Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial.

AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.

PURPOSE: Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability. METHODS: This randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs. FINDINGS: Of the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens. IMPLICATIONS: No significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.

Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers.

PURPOSE: Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. METHODS: The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. FINDINGS: Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. IMPLICATIONS: In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing. ClinicalTrials.gov identifier: NCT00800319.

Traffic-related air pollution and sleep in the Boston Area Community Health Survey.

Little is known about environmental determinants of sleep. We investigated the association between black carbon (BC), a marker of traffic-related air pollution, and sleep measures among participants of the Boston Area Community Health Survey. We also sought to assess the impact of sociodemographic factors, health conditions, and season on associations. Residential 24-h BC was estimated from a validated land-use regression model for 3821 participants and averaged over 1-6 months and 1 year. Sleep measures included questionnaire-assessed sleep duration, sleep latency, and sleep apnea. Linear and logistic regression models controlling for confounders estimated the association between sleep measures and BC. Effect modification was tested with interaction terms. Main effects were not observed between BC and sleep measures. However, in stratified models, males experienced 0.23 h less sleep (95% CI: -0.42, -0.03) and those with low SES 0.25 h less sleep (95% CI: -0.48, -0.01) per IQR increase in annual BC (0.21 µg/m(3)). In blacks, sleep duration increased with annual BC (ß=0.34 per IQR; 95% CI: 0.12, 0.57). Similar findings were observed for short sleep (≤5 h). BC was not associated with sleep apnea or sleep latency, however, long-term exposure may be associated with shorter sleep duration, particularly in men and those with low SES, and longer sleep duration in blacks.

Restless nocturnal eating: a common feature of Willis-Ekbom Syndrome (RLS).

STUDY OBJECTIVES: To determine the frequency of nocturnal eating (NE) and sleep related eating disorder (SRED) in restless legs syndrome (RLS) versus psychophysiological insomnia (INS), and the relationship of these conditions with dopaminergic and sedative-hypnotic medications. DESIGN: Prospective case series. SETTING: Sleep disorders center. PATIENTS: Newly diagnosed RLS or INS. INTERVENTION: RLS or INS pharmacotherapy with systematic follow up interview for NE/SRED. MEASUREMENTS AND RESULTS: Patients presenting with RLS (n = 88) or INS (n = 42) were queried for the presence of NE and SRED. RLS patients described nocturnal eating (61%) and SRED (36%) more frequently than INS patients (12% and 0%; both p < 0.0001). These findings were not due to arousal frequency, as INS patients were more likely to have prolonged nightly awakenings (93%) than RLS patients (64%; p = 0.003). Among patients on sedative-hypnotics, amnestic SRED and sleepwalking were more common in the setting of RLS (80%) than INS (8%; p < 0.0001). Further, NE and SRED in RLS were not secondary to dopaminergic therapy, as RLS patients demonstrated a substantial drop (68% to 34%; p = 0.0026) in the frequency of NE after dopamine agents were initiated, and there were no cases of dopaminergic agents inducing novel NE or SRED. CONCLUSION: NE is common in RLS and not due to frequent nocturnal awakenings or dopaminergic agents. Amnestic SRED occurs predominantly in the setting of RLS mistreatment with sedating agents. In light of previous reports, these findings suggest that nocturnal eating is a non-motor manifestation of RLS with several clinical implications discussed here.

[Sleep disturbance induced by cocaine abstinence involving in A2A receptor over-expression in rat hypothalamus].

Adult rats were implanted with sleep-wake recording electrodes in our experiments. Polygraphic signs of undisturbed sleep-wake activities were recorded for 24 h before cocaine administration, cocaine withdrawal day 1 (acute), day 8 (subacute), and day 14 (subchronic). Western blot method was performed to examine the expression levels of adenosine receptor subtypes in hypothalamus and cerebellum. Non rapid eye movement (NREM) sleep was significantly increased during nighttime (P < 0.01) and daytime (P < 0.05) on withdrawal day 8. The increase of NREM sleep was significant during nighttime (P < 0.01) and slight during daytime on withdrawal day 14, whereas both daytime and nighttime rapid eye movement (REM) sleeps were reduced markedly (P < 0.01) on withdrawal day 8 and 14. In addition, A2A receptor level was significantly enhanced on cocaine withdrawal day 8 and day 14 (P < 0.05), whereas A1 receptor level reduced markedly on withdrawal day 14 (P < 0.05). However, compared with that in the control group, no significant changes existed among adenosine A1, A2A and A2B receptors in rat cerebellum on cocaine withdrawal day 1, day 8 and day 14. Our findings suggest that sleep disorder caused by subacute and subchronic cocaine abstinence may be associated with over-expression of adenosine A2A receptor in rat hypothalamus to some extent.

Sleep apnoeas and neurobehavioral effects in solvent exposed workers.

BACKGROUND: Exposure to organic solvents may cause an increase of sleep apnoeas, which may explain the excess of fatigue, concentration and memory problems reported in exposed workers. METHODS: Polysomnography was performed in 21 long-term exposed printers and 27 controls. In addition, a questionnaire regarding sleep related complaints, Q16 questionnaire and computerized neurobehavioral tests were administered. The groups matched well regarding age, weight, neck circumference and schooling level. A semi-quantitative cumulative exposure index was calculated. RESULTS: Excessive sleepiness while watching TV (p<0.01) and diminished sexual interest (p=0.03) was found in the organic solvent-workers. The sleep complaints score correlated positively with the exposure index and duration (both p=0.01). The polysomnography results showed an increase of central apnoeas in the exposed workers (67%) compared to the referents (30%). The presence of central apnoeas was positively correlated with the exposure index (p<0.05) in regression models. Of the neurobehavioral test only hand-eye coordination was dose-related impaired in the exposed workers. The co-existence of abnormal values on at least one neurobehavioral test and the presence of central apnoeas was observed in the exposed workers, but did not reach significance. CONCLUSIONS: Workers chronically exposed to low organic solvent levels may experience mild sleeping problems, however, our data do not support the hypothesis that the clinical picture of chronic toxic encephalopathy can be primarily caused by the induction of sleep apnoea syndrome. It seems thus that the risk to experience central apnoeas rather accompanies the risk of impaired neurobehavioral performance with increasing exposure in a working population.

Probable trimethoprim/sulfamethoxazole-induced higher-level gait disorder and nocturnal delirium in an elderly man.

OBJECTIVE: To report a case of probable trimethoprim/sulfamethoxazole (TMP/SMX)-induced higher-level gait disorder (HLGD) and nocturnal delirium in an elderly patient on high-dose oral therapy. CASE SUMMARY: An 82-year-old man with a recent history of depression became comatose following an overdose of escitalopram and oxazepam. He was admitted, ventilated for 7 days in the intensive care unit, and treated with piperacillin/tazobactam and cefepime for aspiration pneumonia. Following discharge to a medical ward, respiratory symptoms persisted and imaging confirmed pulmonary abscesses. Stenotrophomonas maltophilia was isolated from sputum and, on day 15, TMP/SMX 800 mg/160 mg 1 tablet every 12 hours was initiated. On day 35, the dose was increased to 800 mg/160 mg 2 tablets every 12 hours. By day 37, the patient was unsteady when attempting to stand. From day 40, he was noted to have features of HLGD with gait ignition failure, poor balance, and frequent falls. His other medications at this time were thiamine 100 mg daily, multivitamin 1 tablet daily, omeprazole 20 mg every 12 hours, and modified-release venlafaxine 150 mg daily. Investigation did not reveal any cause for his acute gait disturbance. TMP/SMX was stopped on day 48 and, by day 51, the patient's gait had returned to normal. DISCUSSION: Neuropsychiatric adverse reactions with TMP/SMX have been infrequently reported. The Naranjo probability scale indicated that TMP/SMX was the probable cause of HLGD in this patient. CONCLUSIONS: At time of writing, this was the first reported case of HLGD associated with TMP/SMX. Clinicians should consider this adverse reaction as a potential cause of HLGD, especially in the elderly and those with malnutrition and hepatic or renal dysfunction.

Report of two cases where sleep related eating behavior occurred with the extended-release formulation but not the immediate-release formulation of a sedative-hypnotic agent.

We report two cases in which amnestic sleep related eating disorder (SRED) occurred with extended-release zolpidem but not with the immediate-release formulation. These cases illustrate how even relatively small differences such as formulation can affect the likelihood of experiencing such events.

Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children.

OBJECTIVES: To obtain data on the pharmacokinetics of efavirenz in children in clinical practice. METHODS: HIV-1-infected children received efavirenz capsules or tablets in accordance with manufacturer's dosing recommendations. Plasma was collected at regular visits and analysed by HPLC. The therapeutic range of efavirenz was defined as 1.0-4.0 mg/L. RESULTS: Thirty-three children were included. Median (range) age, body weight, dose and dose/kg were 8.2 (2.1-16.7) years, 24 (12-62) kg, 300 (200-800) mg and 13.3 (9.7-22.5) mg/kg, respectively. Median (range) efavirenz plasma concentration at first sampling was 2.8 (0.13-11.6) mg/L. Plasma concentrations were not dependent on age (P = 0.97) or dose/kg (P = 0.87). A total of 307 efavirenz plasma concentrations were determined. Forty-five samples (14.7%) contained >4.0 mg/L, and 27 samples (8.8%) contained <1.0 mg/L. Eight children (24%) reported persistent adverse events probably caused by efavirenz [concentration problems (5), sleep disorder (1), psychotic reaction (1) and seizure (1)]; six discontinued efavirenz for this reason. A non-significant trend existed towards a higher proportion of toxic efavirenz plasma concentrations (>4.0 mg/L) in subjects who reported efavirenz adverse events: 25.9% versus 12.8% (P = 0.23; t-test). Viral load was <50 copies/mL in all 27 subjects who continued efavirenz, despite occasional subtherapeutic efavirenz plasma concentrations in 12 children. The occasional subtherapeutic levels suggest that temporal non-adherence was present. CONCLUSIONS: Efavirenz as part of highly active antiretroviral therapy was highly effective in children able to tolerate the drug. Therapeutic drug monitoring (TDM) as part of toxicity management may prevent discontinuation in a subset of patients. Temporal non-adherence occurs frequently. TDM may allow initiation of adherence interventions before viral load becomes detectable.

A study of quetiapine: efficacy and tolerability in psychotic adolescents.

OBJECTIVE: To study the effectiveness, safety, and tolerability of quetiapine in adolescents with psychotic disorders. METHODS: This study was an 8-week, open trial using quetiapine with 15 adolescents, ages 13-17 years, mean age 15.1 years, with a diagnosis of a psychotic disorder. Our primary instruments focused on psychotic symptomatology as measured by the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Positive and Negative Syndrome Scale (PANSS), and the Young Mania Rating Scale (YMRS). Other measures included adverse events, clinical laboratory tests, vital signs, electrocardiogram (ECG), extrapyramidal (EPS) measures, and ophthalmologic examination. RESULTS: Quetiapine significantly reduced psychotic symptoms as measured by the BPRS, PANSS, YMRS, CGI, and CGI Severity of Illness scale. The average weight gain was 4.1 kg. After correction for expected weight gain, the mean weight gain over the 8-week period was 3.4 kg. Prolactin and cholesterol remained unchanged. Trends were found for a decrease in T4 and an increase in thyroid-stimulating hormone. Common adverse effects were somnolence, agitation, drowsiness, and headache. No significant findings were noted on repeat ECGs, EPS measures, or ophthalmic examination. The final average treatment dose was 467 mg/day (range 300-800 mg/day). CONCLUSIONS: Quetiapine is suggested to be effective treatment of youths with psychotic disorders and to have a favorable side-effect profile.

Sleep disturbances after acute exposure to alcohol in mothers' milk.

The results of previous research in our laboratory revealed that breast-fed infants experience significantly less active sleep after exposure to alcohol in their mothers' milk than do breast-fed infants not exposed to alcohol. The present study tested the hypothesis that infants would compensate for such reductions if their mothers then refrained from drinking alcohol. To this end, 23 breast-fed infants from 3 to 5 months of age and their mothers were tested on 2 days separated by 1 week. A small, computerized movement detector, an actigraph, was placed on the infants' left ankles to monitor sleep and activity patterning after which they were bottle fed mother's milk alone (control condition) on 1 test day and mother's milk containing 32 mg of ethanol per 100 ml--the average concentration detected in human milk after lactating women drank an acute dose (0.3 g/kg) of alcohol--on the other. The infants' behaviors were monitored for the next 24 h; the first 3.5 h of monitoring on each test day took place at the Monell Center. Consistent with previous findings, infants exhibited significantly less active sleep during the 3.5 h immediately after exposure to alcohol in mothers' milk compared with the control condition; the decrease in active sleep was observed in all but 4 of the infants tested. Compensatory increases in active sleep were then observed in the next 20.5 h, when mothers refrained from drinking alcohol. Although the mechanisms underlying the reduction in sleep remain to be elucidated, these findings demonstrate that short-term exposure to small amounts of alcohol in mothers' milk produces distinctive changes in the infants' sleep-wake patterning.