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Nocturnal wheeze is common in patients with asthma, and slow release theophyllines may reduce symptoms. As theophyllines are stimulants of the central nervous system the effect of 10 days' twice daily treatment with sustained release choline theophyllinate or placebo on symptoms, overnight bronchoconstriction, nocturnal oxygen saturation, and quality of sleep were studied in a double blind crossover study in nine stable patients with nocturnal asthma (five men, four women, age range 23-64 years; forced expiratory volume in one second (FEV1) 0.85-3.8 1; vital capacity 1.95-6.1 1). When treated with the active drug all patients had plasma theophylline concentrations of at least 28 mmol/l (5 micrograms/ml) (peak plasma theophylline concentrations 50-144 mmol/l (9-26 micrograms/ml]. Morning FEV1 was higher when treated with sustained release choline theophyllinate (2.7 (SEM 0.3) 1) than placebo (2.1 (0.3) 1) (p less than 0.01). Both daytime and nocturnal symptoms were reduced when the patients were treated with sustained release choline theophyllinate and subjective quality of sleep was improved (p less than 0.002). When treated with the active drug, however, quality of sleep determined by electroencephalography deteriorated with an increase in wakefulness and drowsiness (p less than 0.05) and a reduction in non-rapid eye movement sleep (p less than 0.005). Treatment with choline theophyllinate had no effect on either the occurrence or the severity of transient nocturnal hypoxaemic episodes or apnoeas or hypopnoeas. In conclusion, sustained release choline theophyllinate prevents overnight bronchoconstriction, but impairs quality of sleep defined by electroencephalography.
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PMID:Sustained release choline theophyllinate in nocturnal asthma. 393 4

Patients with asthma often wheeze at night and they also become hypoxic during sleep. To determine whether ketotifen, a drug with sedative properties, is safe for use at night in patients with asthma, we performed a double blind crossover study comparing the effects of a single 1 mg dose of ketotifen and of placebo on arterial oxygen saturation (SaO2), breathing patterns, electroencephalographic (EEG) sleep stage, and overnight change in FEV1 in 10 patients with stable asthma. After taking ketotifen, the patients slept longer and their sleep was less disturbed than after taking placebo, true sleep occupying 387 (SEM 8) minutes after ketotifen and 336 (19) minutes after placebo (p less than 0.02). On ketotifen nights the patients had less wakefulness and drowsiness (EEG sleep stages 0 and 1) and more non-rapid eye movement (non-REM) sleep than on placebo nights, but the duration of REM sleep was similar on the two occasions. Nocturnal changes in SaO2, the duration of irregular breathing, and overnight change in FEV1 were unaffected by ketotifen.
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PMID:Ketotifen and nocturnal asthma. 635 63

We wanted to investigate the natural evolution of Obstructive Sleep Apnoea Syndrome (OSAS). We therefore followed 58 patients who refused any treatment at the time of diagnosis. Of the eligible patients 32 subjects enrolled in instrumental follow-up. The effects on daytime somnolence, daytime lung function and nocturnal respiratory disturbances were retrospectively evaluated by repeating Multiple Sleep Latency Test (MSLT), spirometry and polysomnography after a follow-up period of at least 5 years (5.7 +/- 0.2 SEM yrs). In the patient group as a whole the mean Apnoea+Hypopnoea Index (AHI), the mean low arterial oxygen saturation (Sao2) and the mean Body Mass Index (BMI) did not change over time. The only significant differences were the increase in mean duration of apnoeas (21.0 vs 23.5 s) and hypopneas (13.5 vs 16.3 s) and the decrease in AHI < 80% (13.3 vs 7.9). No correlations were found between the changes in AHI or mean low Sao2 and age, BMI, AHI, mean low Sao2, pulmonary function tests or arterial blood gases at baseline. No significant changes were observed in systemic blood pressure, pulmonary function tests, blood gases analysis or MSLT. "Improved" (n = 6) and "worsened" (n = 7) groups were defined by a reduction or increase in AHI over 35% of baseline value. At baseline the "worsened" group tended to have lower AHI and higher mean low Sao2 compared with the "improved" group. In the "worsened" group the BMI rose significantly from 26.0 to 29.2, AHI rose significantly from 14.1 to 51.3 and mean low Sao2 decreased from 92 to 90 (NS).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Natural evolution of sleep apnoea syndrome: a five year longitudinal study. 782 77

Nasal continuous positive airway pressure (NCPAP) improves sleepiness and prognosis in obstructive sleep apnea (OSA). Our objective was to document NCPAP compliance and the percentage of time that the effective pressure shown to eliminate 95% of the obstructive apneas and hypopneas was maintained. We built and covertly installed an elapsed timer and mask pressure transducer recorder in NCPAP units of 47 OSA patients. Subjects were seen at 2- to 8-wk intervals over 6 months. Group mean age was 51 yr; 38 males, with mean body mass index of 42; all complained of daytime sleepiness. Initial full night polysomnography demonstrated a mean apnea-hypopnea index (AHI) of 58 +/- 2.6 SEM (range, 10 to 115). Nine subjects discontinued therapy within 3 months for various reasons. In the remaining subjects (n = 38) the actual mean nightly hours of use was 4.7 which represents 68% of the stated total sleep time (compliance). However, effective mean hours of use was 4.3 which represents 91% of the time that prescribed effective pressure was maintained at the mask. The AHI did not correlate with compliance, but did correlate with effective use (R = 0.27048, p = 0.0006). Subjective initial complaints of daytime sleepiness correlated with compliance only during the first visit (R = 0.38590, p = 0.05). No predictors for compliance were found.
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PMID:Nasal CPAP: an objective evaluation of patient compliance. 811 74

1. To assess the influence of counterregulatory hormones, independently of neuroglycopaenia, on higher cerebral (cognitive) function, 'hypoglycaemic' warning symptoms and glucose kinetics, 10 healthy subjects participated in two hyperinsulinaemic (2 m-units min-1 kg-1) glucose clamp studies. After 100 min of euglycaemia (plasma glucose level 5 mmol/l), the plasma glucose level was either (a) maintained at 5 mmol/l for 120 min by glucose infusion with concomitant replacement of counterregulatory hormones (continuous infusions of glucagon, adrenaline, noradrenaline, cortisol and growth hormone) to mimic the hormonal milieu normally associated with hypoglycaemia (hormone infusion study) or (b) lowered to 2.8 mmol/l for 120 min (hypoglycaemia study). Assessments were made of cognitive function (P300 auditory evoked responses), symptoms (visual analogue scales) and glucose kinetics (3-[3H]glucose). 2. Hypoglycaemia was associated with an increase in all symptoms (facial flushing, palpitations, tingling, trembling, sweating, hunger, light-headedness and sleepiness, P < 0.01) and all subjects were aware that blood glucose levels had fallen. P300 evoked potential latency increased from 280 +/- 6 to 312 +/- 5 ms (mean +/- SEM, P < 0.01). In contrast, P300 latency and several individual symptoms (hunger, facial flushing, sweating and light-headedness) did not change from baseline during the hormone infusion study (P < 0.05 versus hypoglycaemia). Hepatic glucose production was lower (1.5 +/- 0.4 versus 2.3 +/- 0.3 mg min-1 kg-1, P < 0.05) and peripheral glucose uptake was higher (7.4 +/- 1.0 versus 5.6 +/- 0.6 mg min-1 kg-1, P < 0.01) during infusion of the hormones compared with during hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of counterregulatory hormones, independently of hypoglycaemia, on cognitive function, warning symptoms and glucose kinetics. 840 88

The objective of the present experiment was to assess ethyl alcohol (ETOH) dependence brought about by a semivoluntary intermittent intake regimen in rats. Male Wistar rats weighing 150-250 g at the onset of the experiment were assigned to the following groups: 0% ETOH (N = 11), 5% ETOH (N = 20), 20% ETOH (N = 20) and 40% ETOH (N = 18). ETOH solutions were offered at the end of the day and overnight from Monday to Friday, and throughout weekends, for 90 days. The concentration of the ETOH solutions was increased in a stepwise fashion allowing the rats to get used to the taste of alcohol. Reposition of pure water was permitted during 1-h water drinking periods in the morning. Daily volume intake (+/- SEM) averaged 25.4 +/- 0.4 ml (0% ETOH), 23.8 +/- 0.6 ml (5% ETOH), 17.6 +/- 0.7 ml (20% ETOH) and 17.5 +/- 0.6 ml (40% ETOH). ETOH consumption differed significantly (P < 0.05) among groups, averaging 4.4 +/- 0.2 g kg-1 day-1 (5% ETOH), 10.3 +/- 0.3 g kg-1 day-1 (20% ETOH) and 26 +/- 1.2 kg-1 day-1 (40% ETOH). Furthermore, ETOH detection in plasma 10-12 h after offering the solution indicated that its consumption in the 40% ETOH group was sufficient to override its metabolism. Overt signs of ETOH dependence, such as increased thirst, hyperactivity, puffing, hair ruffling and startle responsiveness as well as reduced drowsiness, were significantly increased in the 20% and 40% ETOH groups compared to the 0% and 5% groups. Accordingly, the model described here proved to be a useful tool for the evaluation of subtle or moderate behavioral and physical consequences of long-term ETOH intake.
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PMID:Alcohol dependence induced in rats by semivoluntary intermittent intake. 945 71

Melatonin has been shown to have hypnotic and hypothermic effects in young adults and has been proposed as treatment for insomnia. However, the hypnotic and thermoregulatory effects of melatonin remain to be simultaneously investigated for aged good and poor sleepers. The aim of this study was to explore the short-term effects of exogenous oral daytime melatonin on core body temperature, sleep latency, and subjective vigor and affect in aged women. Twelve sleep maintenance insomniacs and 10 good sleeping postmenopausal female subjects [mean (SD) age = 65.2 (7.4) years] participated in a double-blind, crossover study in which they received a capsule containing either melatonin (5 mg) or a placebo at 1400 hours. Continuous core body temperature and hourly multiple sleep latency tests (MSLT) were collected from 1100-2030 hours. Self-reported estimates of global vigor (sleepiness) and affect were collected prior to each MSLT using visual analog scales. Comparison of good and poor sleepers failed to reveal any significant differences in core body temperature, sleep latency, or subjective vigor and affect. However, for both groups combined, melatonin administration [absolute postadministration mean (SEM) = 36.9 (0.05) degrees C] significantly lowered core body temperature compared with placebo [37.1 (0.05) degrees C]. Similarly, melatonin administration significantly reduced latency to stage 1 (SOL1) and stage 2 (SOL2) [absolute postadministration mean SOL1 = 20.1 (1.7) and SOL2 = 20.7 (1.6) minutes] compared with placebo [SOL1 = 24.3 (1.2) and SOL2 = 25.2 (1.1) minutes]. Treatment had no significant effect on either vigor or affect. Overall, our results suggest that although short-term exogenous oral daytime melatonin has significant hypothermic and hypnotic effects in aged women, the size of the effects is modest.
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PMID:Daytime melatonin administration in elderly good and poor sleepers: effects on core body temperature and sleep latency. 949 23

Fentanyl has been incorporated into a transdermal therapeutic system (TTS) containing a rate-limiting membrane that provides constant release of the opioid. TTS fentanyl provides continuous opioid delivery for up to 72 hr without the need for special equipment. After Institutional Review Board approval, 53 patients with cancer pain requiring 45 mg or more of oral morphine daily were admitted into an open-label, prospective, multicenter evaluation of TTS fentanyl for the relief of pain. After a 1-week stabilization on oral morphine, patients were transferred from morphine to an appropriate dose of TTS-fentanyl (25, 50, 75, or 100 micrograms/hr) administered as a transdermal patch every 3 days. TTS fentanyl was titrated to pain relief, and patients were followed up for as long as 3 months. Pain relief and the side effects of the medications were assessed daily. Twenty-six men and 27 women with a mean (+/- SD) age of 61 (+/- 12) years entered the study; 23 patients completed the full 84-day study. The mean duration of TTS fentanyl use was 58 +/- 32 days. The mean (+/- SEM) daily morphine dose during the last 2 days of stabilization was 189 (+/- 20) mg, and the mean initial fentanyl patch dose was 58 (+/- 6) micrograms/hr. The mean daily morphine dose taken "as needed" for breakthrough pain at study completion was 35 mg. The mean final fentanyl dosage at study completion was 169 (+/- 29) micrograms/hr. Pain relief was rated as good or excellent by 82% of patients during the treatment period. When asked to compare pain relief during the first month of TTS-fentanyl use to that provided by their last analgesic before study entry, 63% preferred TTS fentanyl. Side effects considered related to the fentanyl patch were nausea (13%), vomiting (8%), skin rash (8%), and drowsiness (4%). Thirty percent of patients reported adverse experiences related to the fentanyl patch, and 17% had to be discontinued from the study. We conclude that TTS fentanyl administered every 3 days for the treatment of cancer pain is effective, safe, and well tolerated by most patients.
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PMID:A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain. 973 1

Recent research has shown a close temporal relationship between the nocturnal decrease in rectal core temperature and the initiation of sleep. However, there is not yet a clear temporal relationship between changes in peripheral and core temperatures and nocturnal sleep onset. We recorded body temperatures in 14 adult males (age +/- SEM = 22.1 +/- 0.6 y), who attended the sleep laboratory for an adaptation night and two counterbalanced experimental sessions. Subjects self-selected lights-out on one experimental night (the Habitual Sleep condition). To determine the relationship between body temperature changes and sleep onset, lights out was delayed until after 01.00 hours on the other experimental night (Delayed Sleep condition). Individual datasets in both conditions were expressed relative to the time of sleep onset in the Habitual Sleep condition only, so that they were aligned at identical clock times. Saliva samples confirmed that mean dim light melatonin onset (DLMO) occurred at 00.10 +/- 00.16 hours in the Delayed Sleep condition, which was after habitual sleep onset at 23.44 +/- 00.08 hours. Rectal core temperature (Tc) decreased significantly over time only in the Habitual Sleep condition (P < 0.01). For the 20 min before habitual sleep onset, Delayed Sleep Tc was on average 0.1 degree C higher than Tc in the Habitual Sleep condition (P < 0.01). The greater decline in Habitual Sleep Tc was associated with significantly increased peripheral hand and foot skin temperatures before sleep (both P < 0.05). Subjective sleepiness measures were higher in the Habitual Sleep onset condition from 150 min prior until sleep onset (P < 0.01). From these results it is reasonable to infer that a sequence of thermoregulatory and sleep propensity changes occur before, but are associated with habitual sleep onset, as the changes are significantly attenuated if sleep is delayed.
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PMID:Changes in sleepiness and body temperature precede nocturnal sleep onset: evidence from a polysomnographic study in young men. 978 70

Objectives: To assess the long-term efficacy and safety of modafinil in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.Background: Modafinil has been shown to be effective and well tolerated for treating EDS associated with narcolepsy in two large-scale, well-controlled, 9-week clinical trials.Methods: Four hundred and seventy eight adult patients with a diagnosis of narcolepsy who had completed one of two 9-week, double-blind, placebo-controlled, multicenter, clinical trials of modafinil were enrolled in two 40-week, open-label, extension studies. A flexible-dose regimen (i.e. 200, 300, or 400 mg daily) was followed in one study. In the second study, patients received 200 mg/day for 1 week, followed by 400 mg/day for 1 week. Investigators then prescribed either 200- or 400-mg doses for the duration of the study. Efficacy was evaluated using Clinical Global Impression of Change (CGI-C) scores, the Epworth Sleepiness Scale (ESS), and the 36-item Medical Outcomes Study health survey (SF-36). Adverse events were recorded. Data from the two studies were combined.Results: The majority of patients ( approximately 75%) received 400 mg of modafinil daily. Disease severity improved in >80% of patients throughout the 40-week study. At weeks 2, 8, 24, and 40, disease severity was 'much improved' or 'very much improved' in 49, 58, 59, and 58% of patients, respectively. The mean (+/-SEM) ESS score improved significantly from 16.5+/-0.2 at open-label baseline to 12.4+/-0.2 at week 2 and remained at that level through week 40 (P<0.001). Quality of life scores at weeks 4, 8, 24, and 40 were significantly improved versus open-label baseline scores for six of the eight SF-36 domains (P<0.001). The most common treatment-related adverse events were headache (13%), nervousness (8%), and nausea (5%). Most adverse events were mild to moderate in nature. A total of 341 patients (71%) completed the studies. Forty-three patients (9.0%) discontinued treatment because of adverse events.Conclusions: Modafinil is effective for the long-term treatment of EDS associated with narcolepsy and significantly improves perceptions of general health. Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment.
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PMID:Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. 1082 34


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