piperidines and Sleep-Apnea--Obstructive

Excessive daytime sleepiness (EDS) and fatigue are major complaints in patients with obstructive sleep apnoea (OSA) syndrome. Pitolisant is an orally active selective histamine H3 receptor (H3R) antagonist/inverse agonist, which enhances histaminergic transmissions in the brain and thereby elicits strong wake-promoting effects. This article assesses the efficacy and safety of pitolisant 20 mg in patients with OSA, based on existing randomised controlled studies.. An individual patient data (IPD) meta-analytical two-level (study-patient) hierarchical model was used assuming a random treatment effect. The Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSleR) tests were co-primary endpoints.. A total of 512 patients, including 384 treated with pitolisant and 128 with placebo, were included in the analysis. Compared with placebo, pitolisant reduced mean ESS by - 3.1 (95% CI [- 4.1; - 2.1]; p < 0.001) and improved OSleR by 1.18 (1.02; 1.35, p = 0.022); 30% more patients had reduced fatigue (risk ratio [RR] = 1.3, [1.11; 1.53]), p = 0.001) and 46% more patients had improved Clinical Global Impression (CGI) (RR = 1.46 [1.12; 1.89], p = 0.005). No significant differences in safety endpoints were found. These results proved homogeneous across studies and subgroups of the population.. The results provide evidence of a significant benefit of pitolisant in improving EDS and fatigue, irrespective of baseline conditions.

Topics: Disorders of Excessive Somnolence; Fatigue; Humans; Piperidines; Sleep Apnea, Obstructive; Treatment Outcome

Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI: -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI: 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI: 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI: 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.

Topics: Disorders of Excessive Somnolence; Histamine Antagonists; Humans; Narcolepsy; Piperidines; Placebo Effect; Quality of Life; Randomized Controlled Trials as Topic; Sleep Apnea, Obstructive

OSA is a highly prevalent sleep disorder, and subjective excessive daytime sleepiness (EDS) is the cardinal symptom for which many individuals seek medical advice. Positive airway pressure (PAP) devices, first-line treatment for OSA, eliminates EDS in most patients. However, a subset of patients suffers from persistent EDS despite adherence to therapy. Multiple conditions, some reversible, could account for the residual sleepiness and need to be explored, requiring detailed history, review of PAP data from the smart card, and sometimes additional testing. When all known causes of EDS are excluded, in adequately treated subjects, the purported mechanisms could relate to long-term exposure to the OSA-related sleep fragmentation, sleep deprivation, and hypoxic injury to the arousal system, shifts in melatonin secretion, or altered microbiome. Independent of the mechanism, in well-treated OSA, pharmacological therapy with approved drugs can be considered. Modafinil is commonly prescribed to combat residual EDS, but more recently two drugs, solriamfetol, a dual dopamine-norepinephrine reuptake inhibitor, and pitolisant, a histamine H3 receptor inverse agonist, were approved for EDS. Solriamfetol has undergone randomized controlled trials for treatment of EDS associated with both OSA and narcolepsy, exhibiting robust efficacy. Solriamfetol is renally excreted, with no known drug interactions. Pitolisant, which is nonscheduled, has undergone multiple RCTs in narcolepsy, showing improvement in subjective and objective EDS and one OSA trial showing improvement in subjective EDS.

Topics: Carbamates; Disorders of Excessive Somnolence; Humans; Modafinil; Phenylalanine; Piperidines; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents

Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates.. Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings.. Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Topics: Azepines; Carbamates; Dementia; Disorders of Excessive Somnolence; GABA-A Receptor Agonists; Humans; Orexin Receptor Antagonists; Phenylalanine; Piperidines; Pyridines; Pyrimidines; Sleep Aids, Pharmaceutical; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Trazodone; Triazoles; Zolpidem

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.. Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?. In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety.. Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported.. Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.. ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.

Topics: Continuous Positive Airway Pressure; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Piperidines; Quality of Life; Receptors, Histamine H3; Sleep Apnea, Obstructive; Surveys and Questionnaires

The treatments of obstructive sleep apnea (OSA) consist of surgical such as uvulopalatopharyngoplasty and\ non-surgical approaches such as continuous positive airway pressure (CPAP), weight reduction, dental appliance, and some medications. Cholinergic nerve system has been shown an important role in respiratory regulation and in sleep apnea. Donepezil, a reversible acetylcholine esterase inhibitor, can increase cholinergic nerve activity especially during sleep. There were some studies on the efficacy of donepezil in treatment of OSA patients and found significant improvement in the apneahypopnea index (AHI) and oxygen saturation compared to pretreatment and placebo.. To evaluate the efficacy of donepezil in the treatment of obstructive sleep apnea (OSA).. A prospective, randomized study was conducted at HRH Princess Maha Chakri Sirindhorn Medical\ Center. OSA patients diagnosed by polysomnography and Epworth Sleepiness Scale scores were randomly allocated into study group and control group. The study group received donepezil (5 mg), 1 tablet a day for 4 weeks then increased to 2 tablets a day for the next 4 weeks. The control group received placebo drug in the same doses. The value of apnea-hypopnea index (AHI), minimum oxygen saturation (minimum SpO2) and Epworth Sleepiness Scale scores were used in comparison both before and after the end of the study.. At the end of the study, 41 patients were collected of which 21 patients were in study group and 20 patients were in control group. Before treatment, there were no significant difference in age (p = 0.53), body mass index (p = 0.80), sex (p = 0.44), minimum SpO2 (p = 0.36), Epworth sleepiness Scale scores (p = 0.86), and AHI (p = 0.06) between two groups. After treatment, no statistically significant difference in the value of AHI, minimum SpO2 and Epworth Sleepiness Scale scores were identified both in the same group and between two groups (p>0.05).. Treatment OSA patients with donepezil did not show better results than placebo.

Topics: Adult; Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Prospective Studies; Sleep Apnea, Obstructive

Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown.. To determine whether a single dose of donepezil lowers the apnea-hypopnea index by modulating the ArTh or loop gain.. In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered.. A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture. Clinical trial registered with www.clinicaltrials.gov (NCT02264353).

Topics: Adult; Arousal; California; Cholinesterase Inhibitors; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Oximetry; Piperidines; Polysomnography; Respiratory System; Severity of Illness Index; Sleep; Sleep Apnea, Obstructive; Treatment Outcome

Drug-induced sleep endoscopy (DISE) allows for direct airway observation in patients with obstructive sleep apnea. This study compared the safety profiles and efficacies of three regimens for DISE.. Sixty-six patients were randomly assigned to receive propofol alone (n = 22), a propofol-remifentanil combination (n = 22), or a dexmedetomidine-remifentanil combination (n = 22). Remifentanil was infused at a concentration of 1.5 ng·ml(-1) in the propofol-remifentanil and dexmedetomidine-remifentanil groups, whereas saline was infused in the propofol group. The propofol and propofol-remifentanil groups received propofol at a starting concentration of 1.0 μg·ml(-1), then 0.1 μg·ml(-1) increments at 5 min intervals. The dexmedetomidine-remifentanil group received 1.0 μg·kg(-1) loading dose of dexmedetomidine for 10 min and then 0.2 μg·kg(-1)·h(-1) increments at 5 min intervals.. The incidence of oxygen desaturation was significantly higher in the propofol-remifentanil group compared with that of the dexmedetomidine-remifentanil group (77 vs. 45%, respectively, P = 0.024). Even with a maximum dose of dexmedetomidine (1.4 μg·kg(-1)·h(-1)), 50% of the dexmedetomidine-remifentanil group did not reach sufficient sedation and required additional propofol. Cough reflex occurred in five patients of propofol group and in neither of the other groups (P = 0.004).. The propofol-remifentanil combination was associated with a higher incidence of desaturation. The dexmedetomidine-remifentanil combination was associated with inadequate sedation in one half of the patients, even though it produced less respiratory depression. Addition of remifentanil reduced the cough reflex.

Topics: Adult; Airway Resistance; Conscious Sedation; Dexmedetomidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endoscopy; Female; Humans; Male; Middle Aged; Oxygen; Piperidines; Polysomnography; Propofol; Remifentanil; Sleep Apnea, Obstructive

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.. After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.. Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).. Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.. Clinicaltrials.gov NCT00672737.

Topics: Adult; Analgesics, Opioid; Biomarkers; Humans; Hypoxia; Inflammation Mediators; Male; Middle Aged; Pain; Pain Threshold; Piperidines; Remifentanil; Sleep; Sleep Apnea, Obstructive; Young Adult

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.

Topics: Adult; Aged; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Humans; Indans; Male; Middle Aged; Oxygen; Piperidines; Placebos; Polysomnography; Sleep Apnea, Obstructive; Sleep Stages; Treatment Outcome

There is concern that opioid-based analgesia will worsen sleep-related respiratory insufficiency in patients with obstructive sleep apnea (OSA), resulting in serious morbidity or mortality. However, there are no studies that directly address the merit of this concern. Consequently, the authors designed this study as the first prospective, double-blind, placebo-controlled investigation of opioid pharmacology in patients with documented OSA.. Patients (n = 19) with moderate OSA documented by polysomnography (sleep study) were randomized to undergo an additional sleep study while receiving either a saline infusion or a remifentanil infusion (0.075 microg x kg x h). Sleep stages, apneas, hypopneas, and arterial hemoglobin oxygen saturation were continually recorded during saline or remifentanil infusion, and were compared with values obtained during the patients' earlier sleep study.. Saline infusion had no effect on sleep or respiratory variables. In contrast, remifentanil increased Stage 1 sleep, markedly decreased rapid eye movement sleep, increased arousals from sleep, and decreased sleep efficiency. Remifentanil actually decreased the number of obstructive apneas, but markedly increased the number of central apneas. Arterial hemoglobin oxygen saturation was also significantly lower in OSA patients receiving remifentanil.. The decrease in obstructive apneas likely resulted from the marked decrease in rapid eye movement sleep caused by remifentanil. Despite fewer obstructions, OSA was worse during remifentanil infusion because of a marked increase in the number of central apneas. These data suggest that caution is warranted when administering opioids to subjects with moderate OSA, but that the primary risk may be central apnea, not obstructive apnea.

Topics: Adult; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Polysomnography; Prospective Studies; Remifentanil; Respiration; Sleep; Sleep Apnea, Obstructive; Sleep Stages

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.. ClinicalTrials.gov Identifier: NCT00480870.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Polysomnography; Psychometrics; Sleep Apnea, Obstructive; Sleep, REM; Treatment Outcome

To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA).. In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea-hypopnea index during sleep. SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ.. Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19).. Decreased pontine cholinergic projections may contribute to OSA in MSA.

Topics: Adult; Age Distribution; Aged; Binding, Competitive; Carrier Proteins; Corpus Striatum; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Multiple System Atrophy; Neuropeptides; Pilot Projects; Piperidines; Pons; Receptors, Cholinergic; Reference Values; Regression Analysis; Sex Distribution; Sleep Apnea, Obstructive; Tetrabenazine; Tetrahydronaphthalenes; Thalamus; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Transport Proteins

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Uptake Inhibitors; Amphetamine; Animals; Carbamates; Corpus Striatum; Disorders of Excessive Somnolence; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Evaluation, Preclinical; Drug Inverse Agonism; Feeding Behavior; Histamine Antagonists; Locomotion; Mice; Modafinil; Narcolepsy; Neostriatum; Norepinephrine Plasma Membrane Transport Proteins; Nucleus Accumbens; Phenylalanine; Piperidines; Receptors, Histamine H3; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents

Topics: Continuous Positive Airway Pressure; Humans; Piperidines; Sleep Apnea, Obstructive

Obstructive sleep apnea (OSA) and its main feature, chronic intermit-tent hypoxia (IH) during sleep, is closely associated with insulin resistance (IR) and diabetes. Rimonabant can regulate glucose metabolism and improve IR. The present study aimed to assess the effect of IH and rimonabant on glucose metabolism and insulin sensitivity, and to explore the possible mechanisms.. Thirty-two rats were randomly assigned into 4 groups: Control group, subjected to intermittent air only; IH group, subjected to IH only; IH+NS group, subjected to IH and treated with normal saline; and IH+Rim group, subjected to IH and treated with 10 mg/kg/day of rimonabant. All rats were killed after 28 days of exposure. Then, the blood and skeletal muscle were collected. We measured fasting blood glucose levels, fasting blood insulin levels, and the expression of glucose transporter 4 (GLUT4) in both mRNA and protein levels in skeletal muscle.. IH can slow weight gain, increase serum insulin level, and reduce insulin sensitivity in rats. The expressions of GLUT4 mRNA, total GLUT4, and plasma membrane protein of GLUT4 (PM GLUT4) in skeletal muscle were decreased. Rimonabant treatment was demonstrated to improve weight gain and insulin sensitivity of the rats induced by IH. Rimonabant significantly upregulated the expression of GLUT4 mRNA, PM GLUT4, and total GLUT4 in skeletal muscle.. The present study demonstrates that IH can cause IR and reduced expression of GLUT4 in both mRNA and protein levels in skeletal muscle of rats. Rimonabant treatment can improve IH - induced IR, and the upregulation of GLUT4 expression may be involved in this process.

Topics: Animals; Blood Glucose; Cannabinoid Receptor Antagonists; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Hypoxia; Immunohistochemistry; Insulin Resistance; Male; Muscle, Skeletal; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Sleep Apnea, Obstructive

Microparticles are deemed true biomarkers and vectors of biological information between cells. Depending on their origin, the composition of microparticles varies and the subsequent message transported by them, such as proteins, mRNA, or miRNA, can differ. In obstructive sleep apnea syndrome (OSAS), circulating microparticles are associated with endothelial dysfunction by reducing endothelial-derived nitric oxide production. Here, we have analyzed the potential role of circulating microparticles from OSAS patients on the regulation of angiogenesis and the involved pathway. VEGF content carried by circulating microparticles from OSAS patients was increased when compared with microparticles from non-OSAS patients. Circulating microparticles from OSAS patients induced an increase of angiogenesis that was abolished in the presence of the antagonist of endothelin-1 receptor type B. In addition, endothelin-1 secretion was increased in human endothelial cells treated by OSAS microparticles. We highlight that circulating microparticles from OSAS patients can modify the secretome of endothelial cells leading to angiogenesis.

Topics: Adult; Aged; Aorta; Apoptosis; Blotting, Western; Cell Adhesion; Cell-Derived Microparticles; Endothelial Cells; Endothelin B Receptor Antagonists; Endothelin-1; Flow Cytometry; Humans; Male; Middle Aged; Neovascularization, Physiologic; Oligopeptides; Piperidines; Receptor, Endothelin B; Sleep Apnea, Obstructive; Vascular Endothelial Growth Factor A; Young Adult

The prevalence of obstructive sleep apnea (OSA) in Americans is 9% and increasing. Increased afferent vagal activation may predispose to OSA by reducing upper airway muscle activation/patency and disrupting respiratory rhythmogenesis. Vagal afferent neurons are inhibited by cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors in animal models of vagally-mediated behaviors. Injections of dronabinol, a non-selective CB1/CB2 receptor agonist, into the nodose ganglia reduced serotonin (5-HT)-induced reflex apneas. It is unknown what role CB1 and/or CB2 receptors play in reflex apnea. Here, to determine the independent and combined effects of activating CB1 and/or CB2 receptors on dronabinol's attenuating effect, rats were pre-treated with CB1 (AM251) and/or CB2 (AM630) receptor antagonists. Adult male Sprague-Dawley rats were anesthetized, instrumented with bilateral electrodes to monitor genioglossus electromyogram (EMGgg) and a piezoelectric strain gauge to monitor respiratory pattern. Following intraperitoneal treatment with AM251 and/or AM630, or with vehicle, serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, the nodose ganglia were exposed and 5-HT-induced reflex apneas were again recorded to confirm that the nerves remained functionally intact. Dronabinol was injected into each nodose ganglion and 5-HT infusion was repeated. Prior to dronabinol injection, there were no significant differences in 5-HT-induced reflex apneas or phasic and tonic EMGgg before or after surgery in the CB1, CB2, combined CB1/CB2 antagonist, and vehicle groups. In the vehicle group, dronabinol injections reduced 5-HT-induced reflex apnea duration. In contrast, dronabinol injections into nodose ganglia of the CB1, CB2, and combined CB1/CB2 groups did not attenuate 5-HT-induced reflex apnea duration. However, the CB1 and CB2 antagonists had no effect on dronabinol's ability to increase phasic EMGgg. These findings underscore the therapeutic potential of dronabinol in the treatment of OSA and implicate participation of both cannabinoid receptors in dronabinol's apnea suppression effect.

Topics: Animals; Cannabinoid Receptor Agonists; Dronabinol; Electromyography; Femoral Vein; Indoles; Male; Nodose Ganglion; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Serotonin; Sleep Apnea, Obstructive; Treatment Outcome

Topics: Airway Obstruction; Analgesics, Opioid; Anesthetics, Intravenous; Humans; Models, Biological; Piperidines; Propofol; Remifentanil; Respiratory Mechanics; Sleep Apnea, Obstructive

Topics: Airway Obstruction; Anesthetics, Intravenous; Bradycardia; Cardiotonic Agents; Cholangiopancreatography, Endoscopic Retrograde; Choledocholithiasis; Decerebrate State; Flumazenil; GABA Agonists; Humans; Hypnotics and Sedatives; Hypoxia; Intraoperative Complications; Intubation, Intratracheal; Male; Midazolam; Middle Aged; Naloxone; Piperidines; Propofol; Remifentanil; Sleep Apnea, Obstructive

Topics: Adenoidectomy; Anesthetics, Intravenous; Anticoagulants; Antihypertensive Agents; Bosentan; Child; Down Syndrome; Elective Surgical Procedures; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intubation, Intratracheal; Piperazines; Piperidines; Propofol; Purines; Remifentanil; Severity of Illness Index; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfonamides; Sulfones; Tonsillectomy; Treatment Outcome; Vasodilator Agents; Warfarin

This case report describes airway management during cataract surgery for a patient with known severe obstructive sleep apnea syndrome. Surgery could not be performed using a pure local anesthetic procedure because of the psychological history of the patient. In consideration of the severity of the patient's sleep apnea syndrome, we chose an anesthetic procedure that would compromise the upper airway as little as possible. For respiratory strategy, the patient's own nasal CPAP (continuous positive airway pressure) equipment was used. Anesthesia was maintained with continuous infusion of propofol and remifentanil while the patient was breathing spontaneously. The patient was transferred to the recovery room where nasal CPAP was continued for 1 h until the patient was returned to the ward.

Topics: Anesthesia, General; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Intravenous; Cataract Extraction; Continuous Positive Airway Pressure; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Sleep Apnea, Obstructive