piperidines and Sleep-Wake-Disorders

Topics: Humans; Nervous System Diseases; Piperidines; Receptors, Histamine H3; Sleep; Sleep Wake Disorders

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders encountered in clinical practice. Whilst dementia has long been synonymous with AD, it is becoming more widely accepted as part of the clinical spectrum in PD (PDD). Neuropsychiatric complications, including psychosis, mood and anxiety disorders, and sleep disorders also frequently co-exist with cognitive dysfunctions in AD and PDD patients. The incidence of such symptoms is often a significant source of disability, and may aggravate pre-existing cognitive deficits. Management of AD and PDD involves both pharmacological and non-pharmacological measures. Although research on pharmacological therapies for AD and PDD has so far had some success in terms of developing symptomatic treatments, the benefits are often marginal and non-sustained. These shortcomings have led to the investigation of non-pharmacological and novel treatments for both AD and PD. Furthermore, in light of the diverse constellation of other neuropsychiatric, physical, and behavioural symptoms that often occur in AD and PD, consideration needs to be given to the potential side effects of pharmacological treatments where improving one symptom may lead to the worsening of another, rendering the clinical management of these patients challenging. Therefore, the present article will critically review the evidence for both pharmacological and non-pharmacological treatments for cognitive impairment in AD and PD patients. Treatment options for other concomitant neuropsychiatric and behavioural symptoms, as well as novel treatment strategies will also be discussed.

Topics: Alzheimer Disease; Animals; Antiparkinson Agents; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Exercise Therapy; Galantamine; Humans; Indans; Memantine; Parkinson Disease; Piperidines; Rivastigmine; Sleep Wake Disorders; Treatment Outcome

Topics: Aged; Azepines; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypnotics and Sedatives; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines; Sleep Wake Disorders

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.

Topics: Aged; Alzheimer Disease; Animals; Basal Ganglia Diseases; Bradycardia; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Double-Blind Method; Drug Evaluation; Drug Interactions; Female; Galantamine; Gastrointestinal Diseases; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Memantine; Meta-Analysis as Topic; Mice; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Single-Blind Method; Sleep Wake Disorders; Treatment Outcome

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug-drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single- and multiple-dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug-drug interactions. The incidence of weight loss is very similar between donepezil- and placebo-treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day(-1) or switching to morning dosing can reduce these events to the levels of placebo-treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Piperidines; Sleep Wake Disorders; Weight Loss

This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.. For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS₁₇) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS₁₇ insomnia factor score and KSS score, correlation between the HDRS₁₇ insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6.. At baseline, HDRS₁₇ insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo.. Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function.. ClinicalTrials.gov identifier: NCT03018340.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Piperidines; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders; Treatment Outcome; Urea; Young Adult

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Caregivers; Donepezil; Female; Humans; Hypnotics and Sedatives; Indans; Male; Melatonin; Neuropsychological Tests; Nootropic Agents; Nursing Homes; Piperidines; Polysomnography; Pyridines; Risperidone; Sleep Wake Disorders; Treatment Outcome; Zolpidem

Rapid eye movement (REM) sleep is greatest in the developing brain, is driven by acetylcholine, and may represent a protected time for neuroplasticity. Recently published data from our lab observed that children with autism spent significantly less time in this state during a single night recording than did typically developing children and those with developmental delay without autism. The objective of this study was to determine whether or not donepezil can increase the REM % in children with diagnosed autism spectrum disorder (ASD) found to have REM % values of at least two standard deviations below expected for age.. Five subjects found to have an ASD (ages 2.5-6.9 years) and demonstrated deficits in REM sleep compared with within-lab controls were enrolled in a dose finding study of donepezil. Each subject was examined by polysomnography for REM sleep augmentation after drug administration.. REM sleep as a percentage of Total Sleep Time was increased significantly and REM latency was decreased significantly after drug administration in all subjects. No other observed sleep parameter was changed significantly.. Donepezil can increase the amount of time that children with an ASD spend in the REM sleep state. A double-blind, placebo-controlled trial is needed to assess the association between REM sleep augmentation and learning, cognition, and behavior in such children.

Topics: Autistic Disorder; Child; Child Development Disorders, Pervasive; Child, Preschool; Developmental Disabilities; Donepezil; Dose-Response Relationship, Drug; Electrocardiography; Humans; Indans; Male; Nootropic Agents; Piperidines; Polysomnography; Sleep; Sleep Wake Disorders; Sleep, REM; Treatment Outcome

The intraoperative wake-up test is a standard procedure for early recognition of neurologic complications after posterior correction of idiopathic scoliosis. In this prospective, single-blinded cohort study, the impact of the wake-up test and the opioid used for anesthesia on the quality of the patients' sleep after scoliosis surgery was investigated up to 12 months postoperatively.. Patients were classified into three groups: posterior instrumentation with wake-up test using remifentanil, anterior instrumentation without wake-up test using sufentanil, and posterior instrumentation with wake-up test using sufentanil. The quality of sleep was assessed using the Pittsburgh Sleep Quality Index questionnaire preoperatively as well as 3, 6, and 12 months postoperatively. In addition, data were collected on patients' age, weight, and sex, as well as the duration of the operation and anesthesia, amount of blood loss, specific opioid dosages, and wake-up test times. Statistical analysis was conducted using the Mann-Whitney, Kruskal-Wallis, and Wilcoxon tests.. There were no differences between groups with regard to baseline characteristics. No explicit recall was assessed through all groups. At 3 and 6 months postoperatively, the sleep quality in the posterior-remifentanil group was significantly poorer than preoperatively and compared with the anterior- and posterior-sufentanil groups. No significant differences in wake-up test times between groups undergoing posterior instrumentation occurred.. This study suggests that patients undergoing scoliosis surgery with an intraoperative wake-up test using remifentanil had impaired sleep quality that lasted up to 6 months postoperatively. No deterioration in sleep quality was observed with sufentanil. Large randomized trials are now needed to confirm these preliminary results.

Topics: Adolescent; Adult; Analgesics, Opioid; Cohort Studies; Female; Humans; Male; Monitoring, Intraoperative; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Scoliosis; Single-Blind Method; Sleep Wake Disorders; Wakefulness

Postoperative behavioral disorders are common in children, but the occurrence in infants is not yet clear. In the present study we focus on postoperative sleep disturbances, which we hypothesized would be more common after sevoflurane anesthesia than propofol-remifentanil anesthesia.. In total, 39 infants 4-6-mo-old were prospectively enrolled and randomized to receive either a combination of propofol and remifentanil (n = 17) or sevoflurane and fentanyl anesthesia (n = 22) for surgical repair of cleft lip-gum-palate. Postoperative observations were blinded. The parents kept a sleep diary for 2 wk before admission and 2 wk after returning home. The diary included information about how many times the infant awoke during the night and was difficult to comfort and the longest duration of continuous sleep during the night.. Longest continuous sleep was significantly longer in the sevoflurane group (median 7.2 h) compared with the propofol-remifentanil group (median 5.1 h, P < 0.05). No other significant difference was found between groups. Sleep pattern was impaired after surgery in both groups compared with that before surgery (P < 0.01), but it was considered by the parents to be back to normal after a median of 10 days, with no significant difference between groups.. Postoperative sleep disturbances occur in infants after both propofol-remifentanil and sevoflurane anesthesia. Sevoflurane seems to be associated with less impairment of postoperative sleep than propofol-remifentanil in the first weeks after repair of cleft lip and palate in infants.

Topics: Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Cleft Lip; Cleft Palate; Follow-Up Studies; Humans; Infant; Methyl Ethers; Piperidines; Postoperative Period; Propofol; Prospective Studies; Remifentanil; Reproducibility of Results; Severity of Illness Index; Sevoflurane; Single-Blind Method; Sleep; Sleep Wake Disorders; Surveys and Questionnaires; Time Factors

Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs.. 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed.. AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters.. Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Galantamine; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Polysomnography; Rivastigmine; Sleep Stages; Sleep Wake Disorders

The aim of this study was to observe the effects of donepezil on both the cognitive function and sleep patterns in patients of Alzheimer's Type Dementia (ATD), especially to determine the relationship between the improvement of cognitive function and the amount of rapid eye movement (REM) sleep. A total of 12 patients (7 females, 5 males; age, 73.0 +/- 6.8) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria of probable AD were studied. These patients presented with mild to moderate dementia, which was confirmed by a Clinical Dementia Rating score of 1 or 2. Following baseline examinations consisting of the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and polysomnography (PSG), 5 mg of donepezil was administered to the patients at breakfast every day. All patients were reassessed 6 weeks later using the same examinations. With sleep patterns, the percentage of REM sleep to total sleep time increased after the administration of donepezil. In addition, it was also found that sleep efficiency was increased and sleep latency was shortened by this administration. Although the ADAS-Jcog score did not decrease significantly, there was significant positive correlation between the decrease of the ADAS-Jcog score and the increase in the percentage of REM sleep. These results indicate the increase action of REM sleep due to activate central cholinergic systems and the possibility to improve sleep conditions due to one-time administration after breakfast of donepezil in mild to moderate ATD. It is concluded that the increase in REM sleep may reflect the improvement of cognitive function in ATD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Polysomnography; Psychiatric Status Rating Scales; Sleep; Sleep Wake Disorders; Sleep, REM

As cholinergic mechanisms may be at least partially responsible for hallucinations and delusions in Parkinson's disease (PD), we conducted an open study in 8 PD patients to assess the efficacy and tolerability of the cholinesterase inhibitor donepezil, 5 mg at bedtime for two months, in the treatment of these complications. Hallucinations and delusions improved significantly in all patients. Donezepil was overall well tolerated, but a deterioration in motor disability was noted in 2 out of 8 patients.

Topics: Aged; Aged, 80 and over; Basal Nucleus of Meynert; Cholinergic Fibers; Cholinesterase Inhibitors; Delusions; Donepezil; Female; Hallucinations; Humans; Indans; Male; Movement; Parkinson Disease; Piperidines; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Outcome

Brofaromine is a selective and reversible inhibitor of monoamine oxidase A. The efficacy and safety of this compound as compared with tricyclic antidepressants, classical monoamine oxidase inhibitors and placebo has been demonstrated in several clinical trials. The present 6-week, double-blind, randomized trial compared brofaromine with imipramine in in-patients with major depression. Brofaromine was as effective as imipramine in the treatment of major depression, but exhibited a different side-effect profile, in particular lacking the anticholinergic and certain cardiovascular side-effects of the tricyclic imipramine, but more likely to induce sleep disturbances. In this study, in-patients were examined, since the majority of controlled clinical trials on depressed patients conducted so far have focused on the evaluation of out-patients. If one assumes that a different degree of severity of depression exists between these two patient groups, then the results of those trials conducted on out-patients cannot readily be transferred to in-patients.

Topics: Adolescent; Adult; Aged; Antidepressive Agents, Tricyclic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospitalization; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Sleep Wake Disorders

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Regression Analysis; Sleep Wake Disorders

Ritanserin, a selective and potent serotonin-2 antagonist, is effective in the treatment of a variety of syndromes related to anxiety and depression, including dysthymic disorder. In animals and healthy volunteers, ritanserin specifically increases slow-wave sleep and the hypothesis arises that this effect on sleep may contribute to its therapeutic properties. Therefore, we studied the effects of ritanserin on sleep in a group of dysthymic patients (DSM-III). Polygraphic recording as well as subjective evaluations of the quality of sleep were performed before and at the end of a 4-week period of double-blind medication with either ritanserin (10 mg o.d. in the morning) or placebo. At baseline, patients showed at fragmented and superficial sleep, with low amounts of slow wave sleep. Ritanserin significantly increased Slow Wave Sleep and changed the frequency and distribution of some stage transitions during the night. No other sleep parameters were modified by ritanserin treatment.

Topics: Adult; Depressive Disorder; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Ritanserin; Serotonin Antagonists; Sleep Stages; Sleep Wake Disorders; Sleep, REM

A controlled double blind clinical trial has been conducted in 16 patients with "angina pectoris" in order to investigate the effect of Perexiline maleate as compared with prenilamine. Perexiline at the dose of 400 mg/die and prenilamine at the dose of 120 mg/die have been administered over a period of 4 weeks each. Between these periods placebo has been administered for two weeks. The number of attacks of angina and the number of tablets of nitroglycerine used per week by the patient during each period has been used for the evaluation. Furthermore ECG at rest and after exercise has been performed every two weeks. Our results statistically evaluated show a definite antianginal effect of Perexiline. According to our experience Perexiline should be considered the drug of choise in the treatment of angina complicated by bradicardia, left ventricular failure, bronchospasm, and in angina unresponsive to other drugs.

Topics: Angina Pectoris; Blood Pressure; Body Weight; Drug Evaluation; Electrocardiography; Headache; Humans; Perhexiline; Piperidines; Prenylamine; Pulse; Sleep Wake Disorders

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Chronic Pain; Disease Models, Animal; Fluorobenzenes; Male; Mice; Neuralgia; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

The purpose of the study was to evaluate the influences of cholinesterase inhibitors on sleep pattern and sleep disturbance. A total of 87 mild to moderate stage dementia patients who were not on cholinesterase enzyme inhibitor and memantine treatment were included in the study. The dementia patients were treated with donepezil, galantamine or rivastigmine, depending on the preference of the clinician. Fifty-five dementia patients (63.2 %) completed the study. Twenty-three elderly subjects, who had normal cognitive functions, were included in the study as the control group. The Pittsburgh Sleep Quality Index was used for evaluating the sleep quality at the beginning and at the final assessment. The improvement in sleep quality was better with regard to changes in Pittsburgh Sleep Quality Index scores with galantamine treatment compared to the donepezil and the control groups. A significant decrease in Pittsburgh Sleep Quality Index scores was detected in the galantamine group after treatment. Although statistically not significant, rivastigmine decreased and donepezil increased the Pittsburgh Sleep Quality Index scores after treatment. Dementia patients who had a poor sleep quality (n: 36), the rate of improvement in sleep disturbance was 81.8 % in the galantamine group, 75 % in the rivastigmine, and 50 % in the donepezil group. Galantamine may be the first choice of cholinesterase inhibitor in mild to moderate dementia patients in terms of improving sleep quality.

Topics: Aged; Aged, 80 and over; Chi-Square Distribution; Cholinesterase Inhibitors; Dementia; Donepezil; Dose-Response Relationship, Drug; Female; Galantamine; Humans; Indans; Male; Piperidines; Rivastigmine; Severity of Illness Index; Sleep Wake Disorders; Treatment Outcome

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.

Topics: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Orexin Receptors; Piperidines; Rats; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep Wake Disorders; Stereoisomerism; Structure-Activity Relationship

The present study was undertaken to clarify the effects of anti-dementia drugs on sleep pattern in rats. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscle of rats for the electroencephalogram (EEG) and electromyogram (EMG), respectively. EEG and EMG were recorded with an electroencephalograph. SleepSigh ver. 2.0 was used for analysis of the sleep-wake state. Total times of waking, non-rapid eye movement (non-REM) sleep, and rapid eye movement (REM) sleep were measured from 10:30 to 16:30. Galantamine had no significant influence on the sleep pattern. On the other hand, donepezil and memantine showed significant increases in sleep latency and total waking time and a decrease in total non-REM sleep time. Furthermore, memantine decreased total REM sleep time. To investigate the characteristics of non-REM sleep in detail, non-REM sleep was classified as stage 1, 2, or 3 according to the depth of sleep. Different from donepezil and galantamine, memantine significantly decreased stage 1 and increased stage 3 in non-REM sleep. From these findings, it can be concluded that galantamine caused no sleep disturbance, different from donepezil and memantine.

Topics: Animals; Dementia; Donepezil; Dose-Response Relationship, Drug; Electroencephalography; Electromyography; Excitatory Amino Acid Antagonists; Galantamine; Indans; Male; Memantine; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Sleep; Sleep Wake Disorders; Sleep, REM

Dementia is a neurologic disorder presenting memory impairment as a main symptom. It is well known that patients often complain of sleep disturbance as an associated symptom in dementia. It has been reported that donepezil caused sleep disturbance, but little is known about the effect of galantamine on sleep-wake patterns. In the present study, we investigated the effects of anti-dementia drugs on sleep-wake patterns in sleep-disturbed rats. Single administration of donepezil and galantamine caused no significant effect on sleep-wake patterns at doses used in the present study in rats. On the other hand, piracetam caused a significant decrease in sleep latency at a dose of 500 mg/kg. Next, we examined the changes in sleep-wake patterns from repeated administration of donepezil, galantamine and piracetam. Donepezil caused significant increases in sleep latency and total wake time and decrease in total non-rapid eye movement sleep time at a dose of 1 mg/kg. However, galantamine caused no effect on sleep-wake patterns. Piracetam caused significant decreases in sleep latency and total wake time at a dose of 500 mg/kg. From these results, it is concluded that donepezil deteriorated sleep disturbance, and piracetam caused somnolence. In addition, galantamine showed no influence on the sleep.

Topics: Animals; Donepezil; Galantamine; Indans; Male; Nootropic Agents; Piperidines; Piracetam; Rats; Rats, Wistar; Sleep; Sleep Wake Disorders; Wakefulness

The GABA(A) receptor system is implicated in a number of central nervous system (CNS) disorders, making GABA(A) receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABA(A) receptor complex, reflecting the very strict structural requirements for GABA(A) receptor recognition and activation. A large number of the compounds showing agonist activity at the GABA(A) receptor site are structurally derived from the GABA(A) agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA(A) receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA(A) receptors insensitive to benzodiazepines and containing alpha(4)beta(3)delta subunits. The results of ongoing clinical studies on the effect of the partial GABA(A) agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA(A) receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA(A) receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA(A) agonist derived from THIP, have been performed. In this connection, a series of GABA(A) ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA(A) agonist activity to selective antagonist effect.

Topics: Analgesics, Non-Narcotic; Anxiety; GABA Agonists; GABA Antagonists; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Humans; Hypnotics and Sedatives; Isoxazoles; Piperidines; Sleep Wake Disorders

A severe intractable delirium caused by the basal forebrain vascular lesion and its dramatic recovery after donepezil administration were reported. A 68-year-old man had suffered for a month from delirium of mixed type caused by the right basal forebrain vascular lesion after surgery for craniopharyngioma. Magnetic resonance imaging (MRI) showed hemorrhagic infarcts in the head of the right caudate nucleus and the right basal forebrain of the medial septal nucleus, diagonal band of Broca and nucleus basalis of Meynert. He had been treated with anti-psychotics, anti-depressants and hypnotics, which resulted in little improvement. Donepezil administration dramatically improved his intractable delirium at the 19th post-donepezil administration day, but this was followed by amnestic symptoms. Clinical correlates of delirium with the basal forebrain lesion and efficacy of donepezil support the hypocholinergic theory of delirium.

Topics: Aged; Basal Ganglia Cerebrovascular Disease; Basal Nucleus of Meynert; Craniopharyngioma; Delirium; Donepezil; Humans; Indans; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Pituitary Neoplasms; Postoperative Complications; Prosencephalon; Sleep Wake Disorders; Vision Disorders

In clinical trials, sleep problems have been identified as side effects of donepezil, an acetylcholinesterase (AChE)-inhibiting medication for the treatment of Alzheimer's disease (AD). Poor sleep quality can exacerbate behavior problems among patients and add to the burden experienced by their caregivers. We examined the relationship between co-use of donepezil and hypnotics in a large sample of persons with AD living in the community.. This secondary data analysis used cross-sectional subjects from a multiwave, consumer-based survey of AD caregivers conducted in 1997 and 1998. Rates of hypnotic use among users and non-users of donepezil were compared using chi-square analysis for independent samples, and multivariate logistic regression was used to identify significant independent correlates of hypnotic use.. A total of 2638 caregivers completed at least 1 study wave. Use of hypnotics was higher in the donepezil subgroup (9.78%) compared with subjects not taking this medication (3.93%). Multivariate analysis demonstrated that donepezil use was independently linked to increased hypnotic use after controlling for the potential confounding effects of disruptive behavior and depressive symptoms (adjusted odds ratio = 3.34, p <.001).. In this large community sample, donepezil use was statistically linked to increased hypnotic use. Because sleep quality may be a critical issue for persons with AD and their caregivers, more rigorous evaluation of sleep problems linked to AChE-inhibitor treatment is indicated.

Topics: Aged; Alzheimer Disease; Caregivers; Chi-Square Distribution; Cholinesterase Inhibitors; Cross-Sectional Studies; Data Collection; Donepezil; Female; Humans; Hypnotics and Sedatives; Indans; Male; Piperidines; Polypharmacy; Sleep Wake Disorders

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dreams; Female; Humans; Indans; Male; Piperidines; Sleep Wake Disorders

Treatments in Alzheimer's disease include treatment of cognitive impairment and behavioral manifestations (agitation, depression, anxiety, delusions). It should be noted that many non cognitive behaviors may have some relations to underlying cognitive impairment. In the not too distant future, physicians can expect to see a variety of medications and controversies over the benefits of slowing symptoms with cholinergic therapeutics approved for clinical use and (or) preventing progression of Alzheimer's disease assessed in clinical trials will emerge.

Topics: Aggression; Alzheimer Disease; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Depression; Donepezil; Humans; Indans; Mental Disorders; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Sleep Wake Disorders; Tacrine

Nine subjects who believed themselves to be poor sleepers, of mean age 58 years, took a placebo for 7 days, then ritanserin 5 mg for 20 days, followed by 3 days on placebo. Sleep was recorded electrophysiologically on 2 nights during baseline, 2 early drug nights, 2 late drug nights and the 2nd and 3rd withdrawal nights. Ratings of sleep quality were collected each morning. Ritanserin, a 5HT2 antagonist, caused a persistent doubling of the amount of EEG slow wave sleep, without altering the total duration of sleep. Ritanserin decreased the frequencies of awakening and after about a week it appeared to improve the subjective quality of sleep. Sleep was then impaired during withdrawal, as indicated by decreased duration and poorer subjective quality, being worst on the 3rd withdrawal night.

Topics: Attention; Electroencephalography; Female; Humans; Male; Middle Aged; Piperidines; Ritanserin; Serotonin Antagonists; Sleep; Sleep Stages; Sleep Wake Disorders; Substance Withdrawal Syndrome; Wakefulness

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Time Factors

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Pacing, Artificial; Drug Evaluation; Electrocardiography; Electrophysiology; Female; Humans; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Tachycardia; Time Factors

Topics: Aggression; Criminal Psychology; Feeding and Eating Disorders; Headache; Humans; Nitriles; Phenothiazines; Piperidines; Sleep Wake Disorders; Tranquilizing Agents

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Autistic Disorder; Autonomic Nervous System; Catatonia; Female; Hallucinations; Humans; Hypnotics and Sedatives; Liver Function Tests; Male; Mental Disorders; Nausea; Neurotic Disorders; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Schizophrenia; Sleep Wake Disorders; Stimulation, Chemical; Sweating; Tremor; Vascular Diseases; Vomiting

Topics: Amphetamine; Animals; Antidepressive Agents; Appetite Depressants; Bemegride; Caffeine; Cats; Central Nervous System Stimulants; Chlorphentermine; Desipramine; Electroencephalography; Ephedrine; Glycolates; Humans; Hydroxybutyrates; Imipramine; Mice; Narcolepsy; Pemoline; Phentermine; Piperidines; Rabbits; Rats; Sleep Wake Disorders; Strychnine; Sympathomimetics

Topics: Anticonvulsants; Glutethimide; Health Services; Hypnotics and Sedatives; Piperidines; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders

Topics: Barbiturates; Hypnotics and Sedatives; Piperidines; Sleep Wake Disorders

Topics: Chlorpromazine; Humans; Piperidines; Sleep Wake Disorders

Topics: Aged; Anticonvulsants; Chronic Disease; Disease; Hypnotics and Sedatives; Piperidines; Sleep Wake Disorders

Topics: Anticonvulsants; Health Services; Hypnotics and Sedatives; Piperidines; Sleep Wake Disorders

Topics: Anticonvulsants; Glutethimide; Hypnotics and Sedatives; Piperidines; Sleep Wake Disorders

Topics: Anticonvulsants; Glutethimide; Piperidines; Sleep Wake Disorders

Topics: Anticonvulsants; Piperidines; Piperidones; Sleep Wake Disorders