Absolute bioavailability of intranasal fluticasone furoate in healthy subjects

BACKGROUND: Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS: A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.     

Neuropathic pain after spinal intradural benign tumor surgery: an underestimated complication?

Neurosurgical Review - Neuropathic pain presents a burdening and impairing condition which may occasionally occur after spinal tumor surgery. While it has been described in peripheral nerve sheath...     

A randomized,phase 1b study of the pharmacokinetics,pharmacodynamics, safety,and tolerability of bleselumab,a fully human,anti‐CD40 monoclonal antibody,in kidney transplantation

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC_inf, C_max, and AUC_last. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC_inf and AUC_last demonstrated a more than dose‐proportional increase in the range of 50‐500 mg, and C_max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment‐emergent anti‐bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose‐dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).     

Noninvasive Cerebral Cooling in a Swine Model of Cardiac Arrest

Objective: Mild cerebral hypothermia improves neurologic outcome in animals resuscitated from cardiac arrest. This study examined whether one practical external cooling method, i.e., local application of ice to the heads and necks of swine, during resuscitation induces cerebral cooling.
Methods: Local external cerebral cooling was examined in a prospective laboratory investigation using 24 female swine in a model of cardiac arrest. The swine were randomized into hypothermia and normothermia groups. Intracerebral temperature was measured in the parietal cortex. Eight minutes after induction of ventricular fibrillation, chest compressions and mechanical ventilation were initiated. The hypothermia group was treated with 1,500 mL of ice in plastic bags applied to the head and neck, while the normothermia group received no extra interventions. Data were analyzed using repeated-measures ANOVA.
Results: In the normothermia group, there was no significant change in nasopharyngeal (-0.8 ± 0.6°C), intracerebral (-0.6 ± 0.8°C), or esophageal (-0.2 ± 0.6°C) temperatures during 20 minutes of resuscitation. However, in the hypothermia group, application of ice during resuscitation significantly reduced nasopharyngeal (-2.9 ± 1.4°C), intracerebral (-2.1 ± 0.6°C), and esophageal (-1.4 ± 0.8°C) temperatures.
Conclusions: External application of ice packs during resuscitation effectively reduced intracerebral temperatures in swine by an amount that improved neurologic outcomes in previous large animal studies. These data suggest that clinically significant cerebral cooling could be accomplished with a noninvasive, inexpensive, and universally available intervention. Further studies are required to assess the clinical feasibility and therapeutic efficacy of this intervention.     

Predicting physical activity among urban adolescent girls: A test of the health promotion model

The purpose of this study was to test hypothesized relationships of the health promotion model (HPM) as a means of predicting moderate‐to‐vigorous physical activity (MVPA) among urban, adolescent girls. A secondary analysis of baseline data from a group randomized controlled trial was conducted. The study involved eight urban schools in the Midwestern United States. The sample included girls (N = 517) in the 5th–8th grades. Data were collected on age, body mass index, pubertal status, enjoyment, self‐efficacy, social support, options for physical activity (PA), and commitment to PA. MVPA was measured via accelerometers worn by the girls for 7 days. Structural equation modeling was used to analyze study aims. Mean age of the sample was 11.8 years (standard deviation [SD] = 1.0). Girls attained an average of 3.0 (SD = 1.2) minutes per hour of MVPA. Self‐efficacy had a positive direct (β = .337; p < .001) and total effect (β = .310; p < .001) on MVPA. Social support and options for PA were not significant predictors of commitment to PA or MVPA. Commitment to PA had a negative but nonsignificant effect (β = ?.056; p = .357) on MVPA. The model predicted 10.1% of the variance in MVPA with 9.6% of the variance predicted by self‐efficacy. Limitations include lack of longitudinal analysis and inability to generalize the results to other populations such as boys. PA self‐efficacy continues to emerge as a significant predictor of MVPA in the HPM. Continued theory testing is needed to better understand the correlates and determinants of PA among adolescent girls before designing theory‐based interventions to promote PA.