UMLS:C0037315 - FACTA Search

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Query: UMLS:C0037315 (sleep apnea)
8,000 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disordered nocturnal breathing with significant arterial oxygen desaturation and sleep apnoea is a feature of extreme obesity which is often difficult to manage in the short term. We have evaluated the effect of fluoxetine, a centrally acting 5-HT re-uptake inhibitor, on sleep-breathing patterns in asymptomatic extremely obese subjects. A double-blind cross-over study was used to compare fluoxetine (60 mg for three days) to placebo. Eleven obese subjects (ten males, one female, mean weight +/- s.d. 131 +/- 2 kg) slept overnight in a sleep laboratory with the polysomnographic study recorded after an initial acclimatization night. The obese subjects had normal respiratory function and normal fully awake arterial oxygen saturation (%SaO2 97 +/- 1). Marked O2 desaturation was seen in all the subjects during sleep but the average asleep %SaO2 did not differ between the two treatment phases (placebo 90 +/- 5; fluoxetine 92 + 2%). However, fluoxetine significantly increased the minimum %SaO2 recorded during the study night either by abolishing or reducing REM sleep (placebo 73 +/- 2%; fluoxetine 81 +/- 8%; P < 0.05, 95% CI -12.3 to -2.03). Frequent hypopnoea was observed in all subjects in both REM and non-REM sleep whereas apnoea was uncommon. The total apnoea/hypopnoea index fell in six subjects during the fluoxetine night, the largest reduction being seen in the most severely affected. In five of the six the improvement was associated with the abolition of REM sleep. Total sleep time did not differ between the placebo and fluoxetine nights nor did a qualitative assessment of sleep using a visual analogue score.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Short-term use of fluoxetine in asymptomatic obese subjects with sleep-related hypoventilation. 133 Sep 62

Serotonin enhancing drugs, including L-tryptophan and, more recently, fluoxetine and paroxetine, have been tested as pharmacologic treatments for sleep apnea syndrome. Although some patients have demonstrated reduced apnea expression after treatment with these compounds, this improvement has been restricted to nonrapid eye movement (NREM) sleep, with some patients showing no improvement. This study reports the effects of mirtazapine, an antidepressant with 5-HT(1) agonist as well as 5-HT(2) and 5-HT(3) antagonist effects, on sleep and respiration in an established animal model of central apnea. We studied nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded after intraperitoneal injection of: (1) saline, (2) 0.1 mg/kg +/- mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all three doses reduced apnea index during NREM sleep by more than 50% (p < 0.0001) and during REM sleep by 60% (p < 0.0001) for at least 6 h. In association with this apnea suppression normalized inspiratory minute ventilation increased during all wake/sleep states (p < 0.001 for each state). The duration of NREM sleep was unaffected by any dose of mirtazapine (p = 0.42), but NREM EEG delta power was increased by more than 30% at all doses (p = 0.04), indicating improved NREM sleep consolidation after mirtazapine injection. We conclude that mirtazapine, over a 50-fold dose range, significantly reduces central apnea expression during NREM and REM sleep in the rat. The efficacy of this compound to suppress apnea in all sleep stages most probably arises from its mixed agonist/antagonist profile at serotonin receptors. The implications of these findings for the management of sleep apnea syndrome must be verified by appropriate clinical trials.
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PMID:Mirtazapine, a mixed-profile serotonin agonist/antagonist, suppresses sleep apnea in the rat. 1058 92

Serotonin and serotoninergic drugs have significant effects on respiration, at many sites throughout the nervous system, and serotonin has been implicated in the pathogenesis of obstructive sleep apnea. Thus, understanding the serotoninergic mechanisms underlying respiratory control may help discover novel pharmacotherapies for sleep-disordered breathing. Ondansetron, a serotonin (5-HT) antagonist selective for the 5-HT3 receptor subtype has recently been shown to suppress sleep-related central apneas in rats, particularly in rapid-eye-movement (REM) sleep. To evaluate the potential of ondansetron in the treatment of obstructive sleep-disordered breathing, we have performed randomized trials of two doses of ondansetron (20 and 40 mg orally) and placebo (4 studies for each of the 3 conditions) in our animal model of obstructive sleep apnea, the English Bulldog. Ondansetron significantly reduced the respiratory disturbance index (RDI) in REM sleep from 24.15+/-4.85 events/hour at placebo to 11.01+/-1.56 events/hour with high dose treatment, n=4, p<0.05. In contrast, the effects of drug on the RDI in non-rapid-eye-movement (NREM) sleep (5.23+/-1.30 events/hour, placebo; 4.31+/-1.36, with 20 mg ondansetron and 2.89+/-1.30 with 40 mg ondansetron, n=4) were not significant. Ondansetron, however, had no effect on either sleep efficiency or sleep architecture, and there were no effects on either oxyhemoglobin saturation nadirs or on the sleep time with saturations <90%. Although a trend towards reduction in the latter measure of oxygenation was seen at the higher dose of ondansetron. These data suggest a therapeutic potential for ondansetron in obstructive sleep-disordered breathing, particularly REM sleep apnea.
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PMID:The effects of ondansetron on sleep-disordered breathing in the English bulldog. 1124 51

Experimental and clinical evidences indicate that endocrine mechanisms, particularly involving the pineal gland, exert a role in the development of postural deficits leading to the occurrence of idiopatic scoliosis (IS). In particular, experiments performed in bipedal animals have shown that removal of the pineal gland, which secretes melatonin (M), induced a scoliosis, and that in such preparations, administration of this hormone prevented the development of this deformity (cf. 131). It appears also that adolescents with IS showed a reduced level of serum M with respect to age-related control subjects. The possible mechanisms involved in the M regulation of the tonic contraction of the axial musculature have been discussed. It is known that the pineal gland is implicated in the control of circadian rhythms, including the sleep-waking cycle, and that during this cycle there are prominent changes in postural activity, which affect not only the limbs, but also the axial musculature. These changes are characterized by a decrease followed by a suppression of postural activity, which occur particularly during transition from wakefulness to synchronized sleep and, more prominently, to rapid eye movement (REM) sleep. Episodes of postural atonia may also occur during the cataplectic episodes, which are typical of narcolepsy. Cholinergic and/or cholinoceptive neurons located in the dorsal pontine reticular formation (pRF) and the related medullary inhibitory reticulospinal (RS) system, intervene in the suppression of posture during REM sleep, as well as during the cataplectic episodes which occur in narcolepsy. These structures are under the modulatory (inhibitory) influence of the dorsomedial and the dorsolateral pontine tegmentum, where serotoninergic raphe nuclei (RN) neurons and noradrenergic locus coeruleus (LC) neurons are located. We postulated that M may act not only on the circadian pacemaker, but also directly on the pontine tegmental structures involved in the regulation of posture during the animal states indicated above. This hypothesis is supported by the facts that: 1) the dorsal pRF may contain specific binding sites for M; 2) this structure is particularly sensitive to M in adolescents, as well as in adult subjects affected by narcoleptic disturbances leading to cataplexy; 3) M increases the release of serotonin (5-HT), a neurotransmitter which enhances the postural tone by acting on the dorsal pRF: on the other hand, deficits in M levels may lower the activity of the serotoninergic raphe system, thus leading to a decrease or suppression of postural activity similar to that occurring either during REM sleep or during the cataplectic episodes typical of narcoleptic patients; 4) IS patients may show episodes of sleep apnea, a phenomenon which has been attibuted to a reduced tonic contraction of primary and accessory respiratory muscles during REM, resulting from a reduced release of 5-HT at dorsal pontine level. It has been postulated that, if the reduced M and 5-HT levels are subliminal to produce a complete suppression of posture under the conditions reported above, the reduced postural tone, which results from this condition may lead to the development of IS, due to hypotonia which affects the axial musculature. M secretion could be regulated not only by the activity of the serotoninergic raphe neurons projecting to the pineal gland, but probably also by the activity of noradrenergic LC neurons. It is likely that the development of IS, which results from a reduced level of M and 5-HT, may occur provided that the noradrenergic LC inhibition of the pontine structures is impaired. Such impairment could depend upon genetic factors, similar to those postulated to play a role in narcolepsy. In conclusion, the possibility exists that an impaired activity of brain monoaminergic systems may lead to disfunction in the production of M, which is apparently an important factor in the etiopathogenesis of IS.
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PMID:Pineal gland hormone and idiopathic scoliosis: possible effect of melatonin on sleep-related postural mechanisms. 1200 44

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sleep, suggests that this disorder should be readily amenable to drug therapy. Over the past 10 years, we have gained tremendous insight into the neurochemical mechanisms involved in state-dependent control of respiration. It is apparent from this work that there are many potential avenues for pharmacotherapies, including several seemingly conflicting directions for serotonergic therapies. Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. The dilator motor neuron post-synaptic serotonin receptors are 5-HT(2A) and 5-HT(2C) subtypes, and in adults the presynaptic 5-HT receptor in motor nuclei is 5-HT(1B), an inhibitory receptor. Serotonin receptors are also found within central respiratory neuronal groups, and these receptor subtypes include 5-HT(1A) (inhibitory) and 5-HT(2) receptors. Peripherally, stimulation of 5-HT(2A), 5-HT(2C) and 5-HT(3) receptor subtypes have an inhibitory effect on respiration via action at the nodose ganglion. Many of these receptor subtypes and their signal transduction pathways may be affected by oxidative stress in obstructive sleep apnea. These alterations will make finding drug therapies for sleep apnea more challenging, but not insurmountable. Future directions are suggested for elucidating safe, well-tolerated serotonergic drugs for this disorder. Tryptophan was one of the first serotonergic drugs tested for OSAHS. This drug was withdrawn from the market as a result of reports linking tryptophan use with eosinophilic myalgia syndrome and life-threatening pulmonary hypertension. Newer drugs with serotonergic activity tested in persons with sleep-disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT(2A) and 5-HT(3) antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.
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PMID:Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential. 1472 19

Serotonin (5-hydroxytryptamine; 5-HT) plays key roles in sleep-wakefulness regulation. Evidence indicates that 5-HT2 receptors are involved mainly in non-rapid eye movement sleep (NREMS) regulation and respiratory control. Here, we investigated the relative contribution of 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor subtypes to NREMS and breathing during sleep, using 5-HT2 subtype-selective ligands in wild-type (5-HT(2A)+/+) and knock-out (5-HT(2A)-/-) mice that do not express 5-HT(2A) receptors. Acute blockade of 5-HT(2A) receptors induced an increase in NREMS in 5-HT(2A)+/+ mice, but not 5-HT(2A)-/- mutants, which spontaneously expressed less NREMS than wild-type animals. In 5-HT(2A)+/+ mice, 5-HT(2B) receptor blockade produced a reduction of NREMS, whereas receptor activation induced an increase in this sleep stage. These effects were less pronounced in 5-HT(2A)-/- mice, indicating a lower sensitivity of 5-HT(2B) receptors in mutants, with no change in 5-HT(2B) mRNA. Blockade of 5-HT(2C) receptors had no effect on NREMS in both strains. In addition, an increase in EEG power density after sleep deprivation was observed in 5-HT(2A)+/+ mice but not in 5-HT(2A)-/- mice. Whole-body plethysmographic recordings indicated that 5-HT(2A) receptor blockade in 5-HT(2A)+/+ mice reduced NREMS apneas and bradypneas that occurred after sighs. In contrast, in 5-HT(2A)-/- mutants, NREMS apneas were not modified, and bradypnea after sighs were more pronounced. Our results demonstrate that 5-HT exerts a 5-HT(2B)-mediated facilitation of NREMS, and an influence respectively inhibitory on NREMS and facilitatory on sleep apnea generation, via 5-HT(2A) receptors. Moreover, 5-HT(2A) gene knock-out leads to functional compensations yielding adaptive changes opposite to those caused by pharmacological blockade of 5-HT(2A) receptors in 5-HT(2A)+/+ mice.
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PMID:Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. 1633 18

Prospective clinical trials addressing the role of serotonin (5-HT) in sleep apnea have indicated that the 5-HT uptake inhibitor fluoxetine is beneficial to some patients with obstructive apnea, whereas the 5-HT(3) receptor antagonist ondansetron seems of little value despite its efficacy in rat and dog models of sleep apnea (central and obstructive). Here, we examined the effect of these drugs in transgenic mice lacking monoamine oxidase A (Tg8), which exhibit approximately 3-fold higher rates of central sleep apnea than their wild-type counterparts (C3H), linked to their enhanced 5-HT levels. Acute ondansetron (2 mg kg(-1), intraperitoneal), acute fluoxetine (16 mg kg(-1)) and 13-day chronic fluoxetine (1 or 16 mg kg(-1)) decreased by approximately 80% the total (spontaneous and post-sigh) apnea index in Tg8 mice during non-rapid eye movement sleep, with no statistically significant effect on apnea in C3H mice. Our study shows that both drugs reduce the frequency of apneic episodes attributable to increased monoamine levels in this model of MAOA deficiency, and suggests that both may be effective in some patients with central sleep apneas.
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PMID:Ondansetron and fluoxetine reduce sleep apnea in mice lacking monoamine oxidase A. 1961 72

Phrenic long-term facilitation (pLTF) is a serotonin (5-HT)-dependent augmentation of phrenic motor output induced by acute intermittent hypoxia (AIH). AIH-induced pLTF requires spinal NADPH oxidase activity and reactive oxygen species (ROS) formation. Since 5-HT receptor activation stimulates NADPH oxidase activity in some cell types, we tested the hypothesis that episodic spinal 5-HT receptor activation (without AIH) is sufficient to elicit an NADPH oxidase-dependent facilitation of phrenic motor output (pMF). In anaesthetised, artificially ventilated adult male rats, episodic intrathecal 5-HT injections (3 x 6 microl injections at 5 min intervals) into the cerebrospinal fluid (CSF) near cervical spinal segments containing the phrenic motor nucleus elicited a progressive increase in integrated phrenic nerve burst amplitude (i.e. pMF) lasting at least 60 min post-5-HT administration. Hypoglossal (XII) nerve activity was unaffected, suggesting that effective doses of 5-HT did not reach the brainstem. A single 5-HT injection was without effect. 5-HT-induced pMF was dose dependent, but exhibited a bell-shaped dose-response curve. Activation of different 5-HT receptor subtypes, specifically 5-HT(2) versus 5-HT(7) receptors, may underlie the bell-shaped dose-response curve via a mechanism of 'cross-talk' inhibition. Pre-treatment with NADPH oxidase inhibitors, apocynin or diphenylenodium (DPI), blocked 5-HT induced pMF. Thus, episodic spinal 5-HT receptor activation is sufficient to elicit pMF by an NADPH oxidase-dependent mechanism, suggesting common mechanisms of ROS formation with AIH-induced pLTF. An understanding of the mechanisms giving rise to AIH-induced pLTF and 5-HT induced pMF may inspire novel therapeutic strategies for respiratory insufficiency in diverse conditions, such as sleep apnoea, cervical spinal injury or amyotrophic lateral sclerosis.
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PMID:Episodic spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation by an NADPH oxidase-dependent mechanism. 1980 45

Serotonin (5-HT) is a neuromodulator-transmitter influencing global brain function. Past and present findings illustrate a prominent role for 5-HT in the modulation of ponto-medullary autonomic circuits. 5-HT is also involved in the control of neurotrophic processes during pre- and postnatal development of neural circuits. The functional implications of 5-HT are particularly illustrated in the alterations to the serotonergic system, as seen in a wide range of neurological disorders. This article reviews the role of 5-HT in the development and control of respiratory networks in the ponto-medullary brainstem. The review further examines the role of 5-HT in breathing disorders occurring at different stages of life, in particular, the neonatal neurodevelopmental diseases such as Rett, sudden infant death and Prader-Willi syndromes, adult diseases such as sleep apnoea and mental illness linked to neurodegeneration.
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PMID:The role of serotonin in respiratory function and dysfunction. 2080 Dec 36

There is a growing appreciation that patients with seizures are also affected by a number of comorbid conditions, including an increase in prevalence of depression (Kanner, 2009), sleep apnea (Chihorek et al., 2007), and sudden death (Ryvlin et al., 2006; Tomson et al., 2008). The mechanisms responsible for these associations are unclear. Herein we discuss the possibility that underlying pathology in the serotonin (5-HT) system of patients with epilepsy lowers the threshold for seizures, while also increasing the risk of depression and sudden death. We propose that postictal dysfunction of 5-HT neurons causes depression of breathing and arousal in some epilepsy patients, and this can lead to sudden unexpected death in epilepsy (SUDEP). We further draw parallels between SUDEP and sudden infant death syndrome (SIDS), which may share pathophysiologic mechanisms, and which have both been linked to defects in the 5-HT system.
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PMID:The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP. 2121 37

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