Efficacy of mirtazapine in obstructive sleep apnea syndrome. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. The therapeutic effect of theophylline in mild obstructive sleep Apnea/Hypopnea syndrome: results of repeated measurements with portable recording devices at home. A double-blind, randomized trial of sabeluzole--a putative glutamate antagonist--in obstructive sleep apnea. Surface tension forces in sleep apnea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial. Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome. Reduction of sleep-disordered breathing after physostigmine. Effect of doxapram on obstructive sleep apnea. Effect of clonidine in obstructive sleep apnea. Cardiovascular effects of mibefradil in hypertensive patients with obstructive sleep apnea. Indices of severity of obstructive sleep apnea syndrome do not change during medroxyprogesterone acetate therapy. Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome. Naltrexone improves blood gas patterns in obstructive sleep apnoea syndrome through its influence on sleep. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. [Effect of oral almitrine on the sleep apnea syndrome]. Beneficial effect of donepezil on obstructive sleep apnea: a double-blind, placebo-controlled clinical trial. Theophylline in obstructive sleep apnea. A double-blind evaluation. A double-blind trial of protriptyline in the treatment of sleep apnea syndrome. Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Proof of concept study: does fenofibrate have a role in sleep apnoea syndrome? Does nasal decongestion improve obstructive sleep apnea? Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Obstructive Sleep Apnea and Hypopnea Efficacy and Safety of a Long-Acting beta2-Agonist. Buspirone administration to sleep apnea patients. The effects of aminophylline on sleep and sleep-disordered breathing in patients with obstructive sleep apnea syndrome. Protriptyline in obstructive sleep apnea: a double-blind trial.
Decreased serotonergic facilitation of upper-airway motor neurons during sleep has been postulated as an important mechanism rendering the upper airway vulnerable to obstruction in patients with obstructive sleep apnea syndrome (OSA). Although serotonin reuptake inhibitors have been shown to produce modest reductions in the apnea-hypopnea index (AHI) during non-rapid eye movement (NREM) sleep, they have not been proven to be generally effective as treatments for OSA. Conversely, antagonists of type 3 (5-HT3) serotonin receptors effectively have been shown to reduce the frequency of central apneas during rapid eye movement (REM) sleep in a rodent model of sleep-related breathing disorder. We sought to determine whether mirtazapine, a mixed 5-HT2/5-HT3 antagonist that also promotes serotonin release in the brain would effectively reduce AHI during both NREM and REM sleep in patients with OSA.
                A randomized, double-blind, placebo-controlled, 3-way crossover study of mirtazapine in patients with OSA.
                Laboratory studies were conducted in the Center for Sleep and Ventilatory Disorders at the University of Illinois Medical Center.
                Seven adult men and 5 adult women with newly diagnosed (treatment-naïve) and medically uncomplicated OSA were randomized into the study.
                Each subject self-administered oral medications 30 minutes before bedtime each night for 3 consecutive 7-day treatment periods. These treatments comprised (1) placebo, (2) 4.5 mg per day of mirtazapine, and (3) 15 mg per day of mirtazapine. The order of treatments was randomized for each subject, and orders were counterbalanced for the overall study.
                Each subject charted his or her sleep-wake schedule throughout the study and completed the Stanford Sleepiness Scale every 2 hours during the seventh day of each treatment period. Subjects were studied by laboratory polysomnography on the seventh night of each treatment period. With respect to placebo treatment, 4.5 mg of mirtazapine significantly reduced the AHI in all sleep stages to 52%, with 11 of 12 subjects showing improvement over placebo; 15 mg of mirtazapine reduced the AHI to 46%, with 12 of 12 subjects showing improvement over placebo. Sleep fragmentation was reduced only by the higher dose of mirtazapine. Gross changes in sleep architecture were unremarkable.
                Daily administration of 4.5 to 15 mg of mirtazapine for 1 week reduces AHI by half in adult patients with OSA. This represents the largest and most consistent drug-treatment effect demonstrated to date in a controlled trial. These findings suggest the therapeutic potential of mixed-profile serotonergic drugs in OSA and provide support for future studies with related formulations. Mirtazapine also is associated with sedation and weight gain-2 negative side effects in patients with OSA. In view of the above, we do not recommend use of mirtazapine as a treatment for OSA. Increased nasal airflow resistance (NAR) may contribute to the pathophysiology of obstructive sleep apnoea syndrome (OSAS) but studies investigating the effects of relieving nasal obstruction in OSAS have produced differing results. There are no reports of intranasal corticosteroid therapy in adult OSAS patients with reversible nasal obstruction.
                We evaluated an intranasal corticosteroid, fluticasone propionate, in 24 consecutive snorers with associated rhinitis using a randomised, placebo controlled, crossover design. Patients underwent polysomnography, snoring noise, and NAR measurements at baseline and after each 4 week treatment period.
                Twenty three patients completed the protocol and were divided into an apnoeic group (group A; 13 patients) and a non-apnoeic snoring group (group S; 10 patients) based on an apnoea-hypopnoea frequency (AHI) of > or =10/h or <10/h. AHI was significantly lower following treatment with fluticasone than with placebo in the total population (median (quartile range) 11.9 (22.6) v 20 (26.3); p<0.05) and in group A (23.3 (21.3) v 30.3 (31.9); p<0.05). Median (95% confidence interval) within subject differences for AHI were -3.2 (-17.7 to -0.2) in the total population and -6.5 (-29.5 to 1.8) in group A. NAR was also lower on fluticasone (2.74 (1.21) v 3.27 (1.38), p<0.01), within subject difference being -0.45 (95% CI -0.87 to -0.21). The changes in AHI and NAR in group A were significantly correlated (r=0.56; p<0.05). Snoring noise and sleep quality were unchanged but daily diary records indicated subjective improvements in nasal congestion and daytime alertness with fluticasone (p<0.02).
                Intranasal fluticasone is of benefit to some patients with OSAS and rhinitis. The data suggest that this form of nasal obstruction may contribute to the pathophysiology of OSAS. Theophylline has been recommended in the literature as a therapeutic option in mild OSAHS. In mild obstructive sleep apnea/hypopnea syndrome (OSAHS), night-to-night variability of parameters of sleep-disordered breathing has been determined rarely, we therefore compared the results of serial measurements of sleep apnea/hypopnea parameters under the effects of placebo and theophylline. To this end, we measured the individual variability of the apnea-hypopnea index (AHI) for seven consecutive nights using a portable sleep apnea recording device, in 14 subjects (2 women, 12 men, mean age +/- [standard deviation] 50 +/- 8 years), treated with placebo or theophylline in a double blind, randomized crossover fashion, whose polysomnographically measured AHI was 13 +/- 5 /hour. Under theophylline treatment in comparison with placebo we observed a small but significant decrease in mean (of seven days) AHI at home (9.2 +/- 7.7 to 6.7 +/- 6.1 /hour), which was independent of body position. The night-to-night variability of AHI at home was high (9. 2 +/- 8.9 /hour; range: 0-31.4 /hour) and proved to be independent of body position and alcohol consumption. - In mild OSAHS, repeated measurements of sleep related breathing events should be performed. Theophylline showed a small but clinically insignificant potencial to reduce AHI. The effect of sabeluzole (SAB), an agent with anti-excitatory amino acid activity, on sleep, breathing and daytime symptoms was investigated in 13 patients with obstructive sleep apnea (OSA). There was marked interindividual variation in both the effect on sleep and breathing and the plasma concentration of SAB. However, individual plasma drug concentration was highly correlated (r = 0.82, p = 0.02) with a reduction of the oxygen desaturation index during sleep (ODI) after treatment with SAB. Further investigation of this and agents of this type are warranted in patients with OSA. Upper airway obstruction in patients with sleep apnea may occur in the absence of a negative intraluminal upper airway pressure. We hypothesized that surface tension forces may play a role in the pathogenesis of obstructive sleep apnea (OSA), and that a topical soft tissue lubricant might reduce the severity of OSA. Ten male patients (age 49 +/- 10 yr [mean +/- SD]; body mass index [BMI] 31 +/- 5 kg/m2) with OSA (apnea-hypopnea index [AHI] 17 +/- 9) were studied. The arousal index was lower with the lubricant treatment than with placebo (mean difference 8; 95% CI 4 to 11 arousals/h; p = 0.001). The AHI was lower, in each of the 10 patients, on the lubricant treatment than the placebo (mean change 10, 95% CI 6 to 13; p = 0.0003). The lower AHI with lubricant as compared with placebo was present in both supine (mean difference 13; 95% CI 5 to 20; p = 0.006) and nonsupine (mean difference 6; 95% CI 0 to 12; p = 0.05) positions. There was no significant difference in sleep architecture between the lubricant and placebo treatments. Application of a topical lubricant consistently reduced the severity of OSA. This implies a pathogenetic role for surface tension forces in OSA, and a potential role for surface tension-reducing agents in the treatment of OSA. The role of drug therapy in the treatment of the sleep apnea/hypopnea syndrome is unclear. In a randomised, double-blind, placebo-controlled study, we investigated the value of 14-day therapy with protriptyline (20 mg daily) or acetazolamide (250 mg 4 times per day) on symptoms and on the frequency of apneas, hypopneas, arousals, and 4% desaturations in 10 patients with obstructive sleep apnea/hypopnea syndrome. Overall, protriptyline did not have a significant effect either on symptoms or on any of the above polysomnographic criteria. Acetazolamide reduced the apnea/hypopnea frequency [placebo 50 +/- 26 (SD); acetazolamide 26 +/- 20/h of sleep, p less than 0.03] and tended to decrease the frequency of 4% desaturations (placebo 29 +/- 20; acetazolamide 19 +/- 16/h of sleep, p = 0.06). Despite these physiological improvements, acetazolamide did not significantly improve symptoms and paraesthesiae were common. Contrary to earlier studies, we conclude that protriptyline may have a limited role in the treatment of the sleep apnea syndrome. The reason why acetazolamide produced a physiological, but not a symptomatic, response requires further investigation. The cholinesterase inhibitor physostigmine (PHYS) was investigated in a double-blind, placebo-controlled, randomized, crossover trial of 10 male patients with moderate to severe obstructive sleep apnea. PHYS (0.12 microg/minute/kg, 7-hour infusion) reduced mean apnea/hypopnea index (AHI) by 13.6 (95% confidence interval [CI], 2.2-25.1) corresponding to 21.4% (95% CI, -5.5 to 47.9) and increased minimum SaO2 by 8.7% (95% CI, -0.3 to 17.7) corresponding to 23.2% (95% CI, 4.8-41.3). During the last third of the night, coinciding with predicted plasma concentration steady state, non-REM sleep AHI decreased by 19.2 (95% CI, 0.1-38.3) or 14.9% (95% CI, -43.6 to 77.7) and REM AHI by 33.8 (95% CI, 13.7-54.0) or 67.5% (95% CI, 49.7-85.3). Mean total sleep time was reduced by 74 minutes (95% CI, 33.9-114.9), but patients with the least pronounced sleep shortening had the largest reduction of AHI (r = 0.73, p < 0.02). The nocturnal decline in heart rate was reduced by PHYS. Moreover, resting (early-night placebo heart rate) was positively correlated with proportional reduction of REM apnea index (r = 0.69, p < 0.02). Body mass index was negatively correlated with reduction of REM AHI (r = 0.77, p < 0.02). This, predominantly REM-related, reduction of obstructive sleep apnea after PHYS may provide a new treatment option if the effects are maintained in long-term studies. To determine whether treatment with a respiratory stimulant, doxapram hydrochloride, would improve obstructive sleep apnea, we administered the drug to four patients with this disease. Subjects were given a bolus of doxapram, 0.5 mg X kg-1 lean body mass, followed by a 1 mg X min-1 infusion throughout the night on one night and placebo another night. Doxapram produced improvement in the average oxyhemoglobin desaturation during apneic and hypopneic episodes and decreased average apnea length, but did not change the average number of oxyhemoglobin desaturations per hour of sleep or sleep efficiency. We conclude that doxapram, when administered at levels known to increase ventilatory drive, does not decrease the number of disordered breathing events during sleep but does cause termination of these events at higher levels of oxyhemoglobin saturation. The current treatment of choice for obstructive sleep apnea is continuous positive airway pressure. However, not all patients tolerate this form of therapy. We evaluated the effect of clonidine hydrochloride, an alpha 2-adrenergic agonist with REM-suppressant activity, in eight male patients with obstructive sleep apnea. In each patient, sleep-stage distribution and breathing pattern in two all-night sleep studies performed during a 10-day course of clonidine were compared with those of two control and two placebo nights. A dose of 0.2 mg of clonidine administered orally at bedtime totally suppressed REM sleep in two patients. In the other six patients, the same dose decreased percent time spent in REM sleep from a control of 13.4 +/- 1.0 to 8.6 +/- 1.4% (mean +/- SEM, p less than 0.05). The latency to REM sleep increased in the latter group from a control of 129 +/- 9 to 308 +/- 24 min (p less than 0.001). Clonidine had no effect on the frequency and duration of non-REM breathing abnormalities. Under clonidine, the level of nocturnal hypoxemia improved in six patients. This was due to a total suppression of REM and the consequent lack of REM apneas in two patients. In four patients, upper airway obstruction disappeared during period of unsuppressed REM sleep, and SaO2 remained above 90% throughout this sleep stage. Clonidine transformed the pattern of sleep-disordered breathing during unsuppressed REM in the other two patients from that of repetitive obstructive hypopneas associated with persistent hypoxemia to occlusive apneas and cyclical hypoxemia. These results were observed consistently in all patients during both clonidine-sleep studies.(ABSTRACT TRUNCATED AT 250 WORDS) Hypertension is often seen in obstructive sleep apnea (OSA) and is characterized by increased sympathetic activity, depressed baroreflex and accentuated vascular responsiveness. The objective of this study was to investigate the effects of the new T-selective calcium channel blocker mibefradil on invasively measured blood pressure (BP) and heart rate in hypertensive patients with OSA.
                The present study was a double-blind, randomized and placebo-controlled before and after trial in two parallel groups. Fifty-three men aged 23 69 years with systemic hypertension and OSA were recruited from the Outpatient Department of the Marburg University Sleep Laboratory and hospitalized for 10 days. Mibefradil (50 mg) or placebo were given orally in the morning for 8 days. The main outcome measure was the mean arterial (radial) BP monitored continuously during nocturnal sleep and during standardized daytime physical and psychological performance testing.
                Mibefradil lowered mean arterial BP and heart rate with (SD) during the entire measurement period compared with placebo: -7.25 (9.59) vs -2.11 (8.43) mmHg (P=0.039) and -4.83 (5.94) vs -1.34 (4.13) bpm (P=0.022), respectively. Both effects were observed during nocturnal sleep and performance testing, including graded exercise. Adverse events did not differ compared with placebo.
                Mibefradil is an effective but well-tolerated antihypertensive that also lowers heart rate over 24 h in OSA, in conditions known to increase BP. Medroxyprogesterone acetate (MPA) could change the frequency and/or duration of disordered breathing events (DBEs) in patients with the obstructive sleep apnea (OSA) syndrome by altering pharyngeal muscle function relative to diaphragm and external intercostal function. Ten male patients with OSA syndrome underwent an initial polysomnogram with monitoring of EEG, EOG, myohyoid EMG, oral and nasal airflow, abdominal and thoracic movement, and SaO2. The patients were then entered into a randomized, double-blind crossover study using MPA, 150 mg/day, and MPA placebo. Each patient took tablets for one week and then had a second polysomnogram. After a three week washout, the patient again took tablets for a week prior to the third and final sleep study. There was no significant difference between drug and placebo for DBE time (expressed as a percentage of sleep time), DBE frequency, DBE mean duration or mean fall in O2 saturation during DBEs. We conclude that treatment with MPA does not alter indices of severity of the OSA syndrome. Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT3) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA.
                A prospective, parallel-groups, single-center trial in patients with OSA.
                35 adults with apnea hypopnea index (AHI) > 10; range 10-98.
                Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10.
                AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep.
                Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA. Endogenous opiates have been shown to depress ventilation, and could therefore play a role in sleep apnoea syndrome (SAS). Hence, opiate antagonists have been used to treat SAS. The improvement they seem to give in blood-gas monitoring could derive either from a direct blocking of endorphins that inhibit respiration or else, indirectly, through an influence on sleep patterns. The present study used a double blind cross-over protocol to investigate the relationships between the effects on blood-gas and on sleep patterns of the oral opiate antagonist naltrexone in obstructive SAS. Sleep patterns and transcutaneous blood gas (tcPO2 and tcPCO2) were recorded in parallel. Control recordings, without treatment, were carried out over two nights, followed by two nights of recording after administration either of naltrexone followed by a placebo or of a placebo followed by naltrexone. The number of obstructive apnoea and hypopnoea events per hour of sleep (Apnoea-Hypopnoea Index: AHI), of hypoxic events (defined as a tcPO2 fall of at least 10, 15 or 20 mm Hg) and of hypercapnic events (defined as a tcPCO2 increase of at least 5 mm Hg) were counted. A Metabolic Suffering Index (MSI) was calculated, defined as the product of the number, duration and magnitude of hypoxic and hypercapnic events. Compared to placebo, naltrexone resulted in significant improvements in blood-gas patterns for the duration and MSI of hypoxic events and for the number, duration and MSI of hypercapnic events. Likewise, compared to placebo, naltrexone induced significant decreases in total sleep time, slow-wave sleep and rapid eye movement (REM) sleep, and, on the other hand, significant increases in total wake time and in the number of wakenings per hour of sleep (Nw h-1). Certain naltrexone-linked blood-gas improvements were closely correlated with certain of the sleep pattern changes: the decrease in number and duration of hypoxic events correlated with REM-time decrease and the decrease in number and duration of hypercapnic events correlated with the increase in Nwh-1. These findings suggest that the improvement in blood-gas patterns induced by naltrexone in SAS may be mediated by sleep pattern effects: i.e. a decrease in REM-time and an increase in intra-sleep wakening. Mirtazapine is an a2A antagonist and mixed 5-HT2/5-HT3 antagonist that has been proposed as a potential treatment for obstructive sleep apnea (OSA). A small, randomized, controlled trial has previously found an approximate halving in the severity of OSA with daily doses of 4.5 and 15 mg. We aimed to confirm and extend these findings in 2 randomized placebo-controlled, proof-of-concept trials.
                Two randomized, double-blind, placebo-controlled trials of mirtazapine for OSA (apnea-hypopnea index 10-40/h). Study 1: 3-way crossover, dose-finding study testing the self-administration of mirtazapine (7.5, 15, 30, and/or 45 mg) or placebo 30 minutes prior to bedtime for 2 weeks at each dose. Twenty patients were randomly assigned to 1 of 6 different dose-sequence groups, with each patient exposed to a maximum of 3 doses. Study 2: 3-arm, randomized, parallel-group trial of mirtazapine at 15 mg or mirtazapine 15 mg + Compound CD0012 or placebo for 4 weeks in 65 patients with OSA.
                Two patients withdrew from Study 1 after complaints of unacceptable lethargy. Fifteen patients were withdrawn from study 2, 7 after complaints of unacceptable lethargy or other side-effects. No measurement of sleep apnea improved due to mirtazapine in either study. Weight gain was significantly greater on mirtazapine than on placebo in both trials.
                Mirtazapine did not improve sleep apnea in either trial. Mirtazapine caused weight gain, which may further worsen OSA. Therefore, mirtazapine is not recommended for the treatment of OSA. Almitrine stimulates breathing by activating peripheral chemoreceptors and was given orally in a dose of 200 mg/day to nine patients with sleep apnoea syndrome, after a single blind placebo sequence. No reduction in the number of respiratory events per hour of sleep was observed. On the other hand Almitrine led to a significant fall in the mean duration of respiratory events (p less than 0.02). This fall occurred principally in the obstructive apnoea group and in those with mixed apnoea only during light slow wave sleep. These results are in agreement with the hypothesis that the arousal response to hypoxia mediated by the chemoreceptors could be responsible for the termination of sleep apneas. Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients.
                A randomized, double-blind, placebo-controlled study was conducted. The final sample consisted of 21 male patients with mild to severe OSA and AHI >10 divided into two groups, a donepezil-treated group (n=11) and a placebo-treated group (n=10). The dosage was one tablet/day (5 mg) for the first two weeks and two tablets/day (10 mg) for the last two weeks. Polysomnography and sleepiness evaluations were performed at baseline and after one month of treatment. Groups were compared using two-way ANOVA for repeated measures with treatment-group and treatment-time as the main factors and time-treatment as an interaction effect.
                Considering the effect of the interaction with time-treatment, there was a significant improvement in the obstructive apnea/hypopnea index, desaturation index, percentage of time with O(2) saturation ≤3% lower than baseline, lowest oxygen saturation, and the Epworth Sleepiness Scale (ESS) scores with donepezil treatment (p<0.05). Sleep efficiency significantly decreased (p<0.01).
                Donepezil treatment improved obstructive sleep apnea index, oxygen saturation, and sleepiness in parallel with a reduction in sleep efficiency. Our findings support the concept that cholinergic transmission may influence breathing regulation in OSA patients.
                Copyright © 2011 Elsevier B.V. All rights reserved. Twelve patients with documented obstructive sleep apnea were enrolled in a double-blind placebo controlled crossover trial of oral theophylline, (Uniphyllin) 800 mg, taken at night for four weeks. Overnight polysomnography, using standard techniques, was performed at the end of each treatment period. The total number of apneas (A) and hypopneas (H) decreased significantly while receiving theophylline compared to placebo, from 398 (69), mean (SEM), to 283 (72), p less than 0.01. Sleep quality was, however, significantly worse while receiving theophylline. Obstructive A and H were very much decreased with theophylline (p less than .001), and even when the data were adjusted for the more disturbed sleep with theophylline, this decrease remained significant; the obstructive A and H index fell from 49 (8.7) on placebo to 40 (9) while receiving theophylline, p = 0.02. There was no difference in the numbers of central or mixed A and H, and mean A and H duration was unchanged on the two study nights. Oxygen desaturations greater than 4 percent were less with theophylline treatment (p = 0.02), but mean overnight SaO2 was unchanged. We conclude that theophylline may be beneficial in patients with OSA, but part of the improvement is due to a deterioration in sleep quality. nan There is an association between Alzheimer disease and sleep-disordered breathing. Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease. This study evaluates the effects of donepezil on obstructive sleep apnea in patients with Alzheimer disease.
                Randomized, double-blind, placebo-controlled design. Twenty-three patients with mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12). Polysomnography and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using analysis of variance.
                AHI and oxygen saturation improved significantly after donepezil treatment compared to baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01).
                Donepezil treatment improved AHI and oxygen saturation in patients with Alzheimer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores. Trial registration: ClinicalTrials.gov Identifier: NCT00480870. Recent insights into sleep apnoea pathogenesis reveal that a low respiratory arousal threshold (awaken easily) is important for many patients. As most patients experience stable breathing periods mediated by upper-airway dilator muscle activation via accumulation of respiratory stimuli, premature awakening may prevent respiratory stimuli build up as well as the resulting stabilization of sleep and breathing. The aim of the present physiological study was to determine the effects of a non-benzodiazepine sedative, eszopiclone, on the arousal threshold and the AHI (apnoea/hypopnoea index) in obstructive sleep apnoea patients. We hypothesized that eszopiclone would increase the arousal threshold and lower the AHI in patients with a low arousal threshold (0 to -15 cm H(2)O). Following a baseline overnight polysomnogram with an epiglottic pressure catheter to quantify the arousal threshold, 17 obstructive sleep apnoea patients, without major hypoxaemia [nadir SaO(2) (arterial blood oxygen saturation) >70%], returned on two additional nights and received 3 mg of eszopiclone or placebo immediately prior to each study. Compared with placebo, eszopiclone significantly increased the arousal threshold [-14.0 (-19.9 to -10.9) compared with -18.0 (-22.2 to -15.1) cm H(2)O; P<0.01], and sleep duration, improved sleep quality and lowered the AHI without respiratory event prolongation or worsening hypoxaemia. Among the eight patients identified as having a low arousal threshold, reductions in the AHI occurred invariably and were most pronounced (25±6 compared with 14±4 events/h of sleep; P<0.01). In conclusion, eszopiclone increases the arousal threshold and lowers the AHI in obstructive sleep apnoea patients that do not have marked overnight hypoxaemia. The greatest reductions in the AHI occurred in those with a low arousal threshold. The results of this single night physiological study suggest that certain sedatives may be of therapeutic benefit for a definable subgroup of patients. However, additional treatment strategies are probably required to achieve elimination of apnoea. To investigate the effect of fenofibrate on sleep apnoea indices.
                Proof-of-concept study comprising a placebo run-in period (1 week, 5 weeks if fibrate washout was required) and a 4-week randomized, double-blind treatment period. Thirty-four subjects (mean age 55 years, body mass index 34 kg/m 2 , fasting triglycerides 3.5 mmol/L) with diagnosed sleep apnoea syndrome not treated with continuous positive airways pressure were enrolled and randomized to once daily treatment with fenofibrate (145 mg NanoCrystal(R) tablet) or placebo. Overnight polysomnography, computerized attention/vigilance tests and blood sampling for measurement of lipids, insulin, fasting plasma glucose and fibrinogen were performed at the end of each study period.
                NCT00816829.
                As this was an exploratory study, a range of sleep variables were evaluated. The apnoea/hypopnoea index (AHI) and percentage of time spent with arterial oxygen saturation (SpO(2)) <90% were relevant as they have been evaluated in other clinical trials. Other variables included total apnoeas, hypopnoeas and oxygen desaturations, and non-cortical micro-awakenings related to respiratory events per hour.
                Fenofibrate treatment significantly reduced the percentage of time with SpO(2) <90% (from 9.0% to 3.5% vs. 10.0% to 11.5% with placebo, p = 0.007), although there was no significant change in the AHI (reduction vs. control 14% (95%CI -47 to 40%, p = 0.533). Treatment reduced obstructive apnoeas (by 44%, from 18.5 at baseline to 15.0 at end of treatment vs. 29.0 to 30.5 on placebo, p = 0.048), and non-cortical micro-awakenings per hour (from 23.5 to 18.0 vs. 24.0 to 25.0 with placebo, p = 0.004). Other sleep variables were not significantly influenced by fenofibrate. KEY LIMITATIONS: Exploratory study in patients with mild to moderate sleep apnoea, limited treatment duration; concomitant hypnotic treatment (35%); lack of correction for multiplicity of testing.
                The consistent direction of change in sleep indices in this proof-of-concept study may support further investigation of fenofibrate in moderate to severe sleep apnoea syndrome. Whether nasal congestion promotes obstructive sleep apnea is controversial. Therefore, we performed a randomized placebo-controlled cross-over trial on the effects of topical nasal decongestion in patients with obstructive sleep apnea syndrome (OSA) and nasal congestion. Twelve OSA patients with chronic nasal congestion (mean +/- SD age 49.1 +/- 11.1 years, apnea/hypopnea index 32.6 +/- 24.5/h) were treated with nasal xylometazoline or placebo for 1 week each. At the end of treatment periods, polysomnography including monitoring of nasal conductance by an unobtrusive technique, vigilance by the OSLER test, and symptom scores were assessed. Data from xylometazoline and placebo treatments were compared. Mean nocturnal nasal conductance on xylometazoline was significantly higher than on placebo (8.6 +/- 5.3 versus 6.3 +/- 5.8 mL s(-1)Pa(-1), P < 0.05) but the apnea/hypopnea index was similar (29.3 +/- 32.5/h versus 33.2 +/- 32.8/h, P = NS). However, 30-210 min after application of xylometazoline, at the time of the maximal pharmacologic effect, the apnea/hypopnea index was slightly reduced (27.3 +/- 30.5/h versus 33.2 +/- 33.9/h, P < 0.05). Xylometazoline did not alter sleep quality, sleep resistance time (33.6 +/- 8.8 versus 33.4 +/- 10.1 min, P = NS) and subjective sleepiness (Epworth score 10.5 +/- 3.8 versus 11.8 +/- 4.4, P = NS). The reduced apnea/hypopnea index during maximal nasal decongestion by xylometazoline suggests a pathophysiologic link but the efficacy of nasal decongestion was not sufficient to provide a clinically substantial improvement of OSA. Pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper-airway patency and thus nocturnal breathing in patients with obstructive sleep apnea (OSA). To test this hypothesis, we performed a double-blind, randomized, placebo-controlled crossover study testing the effect of paroxetine (20 mg od) on polysomnographic and psychopathologic outcomes in 20 male OSA patients (mean age 52.1 years, mean BMI 28.7 kg/m2, mean oxygen desaturation index on a previous screening 25.4/hour). The two treatment periods of 6 weeks and the separating washout period of 4 weeks were completed by 17 patients. Paroxetine reduced the apnea index during NREM sleep (-35%, p = 0.003), but not during REM sleep. No significant effect on hypopnea indices was found. With the exception of a previously described REM-postponing effect (p = 0.05), sleep architecture was not significantly influenced by paroxetine. Similarly, the effect of paroxetine on apnea was not associated with a significant overall alleviation of psychopathologic symptoms as rated on the Comprehensive Psychopathological Rating Scale or OSA-related daytime complaints assessed by visual analog scales. We conclude that enhanced serotonergic transmission improves breathing during NREM sleep in OSA. This effect is poorly related to effects on sleep architecture or daytime symptoms. The effect of inhaled long-acting beta2-agonists in obstructive sleep apnea syndrome (OSAS) is unknown, although from the pharmacological point of view both therapeutic and adverse effects need to be considered. The purpose of this study was to obtain data on the efficacy and safety of salmeterol in patients with OSAS. In a randomized, double-blind, placebo-controlled, cross-over study, effects of salmeterol on respiration during sleep and sleep quality were investigated in 20 patients with OSAS. Of these, 4 patients were female, 16 male; the average age was 53.0 +/- 7.8 years, with average body mass index 28.0 +/- 3.0 kg small middle dot m(-2) and average apnea hypopnea index 35.6 +/- 17.8 h(-1). Patients with asthma, chronic obstructive pulmonary disease (COPD), and left heart failure were excluded. Placebo or verum (50 &mgr;g salmeterol) was administered at 7 pm by meter dose inhaler and spacer device. All patients underwent full polysomnography during baseline, placebo, and verum night. Statistical analysis was performed by StudentOs t-test (p > 0.05). Between the placebo and verum there were no differences in total sleep time, sleep stages, apnea index (AI), apnea hypopnea index (AHI), and nadir oxygen saturation. There was, however, 1) a significant deterioration of mean oxygen saturation (SaO2m; placebo 93.1 +/- 2.0 vs. verum 92.5 +/- 2.2%; p = 0.01), 2) of percent of time spent with an oxygen saturation (SaO2) </= 90% (placebo 13.1 +/- 14.5 vs. verum 19.5 +/- 20.8%; p = 0.02), and 3) a significant increase in heart rate (placebo 63.1 +/- 9.2 vs. verum 65.6 +/- 9.3 h(-1); p = 0.01). In patients with OSAS, salmeterol had no adverse effect on quality of sleep, AI or AHI. The slight increase in heart rate and the deterioration of oxygen saturation probably have no clinical relevance; the latter condition might be due to ventilation-perfusion-mismatch. This study excluded any influence of salmeterol on obstructive sleep apnea and hypopnea; on the other hand, salmeterol turned out to be safe in terms of OSAS. This might be of special importance in patients suffering from both OSAS and obstructive airway disease. nan The methylxanthine derivatives are known to have respiratory stimulant properties. To determine whether these drugs would improve obstructive sleep apnea, 10 male patients with obstructive sleep apnea (OSA) (Apnea Index greater than 15/h) were given infusions of aminophylline and a saline placebo on 2 separate nights a week apart, using a randomized crossover design. There was a significant decrease during aminophylline infusion in the frequency of those apneas, which contained periods of complete respiratory inactivity (central and mixed apneas; placebo, 4.3 +/- 1.8/h; aminophylline, 0.7 +/- 0.5/h; p less than 0.05). There was no change in either the frequency (placebo, 31.8 +/- 5.9/h; aminophylline, 28.7 +/- 8.7/h; NS) or duration of obstructive apneas. Mean and minimal arterial oxygen saturation values were also unchanged. Sleep architecture was markedly disturbed by aminophylline. There was a reduction in sleep efficiency (placebo, 84.8 +/- 2.0%; aminophylline, 60.2 +/- 5.0%; p less than 0.005), an increase in sleep fragmentation (sleep stage shifts/h: placebo, 11.6 +/- 1.3: aminophylline, 21.0 +/- 2.9; p less than 0.05) and less Stage 2 and more Stage 1 non-REM sleep. We conclude that aminophylline reduces central apnea and the central component of mixed apneas but has no effect on obstructive apnea. Theophylline is therefore unlikely to be therapeutically useful in patients with OSA, and because it leads to marked sleep disruption, its long-term use could conceivably increase the propensity to upper airway occlusion during sleep. We evaluated protriptyline, a nonsedating tricyclic antidepressant, as a treatment for obstructive sleep apnea in a double-blind crossover study of five men. After two weeks of treatment, with no change in body weight, daytime somnolence was markedly reduced and nocturnal oxygenation was improved, although apnea duration and frequency were not significantly decreased. Rapid-eye-movement (REM) stage time as a fraction of the total sleep time was reduced during treatment from 0.231 +/- 0.031 to 0.107 +/- 0.013 (mean +/- S.E.M.) (P less than 0.05). REM apnea time as a fraction of total sleep time was reduced from 0.145 +/- 0.022 to 0.054 +/- 0.006 (P less than 0.05). REM reduction during treatment with protriptyline can account for decreased REM apnea time. Similar decreases in REM stage time and REM apnea duration and similar improvement in oxygenation continued after six months of treatment. In addition, body weight, apnea, and arousal frequency were decreased at this time. Although the obstructive sleep apnea was not resolved, it was reduced. Protriptyline can be effective in patients with sleep apnea when the disorder is not life-threatening.
There is insufficient evidence to recommend the use of drug therapy in the treatment of OSA. Small studies have reported positive effects of certain agents on short-term outcomes. Certain agents have been shown to reduce the AHI in largely unselected populations with OSA by between 24% and 45%. For donepezil and fluticasone, studies of longer duration with a larger population and better matching of groups are required to establish whether the change in AHI and impact on daytime symptoms are reproducible. Individual patients had more complete responses to particular drugs. It is possible that better matching of drugs to patients according to the dominant mechanism of their OSA will lead to better results and this also needs further study.