Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial.

TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (-2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects. Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD).

Prevalence of self-reported sleep problems amongst adults with obstructive airway disease in the NHANES cohort in the United States.

RATIONALE: Sleep and respiratory problems are common in adults in the USA. However, sleep problems often remain undiagnosed in patients with obstructive airway diseases (OADs). This study was designed to examine the association between sleep problems and different categories of OAD amongst US adults. METHODS: We conducted an observational, cross-sectional study using a nationally representative sample of the US civilian non-institutionalized population from 2007 to 2008 National Health and Nutritional Examination Survey (NHANES). A total of 3204 study participants aged ≥35 years were stratified into four groups, using a self-reported history of asthma and data from spirometry: asthma-COPD overlap (ACO) (n = 70, 2.2%), asthma (n = 168, 5.2%), chronic obstructive pulmonary disease (COPD) (n = 412, 12.8%), and those without any OAD (normal) (n = 2554, 79.7%). After characterizing the baseline demographics and health status of the four groups, multivariate logistic regression analysis was performed to estimate the likelihood of sleep problems in adults after adjusting for age, gender, body mass index, smoking, alcohol, obstructive sleep apnea syndrome (OSAS), depression, and diabetes. The index sample was the normal group. Sleep problems were defined as any complaints which affect or involve sleep. RESULTS: The participants with COPD were older (62.0 ± 11.7 years) as compared to ACO (59.1 ± 11.3 years), asthma (53.6 ± 11.3), and normal groups (53.8 ± 12.1) (p < 0.0001). Comparing baseline characteristics between the four groups, there were significant associations between OAD status and sleep problems including inadequate sleep, sleep-onset insomnia, snoring, frequent trouble sleeping, nocturnal arousals, early morning awakenings, fatigue, daytime sleepiness, use of prescription medication for sleep, leg jerks, leg cramps, difficulty in concentration, and difficulty in remembering things when tired. The multivariate logistic regression models evaluating the prevalence of sleep problems in individual OADs showed a stronger association between asthma and sleep problems as compared to COPD and ACO and sleep disorders. CONCLUSION: All OADs are associated with a higher prevalence of sleep problems. There is a stronger association between asthma and sleep problems as compared to COPD and ACO. We speculate that the nocturnal burden of asthma contributes to sleep problems. Our results suggest that adults with OAD should be aggressively screened for sleep problems.

Proteomic biomarkers of cognitive impairment in obstructive sleep apnea syndrome.

PURPOSE: There are currently no biomarkers that are associated with cognitive impairment (CI) in patients with obstructive sleep apnea syndrome (OSAS). This pilot study performed an exploratory plasma proteomic analysis to discover potential biomarkers and explore proteomic pathways that differentiate OSAS subjects with and without CI. METHODS: Participants were selected from a cohort of women within 5 years of menopause not on hormone replacement therapy between the ages of 45-60 years. The Berlin questionnaire was used to select OSAS participants who then completed the MCFSI (Mail-In Cognitive Function Screening Instrument) to measure cognition. Six subjects with the highest MCFSI scores (≥ 5 denoting CI) were compared to six with normal scores. Proteomic analysis was done by Myriad RBM using a targeted ELISA for 254 serum proteins. Pathway analysis of differentially expressed proteins was performed using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) software. RESULTS: Distinct proteomic signatures were seen in OSAS subjects with CI as compared to those without CI. Proteins including insulin, prostasin, angiopoietin-1, plasminogen activator inhibitor 1, and interleukin-1 beta were overexpressed in OSAS subjects with CI. Proteins underexpressed in CI participants included cathepsin B, ceruloplasmin, and adiponectin. Pathway analysis revealed prominence of insulin-regulated vascular disease biomarkers. CONCLUSIONS: Proteomic biomarkers in participants with cognitive impairment suggest roles for insulin, and vascular signaling pathways, some of which are similar to findings in Alzheimer's disease. A better understanding of the pathogenic mechanisms of CI in OSAS will help focus clinical trials needed in this patient population.

Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations.

RATIONALE: Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. OBJECTIVES: To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. METHODS: Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. RESULTS: A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. CONCLUSIONS: Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. CLINICAL TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (NCT NCT02810327).

Mortality in Asthma-Chronic Obstructive Pulmonary Disease Overlap in the United States.

OBJECTIVES: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is recognized increasingly as a distinct clinical entity and is associated with higher comorbidities compared with patients with asthma and COPD alone. Little is known about the leading causes of death related to ACO in the US general population, however. Our aim was to define the causes of mortality among patients with ACO compared with asthma and COPD in the US population. METHODS: We examined questions using the National Health and Nutrition Examination Survey III database linked to the National Death Index. The data from 4434 participants were stratified into 4 groups, those with asthma, COPD, ACO, and those without any obstructive lung disease. We examined baseline demographics and used multivariate logistic regression to model the impact of demographics, smoking, and self-reported, physician-diagnosed lung disease on mortality generating odds ratios (ORs) and confidence intervals (CIs). RESULTS: Among 4434 participants, 120 (2.7%), 340 (7.6%), and 126 (2.8%) participants self-reported diagnoses of asthma, COPD, and ACO syndrome, respectively. Patients with COPD were older (69.7 ± 10.9 years) than other groups. Cardiovascular disease, malignancy, and chronic lower respiratory disease were frequent causes of death. The mortality rates for cardiovascular disease and malignancy were not significantly different among respiratory disease categories. Deaths resulting from chronic respiratory disease were higher in the ACO group (OR 4.9, 95% CI 2.5-9.4) and the COPD group (OR 2.9, 95% CI 1.5-5.4) when compared with those without obstructive lung disease (P < 0.0001). CONCLUSIONS: Although cardiovascular- and malignancy-related deaths are common, a higher proportion of mortality in ACO and COPD is attributed to chronic lung disease.

Characteristics and Prevalence of Asthma/Chronic Obstructive Pulmonary Disease Overlap in the United States.

RATIONALE: The asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) occurs in patients with fixed airway obstruction that defines COPD and with symptoms more typical of asthma. ACOS prevalence and the comorbidities associated with this syndrome have been inadequately characterized. OBJECTIVES: Because this population is prone to more frequent exacerbations, we hypothesized that comorbidities associated with ACOS are higher than those with COPD, asthma, and control populations in the United States. METHODS: We examined the self-reported demographics, smoking status, comorbidities, and hospitalization or emergency department (ED) visitation experience among study respondents older than 35 years of age (n = 90,851) in the Behavioral Risk Factor Surveillance System survey and compared participants with ACOS to COPD, asthma, and control groups. We used logistic regression to compare ACOS and COPD populations to model the impact of comorbid conditions and hospitalization/ED visits after adjusting for demographic factors and smoking status to generate odds ratios and confidence intervals. MEASUREMENTS AND MAIN RESULTS: The U.S. prevalence of ACOS was 3.2%, COPD alone was 6.0%, and both increased with age. Respondents with ACOS were younger (64.0 ± 11.7 yr) than respondents with COPD (67.1 ± 11.8 yr) and older than respondents with asthma (59.0 ± 13.1 yr; P < 0.0001). The prevalence of comorbidities was higher in the group with ACOS and COPD than in asthma or control groups. The ACOS group had a higher body mass index, lower income, and lower education than other groups. The ACOS group was more likely to have at least one comorbidity (90.2 vs. 84%, P < 0.0001), more hospitalization or ED visits (22.0 vs. 13.2%, P < 0.0001), less exercise (50.0 vs. 58.6%, P = 0.0024), and more disability (70.8 vs. 58.6%, P < 0.0001) than the COPD group. CONCLUSIONS: The patients with a dual diagnosis of asthma and COPD are younger and with more disparities than those diagnosed with COPD alone. ACOS has a higher burden of self-reported comorbidity, disability, and hospitalization or ED visitation than COPD alone.

Impact of obstructive sleep apnea syndrome on cognition in early postmenopausal women.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) has a higher prevalence in postmenopausal women who are not on hormone replacement therapy (HRT), as compared to premenopausal women. Cognitive impairment (CI) is associated with OSAS and the early postmenopausal state. We hypothesized that compared to postmenopausal women at low risk for OSAS, postmenopausal women at high risk for OSAS would report worse cognitive function. METHODS: Early postmenopausal women not on HRT between the ages of 45 and 60 years, within 5 years of natural menopause, were enrolled. Participants completed a REDCap survey which collected information on demographics and risk factors, Berlin questionnaire to screen subjects for OSAS risk, and the Mail-In Cognitive Function Screening Instrument (MCFSI) score which was used to assess CI. RESULTS: Of 381 respondents, 127 were omitted due to missing/duplicate data or not meeting inclusion criteria. One hundred fifty-four women were classified as high risk for OSAS (OSAS+), and 100 were classified as low risk for OSAS (OSAS-). OSAS- women reported lifetime smoking, lifetime drinking, and recreational drug use more often than OSAS+ women, while OSAS+ women reported a depression diagnosis more often. The mean MCFSI score in the OSAS+ group was significantly higher (worse cognition) than in the OSAS- group after controlling for covariates (5.59, 95 % CI 5.08-6.11 vs. 4.29, 95 % CI 3.64-4.93, p < 0.05). CONCLUSION: Early postmenopausal women at high risk for OSAS report more CI than those at low risk for OSAS. Future studies should identify biomarkers of this CI and define the degree of reversibility of CI with OSAS treatment.

Characteristics of COPD Patients Using United States Emergency Care or Hospitalization.

Rationale: Several chronic obstructive pulmonary disease (COPD) studies have evaluated risk factors for emergency department (ED) visits or hospitalizations, and found insufficient data available about social and demographic factors that drive these behaviors. This U.S. study was designed to describe the characteristics of COPD patients with ED visits or a hospitalization and to investigate how often common COPD comorbidities are present in these individuals. Methods: Data for 7180 COPD patients regarding demographic factors, comorbidities, smoking status, and ED visits or hospitalization was obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. Logistic regression analysis was used to adjust demographic factors and smoking status to model the correlation between patients with ED visits or hospitalizations and morbidities generating odds ratios (OR) and confidence intervals (CI). Results: Among diagnosed COPD patients in the BRFSS, 16.5% had ED visits or hospitalization in the previous year. These individuals were younger, had a lower socio-economic status (lower education, lower income, and more often unemployed) and 23.4% of the individuals could not visit a doctor because of the financial difficulties compared to 16.7% who had no visit (p<0.0001 for all comparisons). The prevalence of comorbidities was higher in those with ED visits or hospitalization compared to those without. Conclusion: In a population representative of COPD patients, lower socio-economic status and higher comorbidities are associated with ED visits or hospitalization. Studies are needed to further elucidate the complex relationship between COPD, comorbidities, and ED visits or hospitalization.

The United States Alpha-1 Foundation Research Registry: Genesis, Impact and Future.

The Alpha-1 Foundation Research Registry has a long history of facilitating research studies in the United States. The current contact registry is used to invite participants to research studies. However, the next generation of individuals diagnosed with alpha-1 antitrypsin deficiency may look quite different from historical cohorts. This paper uses data from the Alpha Coded Testing (ACT) study, a home genetic testing program in which deficient individuals are invited to participate in the Registry, to demonstrate the impact that selection bias can introduce into registry data. Environmental tobacco smoke (ETS) exposure is rapidly declining in the United States. We queried whether consecutive non-smokers with or without childhood ETS in ACT (N = 801) had been diagnosed with COPD more often if deficiency genes were defined in subsequent testing. The prevalence of COPD was not different between cohorts with or without ETS exposure between normal (PiMM and PiMS), moderately deficient (PiMZ, PiMNull, and PiSS), and severely deficient (PiSZ, PiZZ, PiSNull, and PiZNull) genotypes. Surprisingly, age adjusted COPD Severity Scores in this cohort were higher for individuals with normal genotypes compared to moderately (P<0.001) and severely (P = 0.04) deficient genotypes. Ascertainment bias of testing within families (which yields the highest incidence of deficiency genotypes) also finds many family members without symptoms, even over the age of 40. We conclude that the future utility of registries will depend on accurate determination of testing mechanics. Larger database initiatives using the COPD Patient Powered Research Network are described.

Impact of medications on cognitive function in obstructive sleep apnea syndrome.

PURPOSE: Medications can impact cognitive function. Obstructive sleep apnea syndrome (OSAS) is associated with cognitive impairment. There is currently a paucity of data evaluating the impact of medications on sleep architecture and cognition in untreated OSAS. Our objective was to evaluate the impact of obstructive sleep apnea syndrome (OSAS) and medications on cognition by a screening questionnaire called the Mail-In Cognitive Function Screening Instrument (MCFSI). METHODS: We conducted a retrospective chart review on consecutive adults (age > 18 years) with OSAS seen in Medical University of South Carolina Sleep Clinic between January 1, 2012 and May 8, 2013, for whom the Mail-In Cognitive Function Screening Instrument (MCFSI) score was available and who were not on continuous positive airway pressure (CPAP). The correlation between different medications, sleep study variables, and MCFSI scores was studied. RESULTS: Univariate analysis revealed that many medications had significant correlations with MCFSI scores, including antidepressants (p = 0.05), antipsychotics (p = 0.01), anxiolytics (p = 0.005), statins (p = 0.077) and narcotics (p = 0.006). The mean percentage of rapid eye movement (REM) sleep (p = 0.04) and Epworth Sleepiness Scale (p = 0.01) were also significantly correlated with MCFSI scores. Multivariate analysis revealed that Epworth Sleepiness Scale and use of antipsychotics, narcotics, and anxiolytics correlated with higher MCFSI scores (worse cognition) and conversely that statin use was associated with improved cognition. CONCLUSIONS: Medications have a significant impact on cognitive function in OSAS. Thus, medication use should be considered in future studies of cognitive function in patients with OSAS.