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ObjectiveThis phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD).DesignEligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.ResultsIn all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.ConclusionsClinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.Trial registration numberNCT01276509; Results.

BackgroundIn the United Arab Emirates (UAE) 35% of the population are aged 0–24 years. A significant proportion of these young people are living with chronic conditions (e.g., asthma, type 1 diabetes, cardiac conditions, and genetically-transmitted conditions such as thalassemia and cystic fibrosis). This group has increased vulnerability to developmental delays and mental health problems, and is increasingly coming to the attention of service providers in mainstream schools, primary healthcare centers, and pediatric hospitals. Despite the government directing attention to improving the mental health of the UAE population, there is concern that mental health services are not growing at the rate needed to meet the mental health needs of children and young people with chronic conditions.MethodA cross sectional survey design was used to determine the mental health literacy of nurses and other healthcare professionals working with children with chronic illnesses. Participants completed a culturally-adapted mental health literacy questionnaire comprising three vignettes of fictional characters meeting diagnostic criteria for posttraumatic stress disorder, psychosis, and depression with suicidal thoughts. Participants also completed the Kessler Psychological Distress Scale (K10).ResultsParticipants were 317 healthcare professionals from across the UAE. The majority were nurses. Correct identification of the diagnosis for each vignette was limited, with the highest level of accuracy achieved for the psychosis vignette (n = 113, 54.3%). Accurate identification of appropriate evidence-based interventions was also limited. K10 scores indicated 40% of participants had moderate to high levels of psychological distress.ConclusionsThese findings are concerning and provide important data to inform the development of undergraduate and continuing education programs for nurses. The K10 scores suggest healthcare professionals are under considerable stress, highlighting the need to support healthcare professionals who experience multiple psychosocial stressors.

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Abstract. Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0 ), body-weight (BW) normalized central elimination rate (K el /BW −0.25 ) and central volume (V c /BW 1.0 ). AAFE of less than three-fold was estimated for the binding affinity constant (K D ). The other four parameters, i.e., complex turnover rate (K int ), target turnover rate (K deg ), central to peripheral distribution rate constant (K pt ) and peripheral to central rate constant (K tp ) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.