Increased long-term health risks attributable to select volatile organic compounds in residential indoor air in southeast Louisiana.

Volatile organic compounds (VOCs) represent a broad class of chemicals, many of which can be found in indoor air including residential indoor air. VOCs derive from a variety of sources including cleaning products, cooking practices, fragrances and fresheners, hobbies and at-home work behaviors. This study examined residential indoor air in homes (n = 99) in southeast Louisiana using passive organic vapor monitors and gas chromatography/mass spectrometry to determine if select VOCs were present, at what concentrations, and if those posed any potential long-term health risks. Twenty-nine VOCs were targeted in cross-sectional analyses using a 48-h sampling period. Twelve VOCs were detected in most of the homes sampled including xylenes, pinenes, benzene, toluene, ethylbenzene, hexane, pentane, chloroform, and carbon tetrachloride. Concentrations of alkanes and BTEX compounds were highly correlated (Spearman's r > 0.63, p < 0.0001). Using health risk measures (i.e. reference concentrations [RfCs] and inhalation unit risks [IURs]) available from the USEPA non-cancer risk assessments and cancer risk assessments were developed for some of these VOCs. Alkanes and BTEX compounds likely come from the same indoor source(s). Using existing health standards published by the USEPA, no unacceptable non-cancer risks were evident except under extremely high concentrations. Lifetime cancer risks, on the other hand, may well be considered unacceptable for chloroform and benzene (upper IUR) and for the combination of chloroform, benzene, and carbon tetrachloride. These exceeded a 1 in 10,000 cancer risk threshold in 35-50% of our simulations. Further study of residential indoor air in low-income women's homes in this area is needed. Including a larger number of VOCs may reveal yet more potential health risks.

Development and validation of a Level A in-vitro in-vivo correlation for tofacitinib modified-release tablets using extrudable core system osmotic delivery technology.

PURPOSE: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. METHODS: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models. RESULTS: The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained. CONCLUSIONS: This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.

Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study.

Objective: Tofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX. Methods: Phase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was <0.6. Results: At week 12, with tofacitinib MR 11 mg QD and IR 5 mg BID, respectively, the change from baseline in least squares mean DAS28-4(CRP) was -2.43 and -2.85; the mean difference was 0.43 (95% CI 0.17, 0.69). Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met. Improvement of DAS28-4(CRP) ⩾1.2 was observed in 89 and 85% of patients, respectively, corresponding to a clinically important, significant change in both groups. The frequency of adverse events (52.9 and 51.4%, respectively) and serious adverse events (4.8 and 3.8%, respectively) was generally similar between treatments. No deaths were reported. Conclusion: Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met in this study. However, clinically meaningful improvements in RA were observed with both tofacitinib formulations in Japanese patients. The safety profile was similar with both formulations. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02281552.

In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor.

The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF-04171327 (fosdagrocorat) is a phosphate ester prodrug of PF-00251802 (dagrocorat), a selective high-affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF-04015475. This study evaluated the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of PF-00251802 and PF-04015475 in vitro and used model-based prediction approaches to estimate clinical impact. PF-00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF-00251802 and PF-04015475 are time-dependent inhibitors and inducers of CYP3A in vitro; PF-00251802 is also a time-dependent inhibitor of CYP2D6. Model-based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open-label, multiple-dose study evaluated the effect of PF-04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF-04171327 resulted in equivalent pharmacokinetic profiles (AUCinf , 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF-04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF-00251802 and PF-04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. METHODS: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated. RESULTS: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed. CONCLUSIONS: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01513902 .

Evaluation of VOC concentrations in indoor and outdoor microenvironments at near-road schools.

A 14-week air quality study, characterizing the indoor and outdoor concentrations of 18 VOCs at four El Paso, Texas elementary schools, was conducted in Spring 2010. Three schools were in an area of high traffic density and the fourth school, considered as a background school, was situated in an area affected minimally by stationary and mobile sources of air pollution. Passive samplers were deployed for monitoring and analyzed by GC/MS. Differences in the concentration profiles of the BTEX species between the high and low traffic density schools confirmed the pre-defined exposure patterns. Toluene was the predominant compound within the BTEX group and the 96-hr average outdoor concentrations varied from 1.16 to 4.25 µg/m3 across the four schools. Outdoor BTEX species were strongly correlated with each other (0.63 < r < 1.00, p < 0.05) suggesting a common source: vehicular traffic emissions. As expected, the strength of the associations between these compounds was more intense at each of the three high-exposure schools in contrast to the low-exposure school. This was further corroborated by the results obtained from the BTEX inter-species ratios (toluene: benzene and m, p- xylenes: ethylbenzene). Certain episodic events during the study period resulted in very elevated concentrations of some VOCs such as n-pentane. Indoor concentration of compounds with known indoor sources such as α -pinene, d-limonene, p-dichlorobenzene, and chloroform were generally higher than their corresponding outdoor concentrations. Cleaning agents, furniture polishes, materials used in arts and crafts activities, hot-water usage, and deodorizing cakes used in urinal pots were the likely major sources for these high indoor concentrations. Finally, retrospective assessment of average ambient BTEX concentrations over the last twenty years suggest a gradual decrement in this border region.

Improved disease activity with fosdagrocorat (PF-04171327), a partial agonist of the glucocorticoid receptor, in patients with rheumatoid arthritis: a Phase 2 randomized study.

AIM: To assess efficacy and safety of fosdagrocorat (PF-04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients. METHODS: This multicenter, double-blind, parallel-group, active- and placebo-controlled Phase 2 study (NCT00938587) randomized 86 patients (1 : 1 : 1 : 1) to receive fosdagrocorat 10 mg, fosdagrocorat 25 mg, prednisone 5 mg or placebo, all with stable background methotrexate therapy. The primary outcome was change from baseline in Disease Activity Score of 28 joints (DAS28-4[C-reactive protein (CRP)]) after 2 weeks of treatment. Secondary outcomes included American College of Rheumatology (ACR) response rates, change from baseline in ACR core components and Health Assessment Questionnaire Disability Index. RESULTS: At week 2, improvements from baseline in DAS28-4(CRP) with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo were -1.69, -2.22, -1.17 and -0.96, respectively, and were statistically significantly greater for both fosdagrocorat doses versus placebo (P < 0.05) and for fosdagrocorat 25 mg versus prednisone 5 mg (P < 0.001). The effects of fosdagrocorat on secondary outcomes were generally consistent with those observed for the primary outcome. Adverse events (AEs) were reported for eight (38%), three (14%), four (19%) and 12 (55%) patients treated with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo, respectively. Most AEs were mild in severity. Four patients discontinued treatment due to AEs (fosdagrocorat 10 mg, n = 2; placebo, n = 2). There were no serious AEs. CONCLUSION: Fosdagrocorat 10 and 25 mg demonstrated efficacy in improving signs and symptoms in RA patients, with manageable AEs. Additional studies are needed to assess the longer-term safety and efficacy of fosdagrocorat.

Comparison of trace elements in size-fractionated particles in two communities with contrasting socioeconomic status in Houston, TX.

Levels of ambient air pollutants, including particulate matter (PM), are often higher in low-socioeconomic status (SES) communities than in high-SES communities. Houston is the fourth largest city in the USA and is home to a large petrochemical industry, an active port, and congested roadways, which represent significant emission sources of air pollution in the region. To compare levels of air pollution between a low-SES and a high-SES community, we simultaneously collected a 7-day integrated size-fractionated PM between June 2013 and November 2013. We analyzed PM mass and elements for three particle size modes: quasi-ultrafine particles (quasi-UFP) (aerodynamic diameter <0.25 µm), accumulation mode particles (0.25-2.5 µm), and coarse mode particles (>2.5 µm). Concentrations of vanadium, nickel, manganese, and iron in the quasi-UFP mode were significantly higher in the low-SES community than in the high-SES community. In the accumulation and coarse modes, concentrations of crustal elements and barium were also significantly higher in the low-SES community compared to the high-SES community. These findings suggest that people living in the low-SES community may experience higher exposures to some toxic elements as compared to people in the high-SES community.

Feasibility of using low-cost portable particle monitors for measurement of fine and coarse particulate matter in urban ambient air.

Exposure to ambient particulate matter (PM) is known as a significant risk factor for mortality and morbidity due to cardiorespiratory causes. Owing to increased interest in assessing personal and community exposures to PM, we evaluated the feasibility of employing a low-cost portable direct-reading instrument for measurement of ambient air PM exposure. A Dylos DC 1700 PM sensor was collocated with a Grimm 11-R in an urban residential area of Houston Texas. The 1-min averages of particle number concentrations for sizes between 0.5 and 2.5 µm (small size) and sizes larger than 2.5 µm (large size) from a DC 1700 were compared with the 1-min averages of PM2.5 (aerodynamic size less than 2.5 µm) and coarse PM (aerodynamic size between 2.5 and 10 µm) concentrations from a Grimm 11-R. We used a linear regression equation to convert DC 1700 number concentrations to mass concentrations, utilizing measurements from the Grimm 11-R. The estimated average DC 1700 PM2.5 concentration (13.2 ± 13.7 µg/m3) was similar to the average measured Grimm 11-R PM2.5 concentration (11.3 ± 15.1 µg/m3). The overall correlation (r2) for PM2.5 between the DC 1700 and Grimm 11-R was 0.778. The estimated average coarse PM concentration from the DC 1700 (5.6 ± 12.1 µg/m3) was also similar to that measured with the Grimm 11-R (4.8 ± 16.5 µg/m3) with an r2 of 0.481. The effects of relative humidity and particle size on the association between the DC 1700 and the Grimm 11-R results were also examined. The calculated PM mass concentrations from the DC 1700 were close to those measured with the Grimm 11-R when relative humidity was less than 60% for both PM2.5 and coarse PM. Particle size distribution was more important for the association of coarse PM between the DC 1700 and Grimm 11-R than it was for PM2.5. IMPLICATIONS: The performance of a low-cost particulate matter (PM) sensor was evaluated in an urban residential area. Both PM2.5 and coarse PM (PM10-2.5) mass concentrations were estimated using a DC1700 PM sensor. The calculated PM mass concentrations from the number concentrations of DC 1700 were close to those measured with the Grimm 11-R when relative humidity was less than 60% for both PM2.5 and coarse PM. Particle size distribution was more important for the association of coarse PM between the DC 1700 and Grimm 11-R than it was for PM2.5.

Source proximity and meteorological effects on residential outdoor VOCs in urban areas: Results from the Houston and Los Angeles RIOPA studies.

Concentrations of volatile organic compounds (VOCs) measured outside homes in Houston, TX and Los Angeles, CA were characterized by the effects of source proximity and meteorological factors. Benzene, toluene, ethylbenzene, m,p-xylene, o-xylene (BTEX), methyl tert butyl ether (MTBE), tetrachloroethylene (perchloroethylene, PCE), and carbon tetrachloride (CCl4) were examined. Multiple stepwise regression analysis converged the best-fit models with predictors from meteorological conditions and the proximity to specific point, area, and mobile sources on the residential outdoor VOC concentrations. Negative associations of wind speed with concentrations demonstrated the effect of dilution by high wind speed. Atmospheric stability increase was associated with concentration increase. Petrochemical source proximity was a significant predictor for BTEX and MTBE concentrations in Houston. Ethylbenzene and xylene source proximity was a significant predictor in Los Angeles. Close proximity to area sources such as scrap metal recycling or dry cleaning facilities increased the MTBE, PCE, and CCl4 concentrations in Houston and Los Angeles. Models for ethylbenzene, m,p-xylene, and MTBE in Houston, and benzene in Los Angeles explained that for the median values of the meteorological factors, homes closest to influential highways would have concentrations that were 1.7-2.2 fold higher than those furthest from these mobile emission sources. If the median distance to sources were used in the models, the VOC concentrations varied 1.7 to 6.6 fold as the meteorological conditions varied over the observed range. These results highlight that each urban area is unique and localized sources need to be carefully evaluated to understand potential contributions to VOC air concentrations near residences, which influence baseline indoor air concentrations and personal exposures. Results of this study could assist in the appropriate design of monitoring networks for community-level sampling. They may also improve the accuracy of exposure models linking emission sources with estimated pollutant concentrations at the residential level.

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady-state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies.

Association Between Ambient Levels of Polycyclic Aromatic Hydrocarbons and Small for Gestational Age Hispanic Infants Born Along the United States-Mexico Border.

Few studies have examined associations between polycyclic aromatic hydrocarbons (PAHs) and birth outcomes, and no studies have been conducted in El Paso County Texas, along the United States-Mexico border. Infants born from 2005-2007 to Hispanic mothers with a birth weight less than the 10th percentile for gestational age and sex were classified as small for gestational age (SGA). PAH exposures were estimated for the entire period of gestation and for each trimester of pregnancy using ambient air monitoring data from 2004-2007. Logistic regression was used to estimate odds ratios for the association between PAH levels and SGA infants. There was marked seasonal variation in the carcinogenic PAHs. Established risk factors for SGA were observed to be associated with SGA births in this population. No associations were detected between PAH levels and SGA births. These findings provide no evidence of an association between PAHs and SGA infants.

Association of short-term increases in ambient air pollution and timing of initial asthma diagnosis among Medicaid-enrolled children in a metropolitan area.

OBJECTIVE: We investigated associations of short-term changes in ambient ozone (O3), fine particulate matter (PM2.5) and nitrogen dioxide (NO2) concentrations and the timing of new-onset asthma, using a large, high-risk population in an area with historically high ozone levels. METHODS: The study population included 18,289 incident asthma cases identified among Medicaid-enrolled children in Harris County Texas between 2005-2007, using Medicaid Analytic Extract enrollment and claims files. We used a time-stratified case-crossover design and conditional logistic regression to assess the effect of increased short-term pollutant concentrations on the timing of asthma onset. RESULTS: Each 10 ppb increase in ozone was significantly associated with new-onset asthma during the warm season (May-October), with the strongest association seen when a 6-day cumulative average period was used as the exposure metric (odds ratio [OR]=1.05, 95% confidence interval [CI], 1.02-1.08). Similar results were seen for NO2 and PM2.5 (OR=1.07, 95% CI, 1.03-1.11 and OR=1.12, 95% CI, 1.03-1.22, respectively), and PM2.5 also had significant effects in the cold season (November-April), 5-day cumulative lag (OR=1.11. 95% CI, 1.00-1.22). Significantly increased ORs for O3 and NO2 during the warm season persisted in co-pollutant models including PM2.5. Race and age at diagnosis modified associations between ozone and onset of asthma. CONCLUSION: Our results indicate that among children in this low-income urban population who developed asthma, their initial date of diagnosis was more likely to occur following periods of higher short-term ambient pollutant levels.

Effects of Air Pollution on Asthma Hospitalization Rates in Different Age Groups in Metropolitan Cities of Korea.

Many studies have shown associations between air pollution and asthma admissions in Korea, but have not reported whether these effects differ by age classification. The purpose of this study was to determine whether air pollution effects on asthmatic hospital admissions are different by three age groups (years): children (less than 15), adults (15-64; reference group), and the elderly (over 65). Daily time-series data from seven metropolitan cities in South Korea were analyzed in two stages. In the first stage, relative asthma morbidity rates associated with air pollution were estimated for each city and age group, using semi-parametric log-linear regression. In the second stage, estimates from all seven cities were combined by age group using Bayesian hierarchical modeling. The effects of exposure to particulate matter <10 micrometers in aerodynamic diameter (PM10), carbon monoxide (CO) and nitrogen dioxide (NO2) varied significantly by age groups. Using adults as the referent, the relative rate (RR) of asthma admissions with 10µg/m3 increase of PM10 is 1.5% (95%CI: 0.1-2.8%) lower for children, and 1.3% (95% CI: 0.7-1.9%) higher for the elderly; RR with 1ppm increase of CO is 1.9% (95% CI: 0.3-3.8%) lower for children; RR with 1ppb increase of NO2(1ppb) is 0.5% (95% CI: 0.3-0.7%) higher for the elderly. No significant age group difference in relative rate was found for ozone or sulfur dioxide.

Evaluating the effects of maternal exposure to benzene, toluene, ethyl benzene, and xylene on oral clefts among offspring in Texas: 1999-2008.

BACKGROUND: There is evidence from previous studies that maternal occupational exposure to hazardous air pollutants (HAPs) is positively associated with oral clefts; however, studies evaluating the association between residential exposure to these toxicants and oral clefts are lacking. Therefore, our goal was to conduct a case-control study examining the association between estimated maternal residential exposure to benzene, toluene, ethyl benzene, and xylene (BTEX) and the risk of oral clefts among offspring. METHODS: Data on 6045 nonsyndromic isolated oral cleft cases (3915 cleft lip with or without cleft palate [CL ± P] and 2130 nonsyndromic isolated cleft palate [CP] cases) delivered between 1999 and 2008 were obtained from the Texas Birth Defects Registry. The control group was a sample of unaffected live births, frequency matched to cases on year of birth. Census tract-level estimates of annual average exposures were obtained from the U.S. Environmental Protection Agency 2005 Hazardous Air Pollutant Exposure Model (HAPEM5) for each pollutant and assigned to each subject based on maternal residence during pregnancy. Logistic regression was used to assess the relationship between estimated maternal exposure to each pollutant (BTEX) separately and the risk of oral clefts in offspring. RESULTS: High estimated maternal exposure to benzene was not associated with oral clefts, compared with low estimated exposure (CL ± P adjusted OR = 0.95; 95% CI = 0.81 - 1.12; CP adjusted OR = 0.85; 95% CI = 0.67 - 1.09). Similar results were seen for the other pollutants. CONCLUSION: In our study, there was no evidence that maternal exposure to environmental levels of BTEX was associated with oral clefts.

Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects.

RATIONALE: A positron emission tomography (PET) study of dopamine D2 receptor occupancy was conducted to support a rational dose selection for clinical efficacy studies with lurasidone, an atypical antipsychotic that was approved for the treatment of schizophrenia by the FDA in late 2010. OBJECTIVES: To determine the dopamine D2 receptor occupancy of lurasidone in the ventral striatum, putamen and caudate nucleus, and to characterize the relationship between lurasidone serum concentration and D2 receptor occupancy. METHODS: A single oral dose of lurasidone (10, 20, 40, 60, or 80 mg) was administered sequentially to healthy male subjects (n = 4 in each cohort). Two PET scans were performed. For each scan, 20 mCi of [¹¹C]raclopride was administered intravenously as a bolus injection, followed immediately by 90 min of PET scan acquisitions. RESULTS: The D2 receptor occupancy levels were 41-43% for 10 mg, 51-55% for 20 mg, 63-67% for 40 mg, 77-84% for 60 mg, and 73-79% for 80 mg of lurasidone. The relationship between D2 receptor occupancy and the mean serum lurasidone concentration during the PET scan (C PET) was similar for the putamen, caudate nucleus, and ventral striatum regions. Mean D2 receptor occupancy levels correlated well with average peak serum concentration of lurasidone. CONCLUSIONS: In healthy volunteers, single doses of lurasidone 40-80 mg resulted in D2 receptor occupancy levels of >60%, a level of receptor occupancy previously associated with clinical response for atypical antipsychotics.

Associations between urban air pollution and pediatric asthma control in El Paso, Texas.

Exposure to traffic-related pollutants poses a serious health threat to residents of major urban centers around the world. In El Paso, Texas, this problem is exacerbated by the region's arid weather, frequent temperature inversions, heavy border traffic, and an aged, poorly maintained vehicle fleet. The impact of exposure to traffic pollution, particularly on children with asthma, is poorly understood. Tracking the environmental health burden related to traffic pollution in El Paso is difficult, especially within school microenvironments, because of the lack of sensitive environmental health indicator data. The Asthma Control Questionnaire (ACQ) is a survey tool for the measurement of overall asthma control, yet has not previously been considered as an outcome in air pollution health effect research. We conducted a repeated measure panel study to examine weekly associations between ACQ scores and traffic- and non-traffic air pollutants among asthmatic schoolchildren in El Paso. In the main one- and two-pollutant epidemiologic models, we found non-significant, albeit suggestive, positive associations between ACQ scores and respirable particulate matter (PM10), coarse particulate matter (PM10-2.5), fine particulate matter (PM2.5), black carbon (BC), nitrogen dioxide (NO2), benzene, toluene, and ozone (O3). Notably, associations were stronger and significant for some subgroups, in particular among subjects taking daily inhaled corticosteroids. This pattern may indicate heightened immune system response in more severe asthmatics, those with worse asthma "control" and higher ACQ scores at baseline. If the ACQ is appropriately used in the context of air pollution studies, it could reflect clinically measurable and biologically relevant changes in lung function and asthma symptoms that result from poor air quality and may increase our understanding of how air pollution influences asthma exacerbation.

Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate.

OBJECTIVE: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX. RESULTS: The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related. CONCLUSION: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial.

INTRODUCTION: The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). METHODS: This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components. RESULTS: Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%). CONCLUSIONS: Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00427934.

Post-Hurricane Katrina passive sampling of ambient volatile organic compounds in the greater New Orleans area.

On August 29, 2005, Hurricane Katrina made landfall near New Orleans, Louisiana, a major metroplex with petroleum industries. In response to the potential impact of the storm on air quality and to assess the exposures to toxic air pollutants of public health concern, the United States Environmental Protection Agency conducted passive monitoring of air toxics for three months, starting in late October 2005 through early February 2006, at up to 18 sites in the New Orleans area affected by Hurricane Katrina. The overall results of the passive ambient monitoring are summarized with the concentrations for the twenty-nine observed volatile organic chemicals, which include benzene, toluene, ethylbenzene, and xylenes, and the measured concentrations are compared with available health-based screening levels. The results of passive monitoring are also compared with those of the collocated canister sampling at one of the sites. The overall results showed that the outdoor levels of atmospheric volatile organic chemcals in the post-Katrina New Orleans area were very low and far below the available screening levels. The results also confirm the effectiveness of passive monitoring in a large geographical area where conventional methods are not feasible, electrical power is not available, and the need for sampling is urgent, as in the aftermath of natural disasters and other catastrophes.