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A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

ABSTRACT: Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

SUBMITTER: Dornbierer DA

PROVIDER: S-EPMC8492773 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sleep inertia, subjectively experienced as grogginess felt upon awakening, causes cognitive performance impairments that can require up to 1.5 hr to dissipate. It is unknown, however, how chronic sleep restriction (CSR) influences the magnitude and duration of sleep inertia-related performance deficits. Twenty-six healthy participants were enrolled in one of two in-laboratory sleep restriction protocols (one 32 day randomized control and one 38 day protocol) that separated the influence of sleep and circadian effects on performance using different "day"-lengths (20 and 42.85 hr day-lengths, respectively). The sleep opportunity per 24 hr day was the equivalent of 5.6 hr for each CSR condition and 8 hr for the Control condition. Participant's performance and subjective sleepiness were assessed within ~2 min after electroencephalogram-verified awakening and every 10 min thereafter for 70 min to evaluate performance and subjective sleepiness during sleep inertia. Performance within 2 min of awakening was ~10% worse in CSR conditions compared with Control and remained impaired across the dissipation of sleep inertia in the CSR conditions when compared with Control. These impairments in performance during sleep inertia occurred after only chronic exposure to sleep restriction and were even worse after awakenings during the biological nighttime. Interestingly, despite differences in objective performance, there were no significant differences between groups in subjective levels of sleepiness during sleep inertia. CSR worsens sleep inertia, especially for awakenings during the biological night. These findings are important for individuals needing to perform tasks quickly upon awakening, particularly those who obtain less than 6 hr of sleep on a nightly basis. The study "Sleep Duration Required to Restore Performance During Chronic Sleep Restriction" was registered as a clinical trial (#NCT01581125) at clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT01581125?term=NCT01581125.&rank=1).

Project description:Introduction: Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats. Methods: Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Blood glucose levels were measured before, then 15, 30, 60 and 120 min after glucose load. CACO-2 cells were used to measure the uptake of [14C] α-MDG for 30 min with or without LA. Gastric content from rats administered LA was collected 15 and 30 min after glucose load, and blood samples were collected for measurement of glucagon-like peptide 1 (GLP-1) and cholecystokinin concentrations. Results: The elevation of postprandial blood glucose levels was slowed by LA but not by trilinolein in rats without promotion of insulin secretion, and this effect was also observed in rats with type 1 diabetes. The uptake of α-MDG, an SGLT-specific substrate, was, however, not inhibited by LA. Gastric emptying was slowed by LA 15 min after glucose load, and GLP-1, but not cholecystokinin, level was elevated by LA 15 min after glucose load. TUG-891, a GPR120 agonist, ameliorated postprandial hyperglycemia but TAK-875, a GPR40 agonist, did not. Pretreatment with AH7614, a GPR120 antagonist, partially canceled the improvement of postprandial hyperglycemia induced by LA. α-LA, which has high affinity with GPR120 as well as LA, slowed the elevation of postprandial blood glucose levels, but oleic acid, which has lower affinity with GPR120 than LA, did not. Conclusion: Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway.

Project description:Study objectivesTo assess the benefit of bedtime long-acting bupropion and/or long-acting methylphenidate in the therapy of severe morning sleep inertia (SI), a chronic condition that has major adverse consequences on level of functioning and quality of life, and for which there is no recognized therapy.MethodsPatients underwent clinical interviews and examinations and completed comprehensive questionnaires. They underwent overnight video-polysomnography and next-day multiple sleep latency testing (apart from 1 case with obstructive sleep apnea). Treatments are described in the case reports.ResultsCase 1, a 16-year-old girl who was very late to school every day from severe morning SI despite obstructive sleep apnea being fully controlled with continuous positive airway pressure therapy, responded to bedtime bupropion-extended release (xl) 150 mg, together with methylphenidate-sr (sustained release), 36 mg (along with 20 mg methylphenidate taken 1 hour before the alarm would go off). She woke up in a timely fashion and has started her classes on time, with benefit maintained at 6-month follow-up. Case 2, a 29-year-old female with idiopathic hypersomnia and major depression and associated severe morning SI while maintained on 20 mg twice-daily generic Adderall, responded immediately (first night) to bedtime bupropion-xl, 150 mg, with benefit maintained at the 4-month follow-up. Case 3, a 74-year-old man with idiopathic hypersomnia and major depression maintained on daily methylphenidate-sr and direct-release methylphenidate, along with 300 mg bupropion-xl, developed progressively severe morning SI that immediately responded to changing his bupropion-xl regimen to 150 mg nightly and 150 mg every morning, with benefit maintained at the 3-year follow-up. Case 4, a 60-year-old female with idiopathic hypersomnia and severe morning SI, was immediately intolerant to bedtime bupropion-xl, which was discontinued.ConclusionsBedtime use of long-acting bupropion and/or long-acting methylphenidate can be effective in the therapy for severe morning SI and warrants further clinical use along with systematic research.

Project description:Vaccines are a critical clinical tool in preventing illness and death due to infectious diseases and are regularly administered to children and adults across the globe. In order to obtain full protection from many vaccines, an individual needs to receive multiple doses over the course of months. However, vaccine administration in developing countries is limited by the difficulty in consistently delivering a second or third dose, and some vaccines, including the inactivated polio vaccine (IPV), must be injected more than once for efficacy. In addition, IPV does not remain stable over time at elevated temperatures, such as those it would encounter over time in the body if it were to be injected as a single-administration vaccine. In this manuscript, we describe microspheres composed of poly(lactic-co-glycolic acid) (PLGA) that can encapsulate IPV along with stabilizing excipients and release immunogenic IPV over the course of several weeks. Additionally, pH-sensitive, cationic dopants such as Eudragit E polymer caused clinically relevant amounts of stable IPV release upon degradation of the PLGA matrix. Specifically, IPV was released in two separate bursts, mimicking the delivery of two boluses approximately one month apart. In one of our top formulations, 1.4, 1.1, and 1.2 doses of the IPV serotype 1, 2, and 3, respectively, were released within the first few days from 50mg of particles. During the delayed, second burst, 0.5, 0.8, and 0.6 doses of each serotype, respectively, were released; thus, 50mg of these particles released approximately two clinical doses spaced a month apart. Immunization of rats with the leading microsphere formulation showed more robust and long-lasting humoral immune response compared to a single bolus injection and was statistically non-inferior from two bolus injections spaced 1 month apart. By minimizing the number of administrations of a vaccine, such as IPV, this technology can serve as a tool to aid in the eradication of polio and other infectious diseases for the improvement of global health.

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A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

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