Determination of asenapine in presence of its inactive metabolites in human plasma by LC-MS/MS.

A highly selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been described for the determination of asenapine (ASE) in presence of its inactive metabolites N-desmethyl asenapine (DMA) and asenapine-N-glucuronide (ASG). ASE, and ASE 13C-d3, used as internal standard (IS), were extracted from 300 µL human plasma by a simple and precise liquid-liquid extraction procedure using methyl tert-butyl ether. Baseline separation of ASE from its inactive metabolites was achieved on Chromolith Performance RP8e (100 mm × 4.6 mm) column using acetonitrile-5.0 mM ammonium acetate-10% formic acid (90:10:0.1, v/v/v) within 4.5 min. Quantitation of ASE was done on a triple quadrupole mass spectrometer equipped with electrospray ionization in the positive mode. The protonated precursor to product ion transitions monitored for ASE and ASE 13C-d3 were m/z 286.1 → 166.0 and m/z 290.0 → 166.1, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) of the method were 0.0025 ng/mL and 0.050 ng/mL respectively in a linear concentration range of 0.050-20.0 ng/mL for ASE. The intra-batch and inter-batch precision (% CV) and mean relative recovery across quality control levels were ≤ 5.8% and 87.3%, respectively. Matrix effect, evaluated as IS-normalized matrix factor, ranged from 1.03 to 1.05. The stability of ASE under different storage conditions was ascertained in presence of the metabolites. The developed method is much simpler, matrix free, rapid and economical compared to the existing methods. The method was successfully used for a bioequivalence study of asenapine in healthy Indian subjects for the first time.

Highly sensitive LC-MS/MS method to estimate doxepin and its metabolite nordoxepin in human plasma for a bioequivalence study.

A selective, sensitive and rugged liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been developed for the simultaneous determination of doxepin (Dox) and its pharmacologically active metabolite, nordoxepin (NDox) in human plasma. The analytes and their internal standards (IS) were extracted from 500 µL of human plasma by liquid-liquid extraction using methyl tert-butyl ether. Chromatographic separation was achieved on Hypurity C8 column (100 mm × 4.6 mm, 5 µm) using a mixture of acetonitrile-methanol (95:5, v/v) and 2.0 mM ammonium formate in 93:7 (v/v) ratio. Detection was accomplished by tandem mass spectrometry in the positive ionization and multiple reaction monitoring acquisition mode. The protonated precursor to product ion transitions studied for Dox, NDox, and their corresponding ISs, propranolol and desipramine, were m/z 280.1→107.0, 266.0 →107.0, 260.1→116.1 and 267.1→72.1, respectively. A linear dynamic range of 15.0-3900 pg/mL for Dox and 5.00-1300 pg/mL for NDox was established with mean correlation coefficient (r 2) of 0.9991 and 0.9993, respectively. The extraction recovery ranged from 86.6%-90.4% and 88.0%-99.1% for Dox and NDox, respectively. The intra-batch and inter-batch precision (% CV) across quality control levels was ≤ 8.3% for both the analytes. Stability evaluated under different storage conditions showed no evidence of degradation and the % change in stability samples compared to nominal concentration ranged from 4.7% to 12.3%. The method was successfully applied to a bioequivalence study of 6 mg doxepin hydrochloride orally disintegrating tablet in 41 healthy Indian subjects under fasting and fed conditions.

Social and Behavioral Determinants of Perceived Insufficient Sleep.

Insufficient sleep is associated with cardiometabolic disease and poor health. However, few studies have assessed its determinants in a nationally representative sample. Data from the 2009 behavioral risk factor surveillance system were used (N = 323,047 adults). Insufficient sleep was assessed as insufficient rest/sleep over 30 days. This was evaluated relative to sociodemographics (age, sex, race/ethnicity, marital status, region), socioeconomics (education, income, employment, insurance), health behaviors (diet, exercise, smoking, alcohol), and health/functioning (emotional support, BMI, mental/physical health). Overall, insufficient sleep was associated with being female, White or Black/African-American, unemployed, without health insurance, and not married; decreased age, income, education, physical activity; worse diet and overall health; and increased household size, alcohol, and smoking. These factors should be considered as risk factors for insufficient sleep.

The development of a questionnaire to assess sleep-related practices, beliefs, and attitudes.

There are no established questionnaires that evaluate habitual sleep practices in the context of beliefs and attitudes about sleep. This study describes an effort to develop and evaluate a questionnaire that assesses habitual sleep; behaviors associated with sleep and potential sleep problems; sleep hygiene; social and environmental determinants of sleep; beliefs and attitudes about sleep as it relates to health, safety, and functioning; and knowledge about sleep. A total of 124 participants completed the final questionnaire. Overall, the questionnaire and subscales demonstrated moderate internal consistency, and concurrent and divergent validity were demonstrated by comparing various subscales to existing measures. Future studies may utilize the descriptive data to determine the role of behavioral, social, and environmental determinants of healthy sleep.

Sleep symptoms, race/ethnicity, and socioeconomic position.

STUDY OBJECTIVES: Growing evidence indicates sleep is a major public health issue. Race/ethnicity and socioeconomics may contribute to sleep problems. This study assessed whether sleep symptoms were more prevalent among minorities and/or the socioeconomically disadvantaged. DESIGN: Cross-sectional. SETTING: Epidemiologic survey. PATIENTS OR PARTICIPANTS: 2007-2008 National Health and Nutrition Examination Survey (N = 4,081). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Sociodemographics included age, sex, race/ethnicity, marital status, and immigration. Socioeconomics included poverty, education, private insurance, and food insecurity. Sleep symptoms assessed were sleep latency > 30 min, difficulty falling asleep, sleep maintenance difficulties, early morning awakenings, non-restorative sleep, daytime sleepiness, snorting/gasping, and snoring. Decreased reported problems for most symptoms were found among minorities, immigrants, and lower education levels. In general, in fully adjusted models, long sleep latency was associated with female gender, being black/African American, lower education attainment, no private insurance, and food insecurity. Difficulty falling asleep, sleep maintenance difficulties, early morning awakenings, and non-restorative sleep were also associated with female gender and food insecurity. Daytime sleepiness was seen in female and divorced respondents. Snorting/gasping was more prevalent among male, other-Hispanic/Latino, and 9(th)- to 11(th)-grade-level respondents. Snoring was prevalent among male, other-Hispanic/Latino, less-educated, and food-insecure respondents. CONCLUSIONS: Sleep symptoms were associated with multiple sociodemographic and economic factors, though these relationships differed by predictor and sleep outcome. Also, reports depended on question wording.

Sleep-related behaviors and beliefs associated with race/ethnicity in women.

Explore how social factors influence sleep, especially sleep-related beliefs and behaviors. Sleep complaints, sleep hygiene behaviors, and beliefs about sleep were studied in 65 black/African American and white/European American women. Differences were found for snoring and discrepancy between sleep duration and need. Sleep behaviors differed across groups for napping, methods for coping with sleep difficulties, and nonsleep behaviors in bed. Beliefs also distinguished groups, with differences in motivation for sleep and beliefs about sleep being important for health and functioning. These findings have important public health implications in terms of developing effective sleep education interventions that include consideration of cultural aspects.

Sleep duration versus sleep insufficiency as predictors of cardiometabolic health outcomes.

OBJECTIVE: The objective of the present study was to investigate the relationship between sleep insufficiency and sleep duration, particularly regarding negative cardiometabolic health outcomes already considered to be affected by reduced sleep time. METHODS: A total of N=30,934 participants from the 2009 Behavioural Risk Factor Surveillance System (BRFSS) answered questions about their sleep duration as well as subjective feelings of sleep insufficiency. Outcomes included body mass index (BMI), obesity (BMI ≥ 30kgm(-2)) and history of hypertension, diabetes, hypercholesterolaemia, heart attack and stroke. Linear and logistic regression models examined whether cardiometabolic outcomes were associated with (1) sleep duration alone, (2) sleep insufficiency alone and (3) the combined effect of sleep duration and sleep insufficiency. RESULTS: Results indicated that, when examined alone, sleep duration <5h (versus 7h) was related to BMI (B=2.716, p<0.01), obesity (B=2.080, p<0.000001), diabetes (B=3.162, p<0.000001), hypertension (B=2.703, p<0.000001), hypercholesterolaemia (B=1.922, p<0.00001), heart attack (B=4.704, p<0.000001) and stroke (B=4.558, p<0.000001), and sleep insufficiency (days per week, continuous) was related to BMI (B=0.181, p<0.01), obesity (B=1.061, p<0.000001) and hypercholesterolaemia (B=1.025, p<0.01). All of these relationships remained significant after adjustment for covariates, except for diabetes and sleep duration. Also, after adjustment, a significant relationship between insufficient sleep and hypertension emerged (B=1.039, p<0.001). When evaluated together, after adjustment for covariates, significant relationships remained between sleep duration <5h (versus 7h) and BMI (B=1.266, p<0.05), obesity (B=1.389, p<0.05), hypertension (B=1.555, p<0.01), heart attack (B=2.513, p<0.01) and stroke (B=1.807, p<0.05). It should be noted that relationships between sleep duration >9h (versus 7h) were seen for heart attack (B=1.863, p<0.001) and stroke (B=1.816, p<0.01). In these models, sleep insufficiency was associated with hypercholesterolaemia (B=1.031, p<0.01) and hypertension (B=1.027, p<0.05). CONCLUSIONS: These analyses show that both sleep duration and insufficiency are related to cardiometabolic health outcomes, and that when evaluated together, both variables demonstrate unique effects.

Vasculitides associated with haematological malignancies: a case-based review.

Autoimmune phenomena including vasculitis are known to be associated with malignancy, especially those that are haematological in origin. Vasculitis syndromes associated with malignant disease include cutaneous leucocytoclastic vasculitis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Wegener's granulomatosis and Henoch-Schönlein purpura. We describe a patient whose initial presentation with vasculitis led to the diagnosis of hairy cell leukaemia.

Perceived racial discrimination as an independent predictor of sleep disturbance and daytime fatigue.

Perceived discrimination is a potential cause of racial and ethnic disparities in health. Disturbed sleep may serve as a mechanism linking perceived racism with health consequences. This study investigates data from 7,148 adults from Michigan and Wisconsin who participated in the 2006 Behavioral Risk Factor Surveillance System. Hierarchical logistic regression analyses explored associations between perceived racial discrimination and self-reported sleep disturbance and daytime fatigue. Sleep disturbance and daytime fatigue were reported in 19% and 21% of the sample, respectively. Black/African American respondents (21%) report perceiving worse experiences, compared to people of other races, when seeking health care at higher rates than non-Hispanic White respondents (3%). Results from logistic regression models show that perceived racial discrimination is associated with increased risks of sleep disturbance (odds ratio [OR] = 2.62, p < .0001) and daytime fatigue (OR = 2.07, p < .0001). After adjustment for all covariates, perceived discrimination remains a significant predictor of sleep disturbance (OR = 1.60, p = .04). The interaction between perceived racism and race (Black/African American vs. non-Hispanic White) was nonsignificant. This population-based research adds to the growing body of data, suggesting that perceived racism may impact health via its influence on sleep-wake behaviors.

Age and sleep disturbances among American men and women: data from the U.S. Behavioral Risk Factor Surveillance System.

STUDY OBJECTIVE: Explore the prevalence of sleep-related complaints across age groups, examining effects of sex, general health, and depressed mood. DESIGN: Cross-sectional analysis of data from the 2006 Behavioral Risk Factor Surveillance System (BRFSS). SETTING: Epidemiologic. PARTICIPANTS: Complete-case analysis included 155,877 participants who responded to questions related to Self-Reported Sleep Disturbance (SLEEPDIST) and Self-Reported Tiredness/Lack of Energy (TIREDNESS). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Outcomes were self-reported complaints in response to survey questions assessing SLEEPDIST and TIREDNESS, dichotomized as reporting a complaint < 6 versus ≥ 6 nights or days, respectively, in a 2-wk period. Predictors were age, general health, and depressed mood. All analyses were adjusted for race/ethnicity, income, education, and time since last medical checkup. Across all age groups, women reported more SLEEPDIST and TIREDNESS. Poor general health, mild depressed mood, and moderate/severe depressed mood were associated with SLEEPDIST and TIREDNESS. Both SLEEPDIST and TIREDNESS generally declined across the life span, with fewest endorsements in respondents older than 80 yr. For SLEEPDIST, odds ratios (ORs, reference = 80+) declined from age 18-54 yr, rose slightly, and then declined again after age 59 yr in men. The pattern was similar for women, except a more marked rise was noted from age 40-59 yr. The pattern was similar for TIREDNESS. CONCLUSIONS: Advancing age was not associated with increased Self-Reported Sleep Disturbance or Self-Reported Tiredness/Lack of Energy. These results suggest that the often-reported increase in sleep problems with age is a nonlinear phenomenon, mediated by factors other than physiologic aging.

State and regional prevalence of sleep disturbance and daytime fatigue.

STUDY OBJECTIVES: Social and demographic influences are important for sleep attainment. Geographic location has not been previously explored. METHODS: Data from the 2006 Behavioral Risk Factor Surveillance System (BRFSS) were used (N = 157,319). Participants answered a question on Sleep Disturbance and Daytime Fatigue. Thirty-six states/regions provided data on these items. Prevalence estimates were adjusted for age, sex, ethnoracial group, education, income, employment, general health, healthcare access, and depression. Chi-squared tests were conducted across states and census regions, and pseudo-R(2) values were computed for the effect of state, relative to other predictors. To evaluate potential mediators of census region differences, an analysis of p value change associated with specific covariates and covariate groups was undertaken. RESULTS: Adjusted prevalence rates of Sleep Disturbance differed across states/regions overall (χ(2) = 412.3, p < 0.0001), as well as separately for men (χ(2) = 139.5, p < 0.0001) and women (χ(2) = 350.0, p < 0.0001), as did rates of Daytime Fatigue overall (χ(2) = 245.7, p < 0.0001), and separately for men (χ(2) = 117.5, p < 0.0001) and women (χ(2) = 181.2, p < 0.0001). Analysis of pseudo-R(2) values revealed that despite these significant findings, state differences were an overall weak predictor, representing 1.30% to 1.73% of the magnitude of the effect of the best predictor (mental health). When Census regions were compared, significant differences were found for Sleep Disturbance (p = 0.002), but after adjustment for covariates, these were no longer significant. Differences existed for Daytime Fatigue in adjusted analyses overall (p < 0.0001), with the West reporting the fewest complaints and the South reporting the most. CONCLUSIONS: These results demonstrate that reports of sleep related complaints vary across states, independent (at least partially) of factors that influence circadian rhythms (e.g., latitude).

Obesity, diabetes, and exercise associated with sleep-related complaints in the American population.

AIM: Previous studies have demonstrated relationships between sleep and both obesity and diabetes. Additionally, exercise may improve sleep and daytime function, in addition to weight and metabolic function. The present study extends these findings by examining how general sleep-related complaints are associated with body mass index (BMI), diabetes diagnosis, and exercise in a large, nationally representative sample. SUBJECT AND METHODS: Participants were respondents to the Behavioral Risk Factor Surveillance System (BRFSS). Sleep complaint (SC) was measured with "Over the last 2 weeks, how many days have you had trouble falling asleep or staying asleep or sleeping too much?" Daytime complaint (DC) was measured with "Over the last 2 weeks, how many days have you felt tired or had little energy?" Responses were dichotomized, with ≥6 days indicating complaint. Covariates included age, race/ethnicity, income, and education. RESULTS: Being overweight was associated with DC in women only. Obesity was significantly associated with SC and DC in women, and DC in men. Diabetes was associated with SC and DC in both genders. Any exercise in the past 30 days did not attenuate any BMI or diabetes relationships, but was independently associated with a decrease in SC and DC in both men and women. CONCLUSION: These results suggest that for both men and women diabetes is a significant predictor of sleep and daytime complaints, and there is a relationship between obesity and sleep and complaints for women to a greater extent than men. Finally, exercise was associated with much fewer sleep and daytime complaints in both genders.

Chronic obstructive pulmonary disease diagnosis and management in older adults.

Chronic obstructive pulmonary disease (COPD) in older adults is a complex disorder with several unique age-related aspects. Underlying changes in pulmonary lung function and poor sensitivity to bronchoconstriction and hypoxia with advancing age can place older adults at greater risk of mortality or other complications from COPD. The establishment of the Global Initiative for Obstructive Lung Disease criteria, which can be effectively applied to older adults, has more rigorously defined the diagnosis and management of COPD. An important component of this approach is the use of spirometry for disease staging, a procedure that can be performed in most older adults. The management of COPD includes smoking cessation, influenza and pneumococcal vaccinations, and the use of short-and long-acting bronchodilators. Unlike with asthma, corticosteroid inhalers represent a third-line option for COPD. Combination therapy is frequently required. When using various inhaler designs, it is important to note that older adults, especially those with more-severe disease, may have inadequate inspiratory force for some dry-powder inhalers, although many older adults find the dry-powder inhalers easier to use than metered-dose inhalers. Other important treatment options include pulmonary rehabilitation, oxygen therapy, noninvasive positive airway pressure, and depression and osteopenia screening. Clinicians caring for older adults with an acute COPD exacerbation should also guard against prognostic pessimism. Although COPD is associated with significant disability, there is a growing range of treatment options to assist patients.

"Sleep disparity" in the population: poor sleep quality is strongly associated with poverty and ethnicity.

BACKGROUND: Little is known about the social determinants of sleep attainment. This study examines the relationship of race/ethnicity, socio-economic status (SES) and other factors upon sleep quality. METHODS: A cross-sectional survey of 9,714 randomly selected subjects was used to explore sleep quality obtained by self-report, in relation to socioeconomic factors including poverty, employment status, and education level. The primary outcome was poor sleep quality. Data were collected by the Philadelphia Health Management Corporation. RESULTS: Significant differences were observed in the outcome for race/ethnicity (African-American and Latino versus White: unadjusted OR = 1.59, 95% CI 1.24-2.05 and OR = 1.65, 95% CI 1.37-1.98, respectively) and income (below poverty threshold, unadjusted OR = 2.84, 95%CI 2.41-3.35). In multivariable modeling, health indicators significantly influenced sleep quality most prominently in poor individuals. After adjusting for socioeconomic factors (education, employment) and health indicators, the association of income and poor sleep quality diminished, but still persisted in poor Whites while it was no longer significant in poor African-Americans (adjusted OR = 1.95, 95% CI 1.47-2.58 versus OR = 1.16, 95% CI 0.87-1.54, respectively). Post-college education (adjusted OR = 0.47, 95% CI 0.31-0.71) protected against poor sleep. CONCLUSIONS: A "sleep disparity" exists in the study population: poor sleep quality is strongly associated with poverty and race. Factors such as employment, education and health status, amongst others, significantly mediated this effect only in poor subjects, suggesting a differential vulnerability to these factors in poor relative to non-poor individuals in the context of sleep quality. Consideration of this could help optimize targeted interventions in certain groups and subsequently reduce the adverse societal effects of poor sleep.

Who gets the best sleep? Ethnic and socioeconomic factors related to sleep complaints.

OBJECTIVES: Lower socioeconomic status is associated with short or long sleep duration and sleep disturbance (e.g., sleep apnea), which are all related to increased mortality risk. General sleep complaints, however, which may better approximate symptoms as they are experienced, have not been examined in a large population sample. METHODS: Sample consisted of n=159,856 participants from the Behavioral Risk Factor Surveillance System, representing 36 states/regions across the US. Sleep complaints were measured with a telephone survey item that assessed "trouble falling asleep," "staying asleep" or "sleeping too much." Data analysis utilized hierarchical logistic regression and Rao-Schott chi(2). RESULTS: Asian respondents reported the least complaints, and Hispanic/Latino and Black/African-American individuals reported fewer complaints than Whites. Lower income and educational attainment was associated with more sleep complaints. Employment was associated with less sleep complaints and unemployment with more. Married individuals reported the least sleep complaints. Significant interactions with race/ethnicity indicate that the relationship between sleep complaints and marital status, income and employment differs among groups for men, and the relationship with education differs among groups for women. CONCLUSIONS: Rates of sleep complaints in African-American, Hispanic/Latino and Asian/Other groups were similar to Whites. Lower socioeconomic status was associated with higher rates of sleep complaint.

Mortality associated with short sleep duration: The evidence, the possible mechanisms, and the future.

This review of the scientific literature examines the widely observed relationship between sleep duration and mortality. As early as 1964, data have shown that 7-h sleepers experience the lowest risks for all-cause mortality, whereas those at the shortest and longest sleep durations have significantly higher mortality risks. Numerous follow-up studies from around the world (e.g., Japan, Israel, Sweden, Finland, the United Kingdom) show similar relationships. We discuss possible mechanisms, including cardiovascular disease, obesity, physiologic stress, immunity, and socioeconomic status. We put forth a social-ecological framework to explore five possible pathways for the relationship between sleep duration and mortality, and we conclude with a four-point agenda for future research.

Problems associated with short sleep: bridging the gap between laboratory and epidemiological studies.

Existing data from laboratory studies suggest a number of negative consequences of acute reductions in sleep time. Also, epidemiological data suggest links between shorter self-reported sleep duration and negative health outcomes. These bodies of work are growing, revealing several key points of convergence and opportunities for future exploration. In addition, they begin to highlight possible problems experienced by "short sleepers," who sleep approximately 6h or less per night. While it is likely that this group is heterogeneous, comprised both of individuals with less need for sleep and those not sleeping enough, the laboratory and epidemiological findings point towards directions that can be more fully explored in verified short sleepers. This paper discusses problems associated with the terminology used to describe "short sleep," summarizes laboratory studies exploring neurobehavioral performance, metabolism and obesity, and psychological health and epidemiological studies exploring mortality risk, obesity and metabolism, cardiovascular disease, and general health/psychosocial stress, describes studies of verified short sleepers and explores areas of convergence, laying out possible future directions.