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Biomedical subjects

Christian Guilleminault

Publications and source records attributed to Christian Guilleminault.

At least 19 recordsLinked to original sources
PubMed2006

Attention-deficit/hyperactivity disorder with obstructive sleep apnea: a treatment outcome study.

BACKGROUND: Children diagnosed with attention-deficit/hyperactivity disorder (ADHD), based on Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) criteria, may also have obstructive sleep apnea (OSA), but it is unclear whether treating OSA has similar results as methylphenidate (MPH), a commonly used treatment for ADHD. METHODS: This study enrolled 66 school-age children, referred for and diagnosed with ADHD, and 20 healthy controls. Polysomnography (PSG) performed after ADHD diagnosis showed the presence of mild OSA. After otolaryngological evaluation, parents and referring physicians of the children could select treatment of ADHD with MPH, treatment of OSA with adenotonsillectomy or no treatment. Systematic follow-up was performed six months after initiation of treatment, or diagnosis if no treatment. All children had pre- and post-clinical interviews; pediatric, neurologic, psychiatric and neurocognitive evaluation; PSG; ADHD rating scale, child behavior checklist (CBCL) filled out by parents and teacher; test of variables of attention (TOVA); and the quality of life in children with obstructive sleep disorder questionnaire (OSA-18). RESULTS: ADHD children had an apnea-hypopnea index (AHI)>1<5 event/hour; 27 were treated with MPH, 25 had adenotonsillectomy, and 14 had no treatment. The surgical and MPH groups improved more than the non-treatment group. When comparing MPH to post-surgery, the PSG and questionnaire sleep variables, some daytime symptoms (including attention span) and TOVA subscales (impulse control, response time and total ADHD score) improved more in the surgical group than the MPH group. The surgical group had an ADHD total score of 21.16+/-7.13 on the ADHD rating scale (ADHD-RS) post-surgery compared to 31.52+/-7.01 pre-surgery (p=0.0001), and the inattention and hyperactivity subscales were also significantly lower (p=0.0001). Finally, the results were significantly different between surgically and MPH-treated groups (ADHD-RS p=0.007). The surgical group also had a TOVA ADHD score lower than -1.8 and close to those obtained in normal controls. CONCLUSION: A low AHI score of >1 considered abnormal is detrimental to children with ADHD. Recognition and surgical treatment of underlying mild sleep-disordered breathing (SDB) in children with ADHD may prevent unnecessary long-term MPH usage and the potential side effects associated with drug intake.

Adenoidectomy↗
PubMed2006

Effect of atrial overdrive pacing on obstructive sleep apnea in patients with systolic heart failure.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) is associated with cardiovascular disease. Preliminary studies suggested breathing improvement in patients with apnea and heart disease when atrial overdrive pacing was applied during sleep. However, more recent studies do not show significant beneficial effect for atrial overdrive pacing in OSA. To further investigate this relationship, we conducted a randomized clinical trial evaluating the effect of atrial overdrive pacing on sleep-related breathing events in subjects with OSA and systolic heart failure. PATIENTS AND METHODS: We screened 33 subjects with symptoms consistent with OSA. On a screening overnight polysomnography (PSG), 15 subjects with mean age of 74 years (standard deviation (SD) 6.6) and ejection fraction of 38% (SD 14.4%) had OSA defined as having an apnea/hypopnea index (AHI) of > or =15 per hour of sleep. These subjects underwent additional PSGs including a night with atrial overdrive pacing (O), a night with pacemaker rate set at 40-50 beats per minutes (N), and a positive airway pressure titration night. The O and N nights were consecutive and the order was randomized. For O, the pacemaker rate was set at 15 beats higher than the average nightly heart rate (determined from the screening night). RESULTS: At baseline, mean AHI was 34.8 (15.5) and mean SaO(2) nadir was 85% (3.2%). Average heart rate was significantly higher on O nights compared to N nights (p<0.005). The apnea index (AI) was statistically lower on O nights compared to N nights (18+/-16.6 vs. 24+/-18.9, p<0.05). However, AHI and minimum and average O(2) saturations did not differ significantly between O and N nights. Interestingly, AHI improved statistically significantly on O nights in younger subjects. CONCLUSIONS: While statistically reliable, the small pacing-related reduction in sleep-disordered breathing (SDB) events is of unknown clinical significance. By contrast, continuous positive airway pressure (CPAP) dramatically improved AHI, AI, respiratory arousal index, and O(2) saturation. Thus our data suggest that overdrive pacing exerts a mild effect on respiratory events in some heart failure patients with OSA; however, atrial overdrive pacing was not therapeutically effective for improving airway patency and sleep-related respiratory function.

Adult↗
PubMed2006

A double-blind, placebo-controlled, crossover study of sildenafil in obstructive sleep apnea.

BACKGROUND: Sildenafil prolongs the action of cyclic guanosine monophosphate and nitric oxide by inhibiting cyclic guanosine monophosphate-specific phosphodiesterase 5. It is largely used for erectile dysfunction, a highly prevalent condition in obstructive sleep apnea. Because nitric oxide promotes upper airway congestion, muscle relaxation, and pulmonary vasodilation, the aim of this study was to establish the impact of a single 50-mg dose of sildenafil on the sleep of patients with severe obstructive sleep apnea. METHODS: Thirteen [corrected] middle-aged men with severe obstructive sleep apnea were consecutively selected for this double-blind, placebo-controlled, crossover study. Exclusion criteria were obesity, cardiovascular and/or respiratory disease, and conditions that interfere with sleep. All-night polysomnography was preceded by a single 50-mg dose of sildenafil or matching placebo randomly administered at bedtime, after a washout period of 1 week. RESULTS: In comparison to placebo, a single 50-mg dose of sildenafil significantly increased the percentage of total sleep time with an arterial oxygen saturation of less than 90% (mean +/- SD, 15.6% +/- 9.6% vs 7.9% +/- 3.3%, [corrected] P < .01), without a difference in the nadir of oxygen desaturation. The mean arterial oxygen saturation also decreased (92.1% +/- 1.9% vs 93.8% +/- 1.3%, P = .03), [corrected] and the desaturation index increased (30.3 +/- 14.5 [corrected] events per hour vs 18.5 +/- 9.1 [corrected] events per hour, P < .001). There was an increase in apnea-hypopnea index (48.1 +/- 20.8 [corrected] events per hour vs 32.3 +/- 11.3 [corrected] events per hour, P = .001), [corrected] involving mostly obstructive events. CONCLUSION: In patients with severe obstructive sleep apnea, a single 50-mg dose of sildenafil at bedtime worsens respiratory and desaturation events.

Cross-Over Studies↗
PubMed2006

Chronic fatigue, unrefreshing sleep and nocturnal polysomnography.

BACKGROUND AND PURPOSE: To investigate the complaint of unrefreshing sleep with study of sleep electroencephalogram (EEG) in patients with chronic fatigue. PATIENTS AND METHODS: Fourteen successively seen patients (mean age: 41.1 9.8) who complained of chronic fatigue but denied sleepiness and agreed to participate were compared to 14 controls (33.6+/-10.2 years) who were monitored during sleep recorded in parallel. After performing conventional sleep scoring we applied Fast Fourier Transformation (FFT) for the delta 1, delta 2, theta, alpha, sigma 1, sigma 2, beta EEG frequency bands. The presence of non-rapid eye movement (NREM) sleep instability was studied with calculation of cyclic alternating pattern (CAP) rate. Two-way analysis of variance (ANOVA) was performed to analyze FFT results and Mann-Whitney U-test to compare CAP rate in both groups of subjects. RESULTS: Slow wave sleep (SWS) percentage and sleep efficiency were lower, but there was a significant increase in delta 1 (slow delta) relative power in the chronic fatigue group when compared to normals (P<0.01). All the other frequency bands were proportionally and significantly decreased compared to controls. CAP rate was also significantly greater in subjects with chronic fatigue than in normals (P=0.04). An increase in respiratory effort and nasal flow limitation were noted with chronic fatigue. CONCLUSIONS: The complaints of chronic fatigue and unrefreshing sleep were associated with an abnormal CAP rate, with increase in slow delta power spectrum, affirming the presence of an abnormal sleep progression and NREM sleep instability. These specific patterns were related to subtle, undiagnosed sleep-disordered breathing.

Adult↗
PubMed2006

Daytime sleepiness with and without cataplexy in Chinese-Taiwanese patients.

BACKGROUND AND PURPOSE: Investigation of Chinese-Taiwanese patients with excessive sleepiness, but no association with other sleep disorders, and with the presence or absence of cataplexy. PATIENTS AND METHODS: Thirty-five patients, successively referred between 2002 and 2004, underwent polysomnography (PSG), repeat multiple sleep latency test (MSLT), and human leukocyte antigen (HLA) typing. Three patients without cataplexy also had cerebrospinal fluid (CSF) hypocretin measurements. RESULTS: DQB1*0602 was associated with cataplexy in over 90% of Chinese-Taiwanese cases. Absence of cataplexy and <2 sleep-onset REM periods (SOREMPs) was seen in only two subjects, but presence of two SOREMPs did not dissociate DQB1*0602 positive and negative or cataplexy positive and negative subjects. As a group, narcoleptics with cataplexy had a higher number of SOREMPs, and the mean sleep latency was much shorter in narcoleptics with cataplexy than in the non-cataplectic patients, independent of the number of SOREMPs. CONCLUSIONS: Chinese-Taiwanese patients with cataplexy present with similar HLA findings as Black and Caucasian patients, but the presence of two or more SOREMPs in Chinese-Taiwanese patients is not a sufficient diagnostic tool to identify narcolepsy. When cataplexy is not present, description of PSG nd HLA findings may be a better approach than using a label with little scientific significance, allowing for better collection of patients' phenotype.

Adolescent↗
PubMed2006

A case-control sleep study in children with polyarticular juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the relationship between clinical manifestations and sleep abnormalities in patients with juvenile rheumatoid arthritis (JRA). METHODS: Twenty-one patients with active polyarticular JRA and 20 healthy controls were enrolled consecutively. Pain and functional impairment were assessed with standardized, validated Brazilian questionnaires. Sleep evaluation was based on parent reporting of their child's sleep habits and polysomnography; subjects underwent an adaptation night in the sleep laboratory. Sleep architecture was analyzed and spectral analysis of non-rapid eye movement (REM) sleep was carried out by electroencephalography. RESULTS: Patients with JRA exhibited higher indexes of periodic leg movements (PLM; p = 0.02), isolated leg movements (LM), and arousals, as well as increases in alpha activity in non-REM sleep (all p < 0.01), in spite of similar frequency of sleep complaints in comparison to controls. Among JRA patients, greater alpha activity in non-REM sleep was observed in the participants with greater joint involvement assessed by the Escola Paulista de Medicina-Pediatric Range of Motion Scale (p = 0.03) or joint count (p = 0.02). Correlation was observed between morning stiffness and PLM and/or LM (rS = 0.75, Sr = 0.74, p < 0.001 for both), and between self-rating scores of pain and alpha activity in non-REM sleep (rS = 0.74, p < 0.001). CONCLUSION: Pain symptoms and disability are related to sleep fragmentation in patients with active polyarticular JRA.

Adolescent↗
PubMed2006

Sleepwalking, a disorder of NREM sleep instability.

BACKGROUND AND PURPOSE: Thirty-two chronic sleepwalkers who were part of a larger, previously reported sleepwalking group all achieved control of sleepwalking after undergoing treatment for an associated sleep disorder. In the current study, all records were blindly scored to perform a cyclic alternating pattern (CAP) analysis. PATIENTS AND METHODS: Thirty-two young adult chronic sleepwalkers had polysomnography (PSG) on initial nights without sleepwalking events, as did age-matched normal controls and patients with mild sleep-disordered breathing (SDB). More than 90% of these patients with mild SDB had upper airway resistance syndrome (UARS). Ten randomly selected PSGs for sleepwalkers and matched controls also had quantitative electroencephalographic (EEG) analysis using Fast Fourier Transformation (FFT) with determination of delta power for each non-rapid eye movement (NREM)-REM sleep cycle. RESULTS: Compared to normal controls, an investigation of CAP in sleepwalkers demonstrated the presence of an abnormal CAP rate with a decrease in phase A1 and an increase in phases A2 and A3 on non-sleepwalking nights. The results of CAP analysis in sleepwalkers were similar to those obtained in age-matched UARS patients. Furthermore, the analysis of the first four NREM-REM sleep cycles reconfirmed the presence of an important decrease in delta power in sleep cycles 1 and 2 during a non-sleepwalking night in sleepwalkers compared to normal controls. CONCLUSIONS: The presence of both 'hypersynchronous slow delta' and 'burst of delta waves' have been reported in sleepwalkers, but their significance is controversial. These EEG patterns are similar to phase A1 (and possibly A2) of the CAP. Proper analysis of the sleep EEG of sleepwalkers should integrate CAP analysis. Sleepwalkers on a non-sleepwalking night present instability of NREM sleep, as demonstrated by this analysis. This instability is similar to the one noted in UARS patients. Subtle sleep disorders associated with chronic sleepwalking constitute the unstable NREM sleep background on which sleepwalking events occur. A subtle associated sleep disorder should be systematically searched for and treated in the presence of sleepwalking with abnormal CAP.

Adult↗
PubMed2006

The effect of CNS activation versus EEG arousal during sleep on heart rate response and daytime tests.

OBJECTIVE: To induce a heart rate change in normal subjects using auditory stimulation without inducing EEG arousals and to assess the effects on daytime functioning and compare results to auditory stimulation leading to short EEG arousals. METHODS: Six normal young men initially randomized into two groups (A and B) underwent 4 nights of nocturnal polysomnography (normal sleep on night 1, auditory stimulation without EEG arousal or normal sleep on nights 2 and 3 using Latin square design, and auditory stimulation with EEG arousal on night 4). MSLT and PVT were performed during days following nights 2-4. RESULTS: MSLT and PVT results showed significant differences after EEG arousal compared to stimulation without EEG arousal and to normal sleep; there were no significant differences after normal sleep compared to stimulation without EEG arousal. RR interval showed significant differences during undisturbed sleep compared to stimulation without EEG arousal and to stimulation with EEG arousal; RR interval without EEG arousal also differed significantly from RR interval with EEG arousal. CONCLUSION: Activation of the brain-stem can lead to autonomic nervous system (ANS) response without objective consequences the next day. SIGNIFICANCE: ANS responses induced by auditory stimulation during sleep without EEG arousal do not have the same effects on daytime sleepiness and performance as sleep fragmentation associated with EEG arousals.

Acoustic Stimulation↗
PubMed2006

Vascular endothelial dysfunction in patients with mild obstructive sleep apnea syndrome.

BACKGROUND: We investigated endothelial dysfunction, an early manifestation of atherosclerosis, in patients with mild obstructive sleep apnea syndrome (OSAS) (5/h < AHI < 15/h). PATIENTS AND METHODS: Endothelium-dependent and -independent vasodilatory function was tested in 10 patients with mild OSAS, 12 healthy controls and 20 subjects with moderate to severe OSAS using the hand vein compliance technique. RESULTS: Maximum endothelium-dependent vasodilation to bradykinin (Emax) was significantly blunted in patients with mild OSAS (68.6 +/- 30.2 %) compared to healthy controls (94.8 +/- 9.5 %; p < 0.05; moderate to severe OSAS: 57.1 +/- 23.4 %; p = 0.33). Mean endothelium-independent venodilation was not altered. After 160.7 +/- 82.2 nights of CPAP therapy, mean Emax was significantly improved to 90.8 +/- 23.8 % (p < 0.01 vs. baseline; p = 0.7 vs. healthy controls) in 7 patients with mild OSAS. CONCLUSIONS: Systemic endothelium-dependent venodilation is markedly reduced in subjects with mild OSAS, which may imply adverse cardiovascular consequences. CPAP-treatment leads to a sustained restoration of endothelial dysfunction in these patients and is thus highly recommended.

Adolescent↗
PubMed2006

Antihypertensive treatment and endothelium-dependent venodilation in sleep-disordered breathing.

Sleep-disordered breathing (SDB) is associated with nitric oxide-mediated endothelial dysfunction and increased risk and prevalence of cardiovascular disease, namely, arterial hypertension. A substantial number of patients do not comply with nasal continuous positive airway pressure (nCPAP) treatment. These individuals have a persisting increased cardiovascular risk. Antihypertensive drugs have shown to improve nitric oxide-mediated endothelial dysfunction. We therefore designed a study to test the hypothesis that antihypertensive drug treatment in hypertensive patients with SDB can have beneficial effects on nitric oxide-mediated endothelial function in the absence of treatment with nCPAP. Six patients with SDB and treated arterial hypertension, six normotensive patients with SDB, and six healthy controls received sleep studies and an assessment of venodilation using the dorsal hand vein technique. Polygraphic measures using standard overnight sleep studies and dose-response curves to the endothelium-dependent vasodilator bradykinin were obtained. Maximum nitric-oxide-mediated dilation to bradykinin was significantly higher in patients with SDB who had received antihypertensive drug treatment compared to normotensive SDB patients. Nitric oxide-mediated dilation in hypertensive patients with SDB was similar to nitric oxide-mediated dilation in healthy controls. After treatment of normotensive patients with SDB using nCPAP, nitric oxide-mediated dilation in normotensive SDB patients was comparable to nitric oxide-mediated dilation in SDB patients with antihypertensive drug treatment and normal controls. Hypertensive patients with SDB present a normal nitric oxide-mediated endothelial function under antihypertensive treatment.

Aged↗
PubMed2006

Upper airway resistance syndrome: a long-term outcome study.

UNLABELLED: This prospective study aimed to assess symptomatic evolution of patients diagnosed with Upper Airway Resistance Syndrome (UARS) four and half years after the initial UARS diagnosis. For this purpose, 138 UARS patients were contacted by mail between 43 and 69 months after the initial evaluation; 105 responded to the letter and 94 patients accepted to undergo new clinical and polysomnographic evaluations. Initial and follow-up polysomnographic recordings were scored using the same criteria. RESULTS: Of the 94 patients who completed the follow-up examination, none of them were using nasal CPAP. It was related to refusal by insurance providers to provide equipment based on initial apnea-hypopnea index (AHI) in 90/94 subjects. Percentage of patients with sleep related-complaints significantly increased over the four and half year period: daytime fatigue, insomnia and depressive mood increased by 12 to 20 times. Reports of sleep maintenance sleep onset insomnia and depressive mood was significantly increased. Hypnotic, antidepressant and stimulant prescription increased from initial to follow-up visit (from 11.7% to 61.7%; from 3.2% to 25.5% and from 0% to 9.6%, respectively) with antidepressant given as much for sleep disturbance as mood disorder. The polysomnography results at follow-up showed that 5 subjects had AHI compatible with Obstructive Sleep Apnea Syndrome (OSAS) but overall, respiratory disturbance index had no significant change. Total sleep time was significantly reduced compared to initial visit. CONCLUSIONS: Many UARS patients remained untreated following initial evaluation. Worsening of symptoms of insomnia, fatigue and depressive mood were seen with absence of treatment of UARS.

Adolescent↗
PubMed2006

The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study.

STUDY OBJECTIVE: Examine the effects of donepezil on sleep and rapid eye movement (REM) sleep electroencephalogram (EEG) in patients with Alzheimer disease, using polysomnography, and the correlation between REM sleep EEG parameters and cognitive scores. DESIGN: Randomized, double-blind, placebo-controlled design. SETTINGS: Two sleep research centers, University Hospital. PARTICIPANTS: Thirty-five patients with mild to moderate Alzheimer disease, allocated to 2 groups: donepezil treated (n=17) and placebo treated (n=18). INTERVENTION: Patients were administered donepezil or placebo. OUTCOME MEASURES: Polysomnography with REM sleep EEG spectral analysis and cognitive evaluation using the Alzheimer Disease Assessment Scale, cognitive subscale, were performed at baseline and after 3 and 6 months. Slowing ratio was the ratio between slow and fast EEG frequency bands. Cognitive and sleep data were analyzed using analysis of variance. Correlations between cognitive improvement and REM sleep EEG were also calculated. RESULTS: REM sleep increased significantly after 3 and 6 months of donepezil treatment compared with baseline and placebo (p < .01). Overall theta (p = .04), frontal theta (p < .01) and frontal delta (p = .03) absolute power during REM sleep decreased after 6 months of donepezil treatment. The occipital slowing ratio decreased during treatment (p = .04). REM sleep overall and frontal and centroparietal alpha absolute power significantly correlated with the cognitive improvement rate on the Alzheimer Disease Assessment Scale, cognitive subscale (r = 0.75, r = 0.71, r = 0.78); p < .01). CONCLUSIONS: Donepezil treatment enhanced REM sleep and reduced slow frequencies of REM sleep EEG, suggesting a possible action upon REM sleep-related cholinergic neurons in patients with Alzheimer disease. Furthermore, REM sleep alpha power may predict the cognitive response to donepezil.

Aged↗
PubMed2006

Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine.

A significant number of patients with obstructive sleep apnea neither tolerate positive airway pressure (PAP) therapy nor achieve successful outcomes from either upper airway surgeries or use of an oral appliance. The purpose of this paper, therefore, was to systematically evaluate available peer-reviewed data on the effectiveness of adjunctive medical therapies and summarize findings from these studies. A review from 1985 to 2005 of the English literature reveals several practical findings. Weight loss has additional health benefits and should be routinely recommended to most overweight patients. Presently, there are no widely effective pharmacotherapies for individuals with sleep apnea, with the important exceptions of individuals with hypothyroidism or with acromegaly. Treating the underlying medical condition can have pronounced effects on the apnea/hypopnea index. Stimulant therapy leads to a small but statistically significant improvement in objective sleepiness. Nonetheless, residual sleepiness remains a significant health concern. Supplemental oxygen and positional therapy may benefit subsets of patients, but whether these therapies reduce morbidities as PAP therapy does will require rigorous randomized trials. PAP therapy has set the bar high for successful treatment of sleep apnea and its associated morbidities. Nonetheless, we should strive towards the development of universally effective pharmacotherapies for sleep apnea. To accomplish this, we require a greater knowledge of the neurochemical mechanisms underlying sleep apnea, and we must use this infrastructure of knowledge to design well-controlled, adequately powered studies that examine, not only effects on the apnea/hypopnea index, but also the effects of pharmacotherapies on all health related outcomes shown beneficial with PAP therapy.

Benzhydryl Compounds↗
PubMed2006

Pharmacological management of sleep apnoea.

Obstructive sleep apnoea poses a significant health hazard that is associated with leading causes of mortality and morbidity. Nasal continuous positive airway pressure is the primary treatment modality, with surgical treatments as alternatives. Oral appliances and pharmacological therapy remain adjunctive modalities. Non-specific treatments include weight loss, postural therapy and behavioural measures. Pharmacotherapy goals include the reduction of risk factors for sleep apnoea; correction of underlying predisposing metabolic diseases, such as hypothyroidism or acromegaly; treatment of associated symptoms, including excessive daytime sleepiness; and prevention of apnoeas/hypopnoeas. This paper reviews data supporting the treatment of sleep apnoea with various pharmacological agents, including intranasal corticosteroids, decongestant sprays, nicotine therapy, opiate antagonists, methylxanthine derivatives, oestrogen and progesterone, testosterone, thyroid hormone, growth hormone therapy for acromegaly, beta-blockers, alpha-adrenergic agonists, angiotensin-converting enzyme inhibitors, glutamate antagonists, acetazolamide, selective serotonin re-uptake inhibitors, tricyclic antidepressants, physostigmine, modafinil and TNF-alpha antagonists, in addition to supplemental oxygen, and carbon dioxide inhalation. Some of these drugs have received very little testing and are the subject of few research articles.

Disease Management↗
PubMed2006

Emerging pharmacotherapeutic agents for insomnia: a hypnotic panacea?

The burden of insomnia has had a significant effect not only on the socioeconomic matrix, but also the medical terrain, as signified by the increased morbidity and mortality of its associated psychiatric and organic sequelae. To this end, a plethora of pharmacotherapeutic agents have been recently introduced that address the vital need to combat insomnia and prevent the perpetuation in its chronic form. The previously and currently dispensed barbiturates and benzodiazepines, respectively, have paved the way for newer agents that are purported to be just as effective, or even more so, with a favourable profile in all domains of sleep. In assessing both published clinical studies and unpublished reports conducted on these emerging agents, this article profiles the most contemporary, therapeutic options in lieu of older hypnotics, over-the-counter medications and supplements. Furthermore, this paper aims to indicate both the future course of hypnotics and the developments currently in progress.

Humans↗