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.

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.

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.

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.

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.

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.

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.

Demographic, residential, and behavioral determinants of elevated exposures to benzene, toluene, ethylbenzene, and xylenes among the U.S. population: results from 1999-2000 NHANES.

Volatile organic compounds (VOC) represent a broad spectrum of compounds and there is growing concern that VOC exposures, in addition to increasing risks for cancer, may be implicated in exacerbating asthma and other adverse respiratory effects. Yet little is known about exposures in the U.S. population beyond the seminal Total Exposure Assessment Methodology (TEAM) studies that were conducted by the U.S. Environmental Protection Agency (U.S. EPA) between 1979 and 1987. This investigation was carried out to evaluate the relationship between personal exposures to benzene, toluene, ethylbenzene, and xylenes (BTEX) and socioeconomic, behavioral, demographic, and residential characteristics using a subsample from the National Health and Nutrition Examination Survey (NHANES) (636 participants who represented an estimated 141,363,503 persons aged 20 to 59 yr in the United States). Personal VOC exposures were evaluated using organic vapor monitors for periods that ranged from 48 to 72 h, and participants were administered a questionnaire regarding personal behaviors and residential characteristics while wearing the monitor. Geometric mean (GM) levels were significantly higher for males for all compounds except toluene. For benzene, GM levels were elevated among smokers and Hispanics. Sociodemographic characteristics could not be evaluated simultaneously in the weighted multiple regression models with the VOC questionnaire data because of issues associated with multicollinearity. Results from the regression analyses suggest that the presence of an attached garage (BTEX), having windows closed in the home during the monitoring period (benzene, toluene), pumping gasoline (toluene, ethylbenzene, and xylenes), or using paint thinner, brush cleaner, or stripper (xylenes) results in higher exposure in the general population and confirm previous findings of studies that were more regional in scope. Once the complete NHANES VOC data are released, additional study is warranted to explore whether risk factors associated with elevated VOC exposures differ in subgroups of U.S. adults, which should inform efforts to develop approaches for minimizing VOC exposures and ameliorating environmental health risks.

Evaluation of the use of diffusive air samplers for determining temporal and spatial variation of volatile organic compounds in the ambient air of urban communities.

The Houston-Galveston metropolitan area has a relatively high density of point and mobile sources of air toxics, and determining and understanding the relationship between emissions and ambient air concentrations of air toxics is important for evaluating potential impacts on public health and formulating effective regulatory policies to control this impact, both in this region and elsewhere. However, conventional ambient air monitoring approaches are limited with regard to expense, siting limitations, and representative sampling necessary for adequate exposure assessment. The overall goal of this multiphase study is to evaluate the use of simple passive air samplers to determine temporal and spatial variability of the ambient air concentrations of selected volatile organic compounds (VOCs) in urban areas. Phase 1 of this study, reported here, was a field evaluation of 3M organic vapor monitors (OVMs) involving limited comparisons with commonly used active sampling methods, an assessment of sampler precision, a determination of optimal sampling duration, and an investigation of the utility of a simple modification of the commercial sampler. The results indicated that a sampling duration of 72 hr exhibited generally low bias relative to automated continuous gas chromatography measurements, good overall precision, and an acceptable number of measurements above detection limits. The modified sampler showed good correlation with the commercial sampler, with higher sampling rates, although lower than expected.

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).

Estimating volatile organic compound concentrations in selected microenvironments using time-activity and personal exposure data.

Repeated measures of personal exposure to 14 volatile organic compounds (VOC) were obtained over 3 seasons for 70 healthy, nonsmoking adults living in Minneapolis-St. Paul. Matched data were also available for participants' time-activity patterns, and measured VOC concentrations outdoors in the community and indoors in residences. A novel modeling approach employing hierarchical Bayesian techniques was used to estimate VOC concentrations (posterior mode) and variability (credible intervals) in five microenvironments: (1) indoors at home; (2) indoors at work/school; (3) indoors in other locations; (4) outdoors in any location; and (5) in transit. Estimated concentrations tended to be highest in "other" indoor microenvironments (e.g., grocery stores, restaurants, shopping malls), intermediate in the indoor work/school and residential microenvironments, and lowest in the outside and in-transit microenvironments. Model estimates for all 14 VOC were reasonable approximations of measured median concentrations in the indoor residential microenvironment. The largest predicted contributor to cumulative (2-day) personal exposure for all 14 VOC was the indoor residential environment. Model-based results suggest that indoors-at-work/school and indoors-at-other-location microenvironments were the second or third largest contributors for all VOC, while the outside-in-any-location and in-transit microenvironments appeared to contribute negligibly to cumulative personal exposure. Results from a mixed-effects model indicate that being in or near a garage increased personal exposure to o-xylene, m/p-xylene, benzene, ethylbenzene, and toluene, and leaving windows and doors at home open for 6 h or more decreased personal exposure to 13 of 14 VOC, all except trichloroethylene.

Relationships of Indoor, Outdoor, and Personal Air (RIOPA): part II. Analyses of concentrations of particulate matter species.

During the study Relationships of Indoor, Outdoor, and Personal Air (RIOPA*), 48-hour integrated indoor, outdoor, and personal air samples were collected between summer 1999 and spring 2001 in three different areas of the United States: Elizabeth NJ, Houston TX, and Los Angeles County CA. Air samples suitable for analyzing particulate matter 2.5 microm or smaller in aerodynamic diameter (PM2.5) were collected in 219 homes (twice in 169 homes). Indoor and outdoor air samples suitable for gas-phase and particle-phase organic analyses were collected in 152 homes (twice in 132 homes). Samples or subsets of samples were analyzed for PM2.5 mass, organic functional groups, elements, organic carbon (OC), elemental carbon (EC), gas-phase and particle-phase polycyclic aromatic hydrocarbons (PAHs), and chlordanes. Air exchange rate (AER), temperature, and relative humidity were measured for each residence; questionnaire data and time-activity information were collected from the participants. Median indoor, outdoor, and personal PM2.5 mass concentrations were 14.4, 15.5, and 31.4 microg/m3, respectively. Personal PM2.5 concentrations were significantly higher and more variable than indoor and outdoor concentrations. Several approaches were applied to quantify indoor PM2.5 of ambient (outdoor) and nonambient (indoor) origin, some using PM2.5 mass concentrations and others using PM2.5 species concentrations. PM of outdoor origin was estimated in three ways using increasingly accurate assumptions. Comparing estimates from the three approaches enabled us to quantify several types of errors that may be introduced when central-site PM concentrations are used as surrogate estimates for PM exposure. Estimates made using individual measurements produced broader distributions and higher means than those made using a single infiltration factor for all homes and days. The best estimate (produced by the robust regression approach) of the mean contribution of outdoor PM2.5 to the indoor mass concentration was 73% and to personal exposure was 26%. Possible implications of exposure error for epidemiologic assessments of PM are discussed below. Organic particulate matter was the major constituent of PM2.5 generated indoors. After correcting for artifacts, it constituted 48%, 55%, and 61% of PM2.5 mass inside study homes in Los Angeles, Elizabeth, and Houston, respectively. At least 40% but probably closer to 75% of this organic matter, on average, was emitted or formed indoors. Functional group analysis provided some insights into the composition and properties of the indoor-generated organic PM2.5. Chlordane, a very minor but mutagenic semivolatile organic mixture previously used as a termiticide, was found to be mostly of indoor origin. High emission rates were most frequently found in homes built from 1945 to 1959. Analysis of the change in gas-particle partitioning during transport of outdoor PAHs to indoor environments illustrated that chemical thermodynamics can alter the concentration and composition of outdoor PM as it is transported indoors. (This has been previously noted for nitrate [Lunden et al 2003].) In epidemiologic studies that rely on central-site monitoring data, such transformations may result in measurement error, and this possibility warrants further investigation.

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.

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.

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.

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 .

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.

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.

Relationship of Indoor, Outdoor and Personal Air (RIOPA) study: study design, methods and quality assurance/control results.

The Relationship of Indoor, Outdoor and Personal Air (RIOPA) Study was undertaken to evaluate the contribution of outdoor sources of air toxics, as defined in the 1990 Clean Air Act Amendments, to indoor concentrations and personal exposures. The concentrations of 18 volatile organic compounds (VOCs), 17 carbonyl compounds, and fine particulate matter mass (PM(2.5)) were measured using 48-h outdoor, indoor and personal air samples collected simultaneously. PM2.5 mass, as well as several component species (elemental carbon, organic carbon, polyaromatic hydrocarbons and elemental analysis) were also measured; only PM(2.5) mass is reported here. Questionnaires were administered to characterize homes, neighborhoods and personal activities that might affect exposures. The air exchange rate was also measured in each home. Homes in close proximity (<0.5 km) to sources of air toxics were preferentially (2:1) selected for sampling. Approximately 100 non-smoking households in each of Elizabeth, NJ, Houston, TX, and Los Angeles, CA were sampled (100, 105, and 105 respectively) with second visits performed at 84, 93, and 81 homes in each city, respectively. VOC samples were collected at all homes, carbonyls at 90% and PM(2.5) at 60% of the homes. Personal samples were collected from nonsmoking adults and a portion of children living in the target homes. This manuscript provides the RIOPA study design and quality control and assurance data. The results from the RIOPA study can potentially provide information on the influence of ambient sources on indoor air concentrations and exposure for many air toxics and will furnish an opportunity to evaluate exposure models for these compounds.