63 research outputs found
Dupilumab provides favourable longāterm safety and efficacy in children aged ā„ 6 to < 12 years with uncontrolled, severe atopic dermatitis: results from an openālabel phase IIa study and subsequent phase III openālabel extension study
Background
Children aged ā„ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16āweek, randomized, placeboācontrolled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)ā4/ILā13 signalling, significantly improved signs and symptoms with acceptable safety; longerāterm safety and efficacy data are lacking.
Objectives
To report the pharmacokinetic profile and longāterm safety and efficacy of dupilumab in children (aged ā„ 6 to < 12 years) with severe AD.
Methods
Children (aged ā„ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, openālabel, ascendingādose, sequential cohort study and subsequent openālabel extension (OLE) study. Patients received singleādose dupilumab 2 or 4 mg kgā1 followed by 8āweek pharmacokinetic sampling, then 2 or 4 mg kgā1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentrationātime profile and treatmentāemergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PPāNRS) score.
Results
Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, targetāmediated pharmacokinetics characterized dupilumab concentrations (week 24ā48 mean serum concentrations: 2 mg kgā1, 61ā77 mg Lā1; 4 mg kgā1, 143ā181 mg Lā1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kgā1, 47%; 4 mg kgā1, 56%) and AD exacerbation (29% and 13%, respectively). Singleādose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PPāNRS improved by ā37%/ā33% and ā17%/ā20% at week 2 (phase IIa) and ā92%/ā84% and ā70%/ā58% at week 52 (OLE), respectively.
Conclusions
These safety and efficacy results support the use of dupilumab as a continuous longāterm treatment for children aged ā„ 6 to < 12 years with severe AD
Fetal Programming of Adult Glucose Homeostasis in Mice
BACKGROUND: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes. OBJECTIVES: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters. METHODS: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system. RESULTS: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density. CONCLUSION: Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain
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