Evaluating the effectiveness of reformulated extended-release oxycodone with abuse-deterrent properties on reducing non-oral abuse among individuals assessed for substance abuse treatment with the Addiction Severity Index-Multimedia Version (ASI-MV).

OBJECTIVE: Original brand extended-release (ER) oxycodone tablets (OC) for oral use were reformulated (ORF) with abuse-deterrent properties (ADP) against inhalation and injection routes in August 2010. This product transition provided an opportunity to compare "before and after" reformulation abuse trends. Our goal was to assess the change in abuse of brand oxycodone ER from before and after introduction of ORF. METHODS: Change in self-reported non-oral "OxyContin" abuse in the previous 30 days during two years pre- and four years post-reformulation was assessed among adults evaluated for substance use and treatment planning using the Addiction Severity Index-Multimedia Version (ASI-MV). Comparator opioids were used to provide a frame of reference for changes in abuse due to competing population-level opioid abuse interventions and other factors unrelated to the reformulation. A proportion (PR) and abuse report dispensing ratio (ARDR) are reported because a single measure of abuse has not been identified that can optimally describe opioid abuse or changes in opioid abuse. RESULTS: Interrupted time-series analyses indicated an immediate decline in non-oral abuse measures post-reformulation (PR = -52.1%; ARDR = -32.2%). Significant decreases from pre- to post-reformulation in non-oral abuse overall were observed (PR [95% CI] = -30.7% [-46.9%, -9.5%]; ARDR = -29.3% [-37.5%, -20.1%]). Comparator opioids did not demonstrate similar trends over the period. CONCLUSIONS: Methodology applied in this study suitably assessed the effectiveness of an ADP product. Among individuals assessed for substance use, a differential decline in non-oral abuse of brand ER oxycodone was observed since introduction of ORF.

Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke.

BACKGROUND AND PURPOSE: Evidence suggests the potential to improve motor status in patients with stroke by modifying brain catecholaminergic tone. The current study hypothesized that increased dopaminergic tone via the dopamine agonist ropinirole, when combined with physiotherapy (PT), would significantly and safely increase gait velocity. METHODS: Patients with moderate motor deficits due to stroke 1 to 12 months prior were randomized (double blinded) to 9 weeks of immediate-release ropinirole or placebo, each with PT, and followed up for 3 additional weeks. Drug dose (0.25 to 4 mg once daily) was titrated weekly, as tolerated. The primary end point was gait velocity during the 12 weeks of study participation. RESULTS: Patients in the ropinirole+PT group averaged 2.4 mg/d by end of week 9, although the target dose was at least 3 mg/d. Ropinirole+PT was generally safe and well tolerated, including no drug-related serious adverse events. Across all 33 enrollees, significant gains were found over time for gait velocity and for most secondary end points. However, gains did not differ by treatment assignment. PT and occupational therapy were commonly prescribed outside of the trial, although the extent of these was not correlated with study outcomes. CONCLUSIONS: At doses achieved in this trial, increased dopaminergic tone via ropinirole+PT was generally well tolerated but did not show any improvement over and above the effects of PT alone.

Decline in telomere length by age and effect modification by gender, allostatic load and comorbidities in National Health and Nutrition Examination Survey (1999-2002).

BACKGROUND: This study aims to assess the decline in telomere length (TL) with age and evaluate effect modification by gender, chronic stress, and comorbidity in a representative sample of the US population. METHODS: Cross-sectional data on 7826 adults with a TL measurement, were included from the National Health and Nutrition Examination Survey, years 1999-2002. The population rate of decline in TL across 10-year age categories was estimated using crude and adjusted regression. RESULTS: In an adjusted model, the population rate of decline in TL with age was consistent and linear for only three age categories: 20-29 (ß = -0.0172, 95% CI: -0.0342, -0.0002), 50-59 (ß = -0.0182, 95% CI: -0.0311, -0.0054) and 70-79 (ß = -0.0170, 95% CI: -0.0329, -0.0011) years. The population rate of decline in TL with age was significantly greater for males and those with high allostatic load and a history of comorbidities. When the population rate of decline in TL was analyzed by gender in 10-year age bins, a fairly consistent yet statistically non-significant decline for males was observed; however, a trough in the rate was observed for females in the age categories 20-29 years (ß = -0.0284, 95% CI: -0.0464, -0.0103) and 50-59 years (ß = -0.0211, 95% CI: -0.0391, -0.0032). To further elucidate the gender difference observed in the primary analyses, secondary analyses were conducted with reproductive and hormonal status; a significant inverse association was found between TL and parity, menopause, and age at menopause. CONCLUSIONS: TL was shorter with increasing age and this decline was modified by gender, chronic stress and comorbidities; individuals with chronic morbidity and/or chronic stress and females in their twenties and fifties experienced greater decline. Female reproductive factors, i.e., parity and menopause, were associated with TL.

Is selenium intake associated with the presence of depressive symptoms among US adults? Findings from National Health and Nutrition Examination Survey (NHANES) 2011-2014.

OBJECTIVES: This study aimed to examine the cross-sectional association between dietary and serum selenium measures and depressive symptoms among a nationally representative sample of US adults. METHODS: Dietary selenium intake and serum selenium concentration were evaluated on 7725 adult participants from National Health and Nutrition Examination Survey (NHANES) 2011-2014. Participants' selenium intake, assessed by 24-h recall, was classified based on the recommended dietary allowance (dietary selenium intake ≥ 55 µg/d) and estimated average requirement (dietary selenium intake ≥ 45 µg/d) criteria. Serum selenium and depressive symptoms were assessed using inductively coupled plasma mass spectrometry and a patient health questionnaire or use of an antidepressant, respectively. Univariate and multivariate logistic regression, accounting for the complex survey design of NHANES, were employed to estimate the cross-sectional association between measures of selenium and the presence of depressive symptoms. RESULTS: The median selenium concentration was 193.9 µg/L (interquartile range = 179.3-209.3). Approximately 8% of the participants met the case definition for depressive symptoms. Based on the recommended dietary allowance of selenium, participants not meeting the recommended dietary intake, compared with those meeting the requirement, had higher odds of depressive symptoms (odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.03-2.38). When analyzing by quintile of dietary selenium intakes, compared with the first quintile, participants in higher quintiles had significantly lower odds of depressive symptoms. However, based on quintiles of serum selenium and using the first quintile as referent category, except for quintile 3, results indicated a higher but not significant association (quintile 2 [OR = 1.08, 95% CI: 0.73-1.61], quintile 4 [OR = 1.17, 95% CI: 0.89-1.55], and quintile 5 [OR = 1.14, 95% CI: 0.83-1.58]). Power analysis indicated sufficient power. Notably, study participants had a very high serum selenium concentration. The findings, although not significant, between serum selenium concentrations and depressive symptoms had a U-shaped association, supported by the current literature. CONCLUSIONS: Our study supports an inverse association between participants recommended dietary intake of selenium and depressive symptoms. Although results were not statistically significant for the association by quartile of serum selenium concentrations and depressive symptoms, a U-shaped association was identified.

Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.

BACKGROUND AND OBJECTIVE: Inhibition of the receptor activator of nuclear factor κ-B ligand (RANKL) is a therapeutic target for treatment of bone disorders associated with increased bone resorption, such as osteoporosis. The objective of this analysis was to characterize the population pharmacokinetics of denosumab (AMG 162; Prolia®), a fully human IgG2 monoclonal antibody that binds to RANKL, in healthy subjects and postmenopausal women with osteopenia or osteoporosis. METHODS: A total of 22944 serum free denosumab concentrations from 495 healthy subjects and 1069 postmenopausal women with osteopenia or osteoporosis were pooled. Denosumab was administered as either a single intravenous dose (n = 36), a single subcutaneous dose (n = 469) or multiple subcutaneous doses (n = 1059), ranging from 0.01 to 3 mg/kg (or 6-210 mg as fixed mass dosages), every 3 or 6 months for up to 48 months. An open, two-compartment pharmacokinetic model with a quasi-steady-state approximation of the target-mediated drug disposition model was used to describe denosumab pharmacokinetics, using NONMEM Version 7.1.0 software. Subcutaneous absorption was characterized by the first-order absorption rate constant (k(a)), with constant absolute bioavailability over the range of doses that were evaluated. Clearance and volume of distribution parameters were scaled by body weight, using a power model. Model evaluation was performed through visual predictive checks. RESULTS: The subcutaneous bioavailability of denosumab was 64%, and the k(a) was 0.00883 h-1. The central volume of distribution and linear clearance were 2.49 L/66 kg and 3.06 mL/h/66 kg, respectively. The baseline RANKL level, quasi-steady-state constant and RANKL degradation rate were 614 ng/mL, 138 ng/mL and 0.00148 h-1, respectively. Between-subject variability in model parameters was moderate. A fixed dose of 60 mg provided RANKL inhibition similar to that achieved by equivalent body weight-based dosing. The effects of age and race on the area under the serum concentration-time curve of denosumab were less than 15% over the range of covariate values that were evaluated. CONCLUSIONS: The non-linearity in denosumab pharmacokinetics is probably due to RANKL binding, and denosumab dose adjustment based on the patient demographics is not warranted.

Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors.

Panitumumab is a fully human monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). A comprehensive population pharmacokinetic model of panitumumab was developed using nonlinear mixed-effects modeling of 1200 patients with advanced solid tumors in 14 clinical studies. The disposition of panitumumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. For a typical male patient with colorectal cancer (80 kg, 60 years old), the estimates for the linear clearance (CL), the maximum nonlinear clearance (V(max)/K(m)), the central volume of distribution (V(1)), the peripheral volume of distribution (V(2)), and the Michaelis-Menten constant (K(m)) are 0.273 L/d, 28.4 L/d, 3.95 L, 2.59 L, and 0.426 mcg/mL, respectively. Baseline covariates such as body weight, cancer type, age, sex, and race were studied for their influence on panitumumab pharmacokinetics. Body weight was found to be the most influential covariate on panitumumab exposure, affecting CL, V(max), and V(1). The administration of concomitant chemotherapy (IFL, FOLFIRI, or paclitaxel/carboplatin) or intensity of baseline tumor EGFR expression did not alter the pharmacokinetics of panitumumab. The presence of antipanitumumab antibodies in patients (immunogenicity rate 3.4%) did not appear to affect panitumumab exposure substantially (AUC difference 8%). In support of a new drug application in Japan, the model was used to assess panitumumab pharmacokinetics in Japanese patients compared to other racial groups; there were no significant differences in model-predicted steady-state panitumumab AUC, C(max), or C(min) after accounting for the effect of body weight.

Cortical activation during foot movements: II effect of movement rate and side.

Cerebral control of foot movements has received limited study. Functional MRI compared slow with rapid foot movement, and right (dominant) with left foot movement. Brain activation during right, as compared with left, foot movement was larger, with higher amplitude task-related motor cortex signal change, and higher laterality index. Brain activation during fast, as compared with slow, foot movement was larger in cortical and cerebellar areas but smaller in deep gray areas. Some principles of cerebral control of hand movement extend to foot, but exceptions found include that dominant foot movement showed greater activation than did nondominant, and faster foot movements activated bilateral deep gray matter structures less than did slower. Results might have utility in trials of restorative therapies.