intaining the safety of traditional sedation. Propofol is an anesthetic agent when used in higher doses than those needed for endoscopy. Because of this important feature it may lead to cardiovascular and respiratory depression and, ultimately, to cardiac arrest and death. Fueled by this argument, concern over the safety of its administration by personnel without general anesthesia training has arisen. Propofol usage seems to be increasing but it's still underused. It is a safe alternative for simple endoscopic procedures in low risk patients even if administered by non-anesthesiologists. Evidence on propofol safety in complex procedures and high risk patients is less robust and in these cases, the presence of an anesthetist should be considered. We review the existing evidence on the topic and evaluate the regional differences on sedation practices.

Double-blind randomized controlled study of the efficacy, safety and tolerability of eszopiclone vs placebo for the treatment of patients with post-traumatic stress disorder and insomnia

BACKGROUND Sleep disturbance is a core feature of post-traumatic stress disorder(PTSD).Given the relationship between sleep disturbance and PTSD,there has been a relative paucity of studies examining the potential therapeutic impact of using pharmacotherapy to target sleep disturbance in patients with PTSD.Eszopiclone(ESZ)is a non-benzodiazepine y-aminobutyric acid-A receptor agonist indicated for the treatment of sleep and may affect sleep in patients with PTSD.AIM To evaluate the efficacy of ESZ vs placebo(PBO)for patients with PTSD and insomnia.METHODS The study was a 12-wk,double blind,randomized controlled trial with 3 mg of ESZ(n=13)or PBO(n=12).RESULTS Patients in both arms experienced significant improvement in PTSD symptoms as assessed by the Clinician-Administered PTSD Scale for DSM-IV(CAPS):ESZ(t11=-3.12,P=0.005)and PBO(t11=-3.5,P=0.002)and by self-report with the Short PTSD Rating Interview(ESZ t11=-3.38,P=0.003 and PBO t11=-4.48,P=0.0005).There were no significant differences between treatments on the CAPS(t22=-0.13,P=0.70)or the Short PTSD Rating Interview(t22=-0.58,P=0.56).Similarly,both treated groups improved on sleep measures as assessed by the Pittsburgh Sleep Quality Index with PTSD Addendum(PSQI)and on total sleep time(TST)and sleep latency assessed by actigraphy with no significant differences between groups(PSQI t22=-0.24,P=0.81;total sleep time t10=0.13,P=0.90 and sleep latency t10=0.68,P=0.50).There was a significant correlation between improvement in sleep and overall improvement in PTSD as measured by change scores on the PSQI and CAPS,r(8)=0.79,P=0.01 for ESZ treated subjects,but not for those treated with PBO r(9)=0.16,P=0.69.Adverse events of ESZ were consistent with the known profile of the medication including dysgeusia(30%,mild),sedation(20%,mild)and headache(20%,moderate to severe).CONCLUSION Results do not support the hypothesis of a specific positive effect of ESZ compared to PBO for measures of PTSD and associated sleep disturbance.

A COMPARATIVE STUDY OF IMOVANE AND ESTAZOLAM TREATMENT ON SLEEP DISTURBANCES

Twentysix Patients with sleep disturbances who had completed therapy with hypnotics were observed under single-blind and self-comparable method for 7 days each. We found that patients treated with imovane or estazolam had no statistical differences with respect to sleep time onset. total sleep time. nocturnal awakening. feeling after awakening, dream, drug side effects and sleep qualirty.Imovane performed better than estazolam in sleep time onset and total sleep time. From this study, imovane can he recommended as a new hypuotic to treat patients with sleep disturbances.

Design, Synthesis, and Hypnotic Activity of Pyrazolo[1 ,5-a] pyrimidine Derivatives

On the basis of the Zaleplon structure, novel pyrazolo[l,5-a]pyrimidines were designed and prepared for studies on their hypnotic activity. This paper reported the synthesis of twelve new 5-methyl-7-substituted-pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives by using simple starting materials such as propane dinitrile and triethyl orthoformate. The structures of the derived target compounds were confirmed by their IR and 1H-NMR spectroscopic data. The preliminary pharmacological evaluations indicated that some compounds showed hypnotic activity, while derivative 1c was the most polent one.

Psychopharmacological Profile of Hydroalcoholic Extract and P-Hydroxybenzoic Acid Obtained from <i>Bourreria huanita</i>(Boraginaceae) in Mice

Bourreria huanita (Lex.) Hemsl. (Boraginaceae) is a very rare and highly appreciated tree in Mesoamerica for its medicinal properties and beauty. It grows in a region extending from central Mexico to Costa Rica. Ethnobotanical surveys have shown that the infusion of dried flowers is popularly used as a tranquilizer to cure several diseases. In the present study we report the isolation of p-hydroxybenzoic acid (pHBZ) obtained from the hydroalcoholic extract (HE) of B. huanita, and the effect of both, the extract and the compound on the central nervous system in mice. HE of B. huanita (100, 150, 300 mg/kg) and pHBZ (10 mg/kg) were orally administered to mice and 1 h later, behavioral tests were performed. The effects of HE and pHBZ were tested by pentylenetetrazole (PTZ) and strychnine (STR) induced seizures, pentobarbital-induced hypnosis, the forced swimming test and the tail suspension test, the elevated plus maze, apomorphine-induced stereotypy and the climbing test, the inhibitory avoidance test and the open-field test. B. huanita extract produced hypnotic, anxiolytic and antidepressant effects in animals, with no change in motor performance. On the other hand, the extract did not reduce PTZ and STR-induced convulsions, apomorphine-induced stereotypy or climbing. Moreover, no changes were observed in the animals’ memory. The compound pHBZ was effective only in the depression tests. The results obtained in the present study suggest that B. huanita exhibited sedative, antidepressant and hypnotic activities in mice, and that the antidepressant activity may be mediated by an isolated compound identified as pHBZ.

Remifentanil Has Sufficient Hypnotic and Amnesic Effect for Induction of Anesthesia by Itself

With a small-dose remifentanil, some patients showed no reaction and did not remember it postoperatively. We, therefore, hypothesized that remifentanil may decrease the level of consciousness and/or exhibit amnesic effect when stimulations are avoided. Thirty-patients were divided into two groups: non-stimulation group and stimulation group. Anesthesia was induced with 1 micro-g·kg?1·min?1 of remifentanil using no additional hypnotic agent. In the non-stimulation group, patients were left free from any stimulation except non-invasive blood pressure monitoring. In the stimulation group, patients were asked to follow verbal commands. The level of consciousness was evaluated with electroencephalogram and BIS-value derived from it. In the non-stimulation group, all patients reached the decreased level of consciousness in 5 minutes. In the stimulation group, however, 14 patients were judged to be still conscious. 10 patients could open their mouth at the 5th minute, but 9 of these 10 patients did not remember it postoperatively. In conclusion, remifentanil, with no additional anesthetics, exhibited hypnotic and amnesic effects when stimulations were kept minimal.

THE CLINICAL ANALYSIS OF HYPNOTICS AND SEDATIVES USED IN OUTPATIENT CLINICS IN GENERAL HOSPITAL

Aim. To statistic the usage of hypnotics and sedatives in outpatient and emergency clinics prescriptions in one day. Method. Check all prescriptions on April 29, 1987 and November 13, 1995 in order to know the quantity, kind and distribution of hypnotics and sedatives in different outpatient departments. Result. There were 1 319 prescriptions on April 29, 1987. Among them, hypnotics and sedatives were 122(9. 24%); in comparing with 2 065 prescriptions on November 13, 1995, hypnotics and sedatives were 141 (6. 82%). Benzodiazepine used more than 80% in all prescriptions. Conclusion. The possibility of long-term low-dosage using benzodiazepine is present. It must strengthen the control and education to avoid the drug-abuse.

Global trend of nondrug and nonsedativehypnotic treatment forinsomnia: a bibliometric study

OBJECTIVE: To present a bibliometric analysis of global scientific publications on the nondrug and nonsedative hypnotic treatment of insomnia with regard to influential institutions, publications, countries, research hotspots,trends, and frontiers. METHODS: A literature review was conducted by searching the Web of Science Core Collection(Wo SCC) and China National Knowledge Infrastructure(CNKI) databases to identify all publications related to the nondrug and nonsedative hypnotic treatment of insomnia from 2000 to 2021. Eligible publications were reviewed, including annual publication increments, citation analyses, international collaborations, and keyword analyses. The data were analysed using Cite Space(vers5.8.R3, 6.1.R2 and 6.1.6, College of Computing and Informatics, Philadelphia, PA, USA) and virtualized by knowledge maps. RESULTS:In total, 9832 publications were included in this analysis. The results from the WoSCC showed that the United States of America(Count = 2268, 40.33%), Stanford University(Count = 141, 2.51%), and the United States Department of Health and Human Services were the leading country, institute, and funding agency regarding the number of publications, respectively. “Cognitive-behavioural therapy” was the most popular research topic generated from the cocited reference. The most frequently co-occurring keywords were insomnia, cognitive behavioural therapy, disorder, depression, quality of life, Meta-analysis, older adult, sleep, prevalence and efficacy, while keywords including clinical practice guideline, guideline, and Tai Chi remained popular after 2021. Circadian rhythm was the strongest research frontier for 2000-2021. In China, Chengdu University of Traditional Chinese Medicine(Count = 69, 4.79%) was the most productive institute in this field. The most frequently co-occurring keywords from Chinese literature were sleep disorder, sleep quality, acupuncture and moxibustion, Parkinson's disease, transcranial magnetic stimulation, health education, music therapy, chronic insomnia, quality of life, and nonmotor symptoms. Traditional Chinese medicine was the strongest research frontier for 2019-2021. CONCLUSION: This bibliometric study provides an exhaustive mapping encompassing pertinent institute, publications, influential articles, researchers and topics of the global trend of nondrug and nonsedative hypnotic treatment for insomnia. The results show that the research trend has shifted from primary studies on the efficacy and safety of nondrug and nonsedative hypnotic treatment for insomnia to comorbidity studies. Clinical practice guidelines will potentially become the research frontier for this field post-2021. The findings are important for researchers, clinicians, journal editors, and policymakers working in the field of nondrug and nonsedative hypnotic treatment for insomnia to understand the strengths and potentials in the current studies and guide future clinical practice, research, and science policy.

Determination of five neurotransmitters in the rat brain for the study of the hypnotic effects of Ziziphi Spinosae Semen aqueous extract on insomnia rat model by UPLC-MS/MS

Ziziphi Spinosae Semen(ZSS) has been used for treatment of insomnia in China for centuries. To reveal the influence of insomnia on the levels of the neurotransmitters including serotonin(5-HT), glutamic acid(Glu),γ-aminobutyric acid(GABA),noradrenaline(NE) and dopamine(DA), and to study the role of ZSS aqueous extract in the treatment of insomnia, an UPLC-ESIMS/MS method was developed and validated for simultaneous determination of five neurotransmitters in the rat brain. The brain samples were pretreated by one-step direct protein precipitation with acetonitrile. The analytes were detected in positive mode with multiple reaction monitoring(MRM) and the procedure was completed in less than 10 min. The method showed a good linearity(R^2 >0.9967) with the other validation parameters were within acceptance range. The results indicated that the concentration of 5-HT, GABA and DA is significantly lower(P < 0.01) in para-chlorophenylalanine(PCPA)-induced insomnia rat model group, while Glu and NE significantly higher than those in control group(P < 0.01). Treatment with ZSS aqueous extract(4 or 8 g·kg^1·d^-1 for seven days) could ameliorate the symptoms of insomnia by significantly changing the levels of the neurotransmitter parameters mentioned above. The data obtained in this study demonstrate that ZSS aqueous extract could ameliorate the symptoms of insomnia by modulating the levels of monoamines and amino acid neurotransmitters in the brain.

Sedative and Hypnotic Effects and Transcriptome Analysis of Polygala tenuifolia in Aged Insomnia Rats

Objective:To study the sedative and hypnotic effects and underlying mechanisms of Polygala tenuifolia(PT)on treating aged insomnia rats.Methods:Sixty Sprague-Dawley male rats were divided into 6 groups by a random number table,including control group,model group,diazepam group(0.92 mg/kg),as well as PT low-,medium-and high-dose groups(0.0875,0.175,0.35 g/kg,respectively),10 rats in each group.Aged insomnia rat model was established with subcutaneous injection of D-galactose for 42 days and then intraperitoneal injection of para-chlorophenylalanine for 3 days.PT and diazepam were respectively given to aged insomnia rats by intragastric administration for 7 days after model establishment.Then the rats were investigated by body weight,Morris water maze test,pentobarbital test,enzyme-linked immunosorbent assay,and transcriptome sequencing.Results:Compared with the model group,PT increased the body weight,improved memory ability,and prolonged pentobarbital-induced sleep time of aged insomnia rats(P<0.01 or P<0.05).The medium dose of PT also increased the neurotransmitter levels of 5-hydroxytryptamine(5-HT)and gamma-aminobutyric acid(GABA),and decreased the level of Glu in the hippocampus of aged insomnia rats(P<0.05 or P<0.01).Twenty-four differentially expressed genes(DEGs)were overlapped among model group,medium-dose PT group,and diazepam group in transcriptome analysis.Fuom and Pcp2 were down-regulated by the treatment of medium-dose PT(P<0.01 or P<0.05).The metabolic pathways of PT were relatively less than diazepam(91 vs.104).Conclusions:The sedative and hypnotic effects of PT in aged insomnia rats might be related to neuro,metabolism pathways,especially through GABAergic signaling pathway.It provided more effective herb choice for the treatment of senile insomnia.

Sedative–hypnotic effect of YZG-330 and its effect on chloride influx in mouse brain cortical cells

This study was to examine the sedative–hypnotic effect of YZG-330 and its influence on Cl−influx in mouse cortical cells.In a sleep time-prolongation test in which mice were administered a threshold dosage of sodium pentobarbital(ip),YZG-330(0.125,0.5 and 2 mg/kg,po)prolonged the sleep time by 25%(P40.05),64%(Po0.01)and 506%(Po0.001),respectively.Thereafter,treatment with YZG-330 permitted mice that had woken up after the threshold dose of sodium pentobarbital(ip)to fall asleep again.A Cl−-sensitive fluorescent probe,N-(ethoxycarbonylmethyl)-methoxyquinolinium bromide(MQAE),was used to determine the effect of YZG-330 on Cl−influx.YZG-330(0.3,0.6 and 1.5 mM)increased Cl−influx in mouse cortical cells in a concentration-dependent manner.These data suggest that YZG-330 has a hypnotic effect in mice,and the effect may be related to an increase in Cl−influx in cortical cells.

Hypnotic Effects of A Novel Anti-Insomnia Formula on Drosophila Insomnia Model

Objective： To assess the biological effects of the six-herb mixture Anti-lnsomia Formula （AIF） extract using caffeine-induced insomnia Drosophila model and short-sleep mutants. Methods： Caffeine- induced insomnia wild-type Drosophila and short-sleep mutant flies minisleep （runs） and Hyperkinetic Y（Hk Y） were used to assess the hypnotic effects of the AIF in vivo. The night time activity, the amount of night time sleep and the number of sleep bouts were determined using Drosophila activity monitoring system. Sleep was defined as any period of uninterrupted behavioral immobility （0 count per minute） lasting 〉 5 min. Night time sleep was calculated by summing up the sleep time in the dark period. Number of sleep bouts was calculated by counting the number of sleep episodes in the dark period. Results： AIF at the dosage of 50 mg/mL, effectively attenuated caffeine-induced wakefulness （P〈0.01） in wild-type Canton-S flies as indicated by the reduction of the sleep bouts, night time activities and increase of the amount of night time sleep. AIF also significantly reduced sleeping time of short-sleep Hk y mutant flies （P〈0.01）. However, AIF did not produce similar effect in mns mutants. Conclusion： AIF might be able to rescue the abnormal condition caused by mutated modulatory subunit of the tetrameric potassium channel, but not rescuing the abnormal nerve firing caused by Shaker gene mutation. This study provides the scientific evidence to support the use of AIF in Chinese medicine for promoting sleep quality in insomnia.

Research on Hypnotic and Anticonvulsant Activities of Total Alkaloids in Leaves of Eucommia ulmoides

Objective To study the hypnotic and anticonvulsant activities of the leaves of Eucommia ulmoides（LEU）,the total alkaloids were extracted from LEU using water-acid method.Methods Mice were divided into five groups,including groups contained total alkaloids in three different doses,negative and positive control groups.Direct hypnotic experiment in mice,pentobarbital sodium synergistic experiment,and anticonvulsant experiment were used.The numbers of spontaneous activities,sleep rate,sleep latency,sleep time,convulsion rate,and convulsion latency of the mice were recorded and analyzed.Results The total alkaloids from LEU could increase the sleep rate,significantly lengthen the sleep time,and shorten the sleep latency of mice.Even the low dose of total alkaloids（0.33 g/kg）showed significantly different activities with negative control group（physiological saline）with the synergistic effect of the superthreshold dose of pentobarbital sodium.Furthermore,the total alkaloids efficiently inhibited the convulsion caused by nikethamide.Conclusion The total alkaloids from LEU have the excellent sedative,hypnotic,and anticonvulsant activities in mice,with high safety and little drug side effects.Therefore,they have the protential development prospects in sedative-hypnotic drugs.