Activating Leptin Receptors in the Central Nervous System Using Intranasal Leptin. A Novel Therapeutic Target for Sleep-disordered Breathing.
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SUBMITTER: Ip MSM
PROVIDER: S-EPMC6423110 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7528931 | biostudies-literature
Project description:Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.
| S-EPMC7528928 | biostudies-literature
Project description:Sleep-disordered breathing (SDB) is a common comorbidity in a number of cardiovascular diseases, and mounting clinical evidence demonstrates that it has important implications in the long-term outcomes of patients with cardiovascular disease (CVD). While recognition among clinicians of the role of SDB in CVD is increasing, it too often remains neglected in the routine care of patients with CVD, and therefore remains widely undiagnosed and untreated. In this article, we provide an overview of SDB and its relationship to CVD, with the goal of helping cardiovascular clinicians better recognize and treat this important comorbidity in their patients. We will describe the two major types of SDB and discuss the pathophysiologic, diagnostic, and therapeutic considerations of SDB in patients with CVD.
| S-EPMC4824338 | biostudies-other
Project description:ImportanceObstructive sleep-disordered breathing (SDB) in children is characterized by snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy children and is associated with significant morbidity. Evidence from small clinical trials suggests that intranasal corticosteroids improve SDB as measured by polysomnography; however, the effect on symptoms and quality of life is unclear.ObjectiveTo determine whether intranasal mometasone furoate is more effective than intranasal saline for improving symptoms and quality of life in children with SDB.Design, setting, and participantsThe MIST trial was a multicenter, randomized, double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for significant SDB symptoms were included; exclusions were previous adenotonsillectomy, body mass index greater than the 97th percentile, and severe SDB. Randomization was stratified by site, and data were analyzed on an intention-to-treat basis from October 28, 2020, to September 25, 2022.InterventionsParticipants were randomly assigned to receive mometasone furoate, 50 μg, or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles.Main outcomes and measuresThe primary outcome was resolution of significant SDB symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of symptoms using the SDB Score.ResultsA total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals [53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants (41%) in the saline group (risk difference, 4%; 95% CI, -8% to 16%; P = .51) with 26 participants lost to follow-up and missing values managed by multiple imputation. The main adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting 12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%) in the saline group.Conclusions and relevanceResults of this randomized clinical trial suggest that there was no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. The results suggest that almost one-half of children with SDB could be initially managed in the primary care setting and may not require referral to specialist services, as is currently recommended.Trial registrationAustralian New Zealand Clinical Trials Registry: ANZCTRN12618000448246.
| S-EPMC9857783 | biostudies-literature
Project description:There are limited data on the effect of bronchopulmonary dysplasia (BPD) on sleep disordered breathing (SDB). We hypothesized that both the severity of prematurity and BPD would increase the likelihood of SDB in early childhood. Our secondary aim was to evaluate the association of demographic factors on the development of SDB.This is a retrospective study of patient factors and overnight polysomnogram (PSG) data of children enrolled in our BPD registry between 2008 and 2015. Association between PSG results and studied variables was assessed using multiple linear regression analysis.One-hundred-forty children underwent at least one sleep study on room air. The mean respiratory disturbance index (RDI) was elevated at 9.9 events/hr (SD: 10.1). The mean obstructive apnea-hypopnea index (OAHI) was 6.5 (9.1) events/hr and the mean central event rate of 3.0 (3.7) events/hr. RDI had decreased by 22% or 1.5 events/hour (95%CI: 0.6, 1.9) with each year of age (P?=?0.005). Subjects with more severe respiratory disease had 38% more central events (P?=?0.02). Infants exposed to secondhand smoke had 2.4% lower (P?=?0.04) oxygen saturation nadirs and a pattern for more desaturation events. Non-white subjects were found to have 33% higher OAHI (P?=?0.05), while white subjects had a 61% higher rate of central events (P?<?0.001).RDI was elevated in a selected BPD population compared to norms for non-preterm children. BPD severity, smoke exposure, and race may augment the severity of SDB. RDI improved with age but was still elevated by age 4, suggesting that this population is at risk for the sequelae of SDB.
| S-EPMC5693767 | biostudies-literature
Project description:OBJECTIVE/BACKGROUND:Limited data are available on sleep-disordered breathing (SDB) following intracerebral hemorrhage (ICH). Our aim was to characterize the objective measures of post-ICH SDB and questionnaire-reported pre-ICH sleep characteristics, overall and by ethnicity. PATIENTS/METHODS:Participants with ICH who were enrolled in the population-based Brain Attack Surveillance in Corpus Christi project (2010-2016) reported their pre-ICH sleep duration and completed the Berlin Questionnaire to characterize pre-ICH risk of SDB. A subsample was screened for SDB (respiratory event index ?10) using ApneaLink Plus portable monitoring. Ethnic differences in post-ICH SDB or questionnaire-reported pre-ICH sleep characteristics were assessed using a log binomial model or a linear regression model or a Fisher's exact test. RESULTS:ICH cases (n = 298) were enrolled (median age = 68 years, 67% Mexican American). Among 62 cases with complete ApneaLink data, median time to post-ICH SDB screening was 11 days (IQR: 6, 19). Post-ICH SDB prevalence was 46.8% (95% CI: 34.4-59.2), and this rate did not differ by ethnicity (p = 1.0). Berlin Questionnaires for 109 of the 298 ICH cases (36.6% (95% CI: 31.1-42.0)) suggested a high risk for pre-ICH SDB, and the median pre-ICH sleep duration was eight hours (IQR: 6, 8). After adjusting for confounders, there was no difference in ethnicity in high risk for pre-ICH SDB or pre-ICH sleep duration. CONCLUSIONS:Nearly half of the patients had objective confirmation of SDB after ICH, and more than one-third had questionnaire evidence of high risk for pre-ICH SDB. Opportunities to address SDB may be common both before and after ICH.
| S-EPMC6082385 | biostudies-literature
Project description:IntroductionCystic fibrosis (CF) is a life-shortening, genetic disease that affects approximately 30,000 Americans. Although patients frequently report snoring, mouth breathing, and insomnia, the extent to which sleep-disordered breathing (SDB) may underlie these complaints remains unknown.MethodsSingle-center retrospective review of polysomnography results from referred patients with and without CF individually-matched (1:2) for age, gender, race, and body mass index (BMI).ResultsMean ages were 8.0 ± 5.2 (sd) and 35.9 ± 12.9 years, among 29 children and 23 adults with CF respectively. The CF and non-CF groups were well-matched in age and BMI. Subjects with vs. without CF had three times greater odds of moderate-severe SDB (apnea-hypopnea index (AHI) ≥ 5 in children, ≥ 15 in adults) (p = 0.01). Nocturnal oxygen saturation nadir (Minimum SpO2) was lower among CF vs. non-CF groups (p = 0.002). For every 1-unit increase in AHI, the decline in Minimum SpO2 was larger for subjects with vs. without CF (p = 0.05). In subjects with CF, forced expiratory volume in 1 s percent predicted (FEV1 PPD) was associated with Minimum SpO2 (Pearson r = 0.68, p < 0.0001) but not AHI (r = -0.19, p = 0.27). For every 1-unit increase in AHI, magnitude of decline in Minimum SpO2 was larger for those with low vs. normal FEV1 PPD (p = 0.01).ConclusionSeverity of SDB may be worse among referred patients with vs. without CF. The SDB may modify the relationship between CF lung disease and nocturnal hypoxemia. Markers of lung disease severity including lung function do not predict SDB severity, suggesting the need for routine polysomnography to screen for this sleep disorder.
| S-EPMC7541673 | biostudies-literature
Project description:ObjectiveTo examine the association between sleep-disordered breathing and stroke outcomes, and determine the contribution of sleep-disordered breathing to outcome disparities in Mexican Americans.MethodsIschemic stroke patients (n = 995), identified from the population-based Brain Attack Surveillance in Corpus Christi Project (2010-2015), were offered participation in a sleep-disordered breathing study including a home sleep apnea test (ApneaLink Plus). Sleep-disordered breathing (respiratory event index ≥10) was determined soon after stroke. Neurologic, functional, cognitive, and quality of life outcomes were assessed at 90 days poststroke. Regression models were used to assess associations between sleep-disordered breathing and outcomes, adjusted for sociodemographics, prestroke function and cognition, health-risk behaviors, stroke severity, and vascular risk factors.ResultsMedian age was 67 years (interquartile range [IQR] = 59-78); 62.1% were Mexican American. Median respiratory event index was 14 (IQR = 6-25); 62.8% had sleep-disordered breathing. Sleep-disordered breathing was associated with worse functional outcome (mean difference in activities of daily living/instrumental activities of daily living score = 0.15, 95% confidence interval [CI] = 0.01-0.28) and cognitive outcome (mean difference in modified Mini-Mental State Examination = -2.66, 95% CI = -4.85 to -0.47) but not neurologic or quality of life outcomes. Sleep-disordered breathing accounted for 9 to 10% of ethnic differences in functional and cognitive outcome and was associated with cognitive outcome more strongly for Mexican Americans (β = -3.97, 95% CI = -6.63 to -1.31) than non-Hispanic whites (β = -0.40, 95% CI = -4.18 to 3.39, p-interaction = 0.15).InterpretationSleep-disordered breathing is associated with worse functional and cognitive function at 90 days poststroke. These outcomes are reasonable endpoints for future trials of sleep-disordered breathing treatment in stroke. If effective, sleep-disordered breathing treatment may somewhat lessen ethnic stroke outcome disparities. ANN NEUROL 2019;86:241-250.
| S-EPMC7549189 | biostudies-literature
Project description:Studies in humans and animal models with spinal cord injury (SCI) have demonstrated that medications targeting serotonin receptors may decrease the susceptibility to central sleep-disordered breathing (SDB). We hypothesized that mirtazapine would decrease the propensity to develop hypocapnic central sleep apnea (CSA) during sleep. We performed a single-blind pilot study on a total of 10 men with SDB (7 with chronic SCI and 3 noninjured) aged 52.0 ± 11.2 yr. Participants were randomly assigned to either mirtazapine (15 mg at bedtime) or a placebo for at least 1 wk, followed by a 7-day washout period before crossing over to the other intervention. Split-night studies included polysomnography and induction of hypocapnic CSA using a noninvasive ventilation (NIV) protocol. The primary outcome was CO2 reserve, defined as the difference between eupneic and end of NIV end-tidal CO2 ([Formula: see text]) preceding induced hypocapneic CSA. Secondary outcomes included controller gain (CG), other ventilatory parameters, and SDB severity. CG was defined as the ratio of change in minute ventilation (V̇e) between control and hypopnea to the change in CO2 during sleep. CO2 reserve was significantly widened on mirtazapine than placebo (-3.8 ± 1.2 vs. -2.0 ± 1.5 mmHg; P = 0.015). CG was significantly decreased on mirtazapine compared with placebo [2.2 ± 0.7 vs. 3.5 ± 1.9 L/(mmHg × min); P = 0.023]. There were no significant differences for other ventilatory parameters assessed or SDB severity between mirtazapine and placebo trials. These findings suggest that the administration of mirtazapine can decrease the susceptibility to central apnea by reducing chemosensitivity and increasing CO2 reserve; however, considering the lack of changes in apnea-hypopnea index (AHI), further research is required to understand the significance of this finding.NEW & NOTEWORTHY To our knowledge, this research study is novel as it is the first study in humans assessing the effect of mirtazapine on CO2 reserve and chemosensitivity in individuals with severe sleep-disordered breathing. This is also the first study to determine the potential therapeutic effects of mirtazapine on sleep parameters in individuals with a spinal cord injury.
| S-EPMC8325612 | biostudies-literature
Project description:Over the past two decades, various methods of sophisticated diagnostics of the upper airway have been tested in patients with sleep disordered breathing (SDB). In this context, endoscopic techniques and pharyngeal pressure recordings are of special interest for the otorhinolaryngologist.Whereas the basic otorhinolaryngological examination is able to detect anatomical pathologies which need to and can be corrected, the Müller-Manoeuvre seems to help exclude patients from uvulopalatopharyngoplasty.To a large extent, videoendoscopy during natural sleep has been replaced by videoendoscopy under sedation. Despite good methodological preparation and impressive presentability of the obstructions, there is not sufficent evidence to demonstrate that videoendoscopy under sedation improves the success rate of surgery in SDB. However, in assessing the impact of the epiglottis on upper airway obstructions in the individual patient, videoendoscopy is the only existing option.Multi-channel pressure recordings permit analysing the entire sleep period and are well tolerated. They can be used to determine the Apnea-Hypopnea-Index as well as to quantify obstructive events in the upper and lower pharyngeal segment. On the other hand, obstructions of the tongue base cannot be distinguished from obstructions related to the epiglottis. According to the data available so far, the benefit of sophisticated diagnostics of the upper airway still has to be judged with caution. Therefore, the promising approaches of both videoendoscopy under sedation and multi-channel pressure recordings deserve further intensive research. According to the personal estimation of the author, they will nevertheless become valuable tools for otorhinolaryngologists in the near future, thus complementing the basic ENT-examination and improving the treatment of patients.
| S-EPMC3199806 | biostudies-other