Publications by authors named "Mandy Wan"

20 Publications

  • Page 1 of 1

Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.

Nephrol Dial Transplant 2020 Dec 24. Epub 2020 Dec 24.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background And Objectives: The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30ng/ml in children with CKD stages 2-4.

Design: An open-label multicenter randomized controlled trial randomized children with 25OHD concentrations<30ng/ml in 1:1:1 to oral cholecalciferol 3,000 IU daily, 25,000 IU weekly, or 100,000 IU monthly for 3-months (maximum 3 intensive courses).In those with 25OHD ≥30ng/ml 1,000IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD≥30 ng/ml at end of intensive phase treatment.

Results: 90 children were randomized to daily(n = 30), weekly(n = 29) or monthly(n = 31) treatment groups. At end of intensive phase, 70/90(77.8%) achieved 25OHD ≥30ng/ml; 25OHD concentrations were comparable between groups (median 44.3, 39.4, and 39.3 ng/ml for daily, weekly, and monthly groups respectively; p = 0.24) with no difference between groups for time to achieve 25OHD ≥30ng/ml (p = 0.28). There was no change in calcium, phosphorus, and parathyroid hormone, but fibroblast growth factor 23(p = 0.002) and klotho(p = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 vs 41.8 ng/ml; p = 0.007). One child had 25OHD concentration of 134 ng/ml and 5.5% had hypercalcemia without symptoms of toxicity.

Conclusion: Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared to those with non-glomerular disease.
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http://dx.doi.org/10.1093/ndt/gfaa369DOI Listing
December 2020

Quality and use of unlicensed vitamin D preparations in primary care in England: Retrospective review of national prescription data and laboratory analysis.

Br J Clin Pharmacol 2021 Mar 31;87(3):1338-1346. Epub 2020 Aug 31.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Aim: To evaluate the type (licensed vs unlicensed) and cost of preparations used to fulfil vitamin D prescriptions in England over time, and to compare measured vitamin D content of selected vitamin D preparations against labelled claim.

Methods: Retrospective analysis of vitamin D prescription data in primary care in England (2008-2018). Laboratory analysis of 13 selected vitamin D preparations.

Results: Alongside a rise in the number of oral licensed colecalciferol preparations from 0 to 27 between 2012 and 2018, the proportion of vitamin D prescriptions in which licensed vitamin D preparations were supplied increased from 11.8 to 54.2%. However, the use of unlicensed food supplements (dose strength 400-50 000 IU) remained high, accounting for 39.7% of vitamin D prescriptions in 2018. The two licensed preparations showed mean (±SD) vitamin D content of 90.9 ± 0.7% and 90.5 ± 3.9% of the labelled claimed amount, meeting the British Pharmacopeia specification for licensed medicines (90-125% of labelled claim). The 11 food supplements showed vitamin D content ranging from 41.2 ± 10.6% to 165.3 ± 17.8% of the labelled claim, with eight of the preparations failing to comply with the food supplement specification (80-150% of labelled claim).

Conclusions: Despite the increasing availability of quality assured licensed preparations, food supplements continued to be used interchangeably with licensed preparations to fulfil vitamin D prescriptions. Food supplements, manufactured under less stringent quality standards, showed wide variations between measured and declared vitamin D content, which could lead to the risk of under- and over-dosing.
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http://dx.doi.org/10.1111/bcp.14521DOI Listing
March 2021

Free 25-hydroxyvitamin-D concentrations are lower in children with renal transplant compared with chronic kidney disease.

Pediatr Nephrol 2020 06 22;35(6):1069-1079. Epub 2020 Jan 22.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Total serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes.

Methods: We assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2-3, 18 dialysis, and 21 post-transplant).

Results: Total-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, - 0.6, respectively; R = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p < 0.001).

Conclusions: In transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.
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http://dx.doi.org/10.1007/s00467-020-04472-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184055PMC
June 2020

Vitamin D prescribing in children in UK primary care practices: a population-based cohort study.

BMJ Open 2019 12 3;9(12):e031870. Epub 2019 Dec 3.

Research Department of Primary Care and Population Health, University College London, London, UK.

Objective: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016.

Design: Population-based cohort study.

Setting: UK general practice health records from The Health Improvement Network.

Participants: Children aged 0 to 17 years who were registered with their general practices for at least 3 months.

Outcome Measures: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed.

Results: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually.

Conclusions: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs.
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http://dx.doi.org/10.1136/bmjopen-2019-031870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937102PMC
December 2019

Cinacalcet use in paediatric dialysis: a position statement from the European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders Working Group of the ERA-EDTA.

Nephrol Dial Transplant 2020 01;35(1):47-64

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Children's Hospital, Hannover, Germany.

Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested.
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http://dx.doi.org/10.1093/ndt/gfz159DOI Listing
January 2020

Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease.

Nat Rev Nephrol 2019 09 13;15(9):577-589. Epub 2019 Jun 13.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD-Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3-5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045-0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making.
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http://dx.doi.org/10.1038/s41581-019-0161-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136166PMC
September 2019

Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial (CAP-IT).

BMJ Open 2019 05 22;9(5):e029875. Epub 2019 May 22.

Paediatric Infectious Diseases Research Group, MRC Clinical Trial Unit at UCL, Institute for Infection and Immunity, St George's University of London, London, UK.

Introduction: Community-acquired pneumonia (CAP) is a common indication for antibiotic treatment in young children. Data are limited regarding the ideal dose and duration of amoxicillin, leading to practice variation which may impact on treatment failure and antimicrobial resistance (AMR). Community-Acquired Pneumonia: a randomIsed controlled Trial (CAP-IT) aims to determine the optimal amoxicillin treatment strategies for CAP in young children in relation to efficacy and AMR.

Methods And Analysis: The CAP-IT trial is a multicentre, randomised, double-blind, placebo-controlled 2×2 factorial non-inferiority trial of amoxicillin dose and duration. Children are enrolled in paediatric emergency and inpatient environments, and randomised to receive amoxicillin 70-90 or 35-50 mg/kg/day for 3 or 7 days following hospital discharge. The primary outcome is systemic antibacterial treatment for respiratory tract infection (including CAP) other than trial medication up to 4 weeks after randomisation. Secondary outcomes include adverse events, severity and duration of parent-reported CAP symptoms, adherence and antibiotic resistance. The primary analysis will be by intention to treat. Assuming a 15% primary outcome event rate, 8% non-inferiority margin assessed against an upper one-sided 95% CI, 90% power and 15% loss to follow-up, 800 children will be enrolled to demonstrate non-inferiority for the primary outcome for each of duration and dose.

Ethics And Dissemination: The CAP-IT trial and relevant materials were approved by the National Research Ethics Service (reference: 16/LO/0831; 30 June 2016). The CAP-IT trial results will be published in peer-reviewed journals, and in a report published by the National Institute for Health Research Health Technology Assessment programme. Oral and poster presentations will be given to national and international conferences, and participating families will be notified of the results if they so wish. Key messages will be constructed in partnership with families, and social media will be used in their dissemination.

Trial Registration Number: ISRCTN76888927, EudraCT2016-000809-36.
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http://dx.doi.org/10.1136/bmjopen-2019-029875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538022PMC
May 2019

Renal association commentary on the KDIGO (2017) clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD.

BMC Nephrol 2018 09 20;19(1):240. Epub 2018 Sep 20.

Institute of Pharmaceutical Science, King's College, London, UK.

This report comments on the relevance and utility of the recently published (2017) KDIGO Clinical Practice Guideline Update for the diagnosis, evaluation, prevention and treatment of mineral bone disease in patients with chronic kidney disease (CKD-MBD) with respect to UK clinical practice. This document replaces all previously published Renal Association guidelines on the topic.
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http://dx.doi.org/10.1186/s12882-018-1037-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149202PMC
September 2018

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Nephrol Dial Transplant 2018 12;33(12):2208-2217

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD).

Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated.

Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2.

Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.
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http://dx.doi.org/10.1093/ndt/gfy012DOI Listing
December 2018

Clinical practice recommendations for treatment with active vitamin D analogues in children with chronic kidney disease Stages 2-5 and on dialysis.

Nephrol Dial Transplant 2017 Jul;32(7):1114-1127

Center for Pediatric and Adolescent Medicine, Heidelberg, Germany.

In patients with chronic kidney disease (CKD), renal synthesis of active vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D)] declines and is associated with hypocalcaemia, secondary hyperparathyroidism and the spectrum of CKD-mineral and bone disorder (MBD). In advanced CKD, active vitamin D analogues, including alfacalcidol, calcitriol and paricalcitol, are routinely administered. There are few studies on the use of vitamin D analogues in children with CKD and on dialysis. It is difficult to define bone-specific outcomes that can guide treatment with active vitamin D analogues in children with CKD-MBD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs has developed recommendations for the use of active vitamin D therapy in children with CKD and on dialysis. A second document in parallel with this one covers treatment recommendations for native vitamin D therapy. The WGs have performed an extensive literature review to include systematic reviews and randomized controlled trials in adults and children with CKD and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system was used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate.
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http://dx.doi.org/10.1093/ndt/gfx080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837664PMC
July 2017

Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2-5 and on dialysis.

Nephrol Dial Transplant 2017 07;32(7):1098-1113

Center for Pediatric & Adolescent Medicine, Heidelberg, Germany.

Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate.
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http://dx.doi.org/10.1093/ndt/gfx065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837199PMC
July 2017

Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT): the role of anti-IgE in severe paediatric eczema: study protocol for a randomised controlled trial.

Trials 2017 03 22;18(1):136. Epub 2017 Mar 22.

King's College London, King's Health Partners, Asthma-UK Centre in Allergic Mechanisms of Asthma, Department of Asthma, Allergy and Respiratory Science, Guy's Hospital, London, SE1 9RT, UK.

Background: The evidence for systemic treatments for severe childhood eczema is limited and largely based on extrapolation of data from adult studies. Current therapies are often immunosuppressant and may be associated with both short- and long-term side effects. There is increasing in vitro and murine-model evidence for the role of IgE in the immunopathogenesis of atopic eczema. The aim of the study is to assess whether anti-IgE treatment (omalizumab) improves eczema, compared to placebo.

Methods/design: The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is a randomised, double-blind, placebo-controlled study assessing the role of anti-IgE in the management of severe paediatric eczema. Children with severe atopic eczema, with an objective SCORing Atopic Dermatitis (SCORAD) score of over 40 will be recruited. These children are candidates for systemic therapy, have failed systemic therapy or have experienced side effects from systemic therapy. Sixty-two patients aged between 4 and 19 years will receive anti-IgE for 6 months. The primary outcome measure will be the validated eczema score, the objective SCORAD at 24 weeks. This study has 90% power to detect a 33% relative reduction in SCORAD between active and placebo groups, with 5% significance.

Discussion: IgE may have a role to play in eczema, particularly in childhood. This forms the basis for the hypothesis that anti-IgE may be an effective treatment in this patient population. This will be the largest study to evaluate the efficacy of anti-IgE (omalizumab) versus placebo in children with severe eczema. The findings will help to clarify the role of anti-IgE as a potential treatment option in patients with severe childhood eczema.

Trial Registration: European Clinical Trials Database (EudraCT) Number: 2010-020841-29 . Assigned on 14 May 2010. ISRCTN Registry, Identifier: ISRCTN15090567 . Retrospectively assigned on 3 December 2014. ClinicalTrials.gov, Identifier: NCT02300701 . First received 21 November 2014.
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http://dx.doi.org/10.1186/s13063-017-1809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361704PMC
March 2017

A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability.

Int J Pharm Pract 2017 Oct 16;25(5):326-334. Epub 2016 Sep 16.

School of Pharmacy, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.

Background: The palatability of flucloxacillin oral liquid is poor. Parents/carers use strategies to aid the administration of poorly palatable medicines.

Aim: To assess views on the palatability of flucloxacillin oral liquid and identify factors associated with successful administration.

Methods: A mixed methods study which included a structured review of online forums and a survey of parent/carers of children with cystic fibrosis (CF) to obtain parent/carer views on the administration of flucloxacillin oral liquid.

Results: A total of 18 strategies to aid the administration of flucloxacillin suspension to children were identified on 10 different public online forums. A total of 255 responses to the open online survey were received with 47% of respondents reporting that administration of flucloxacillin was more problematic compared to other medicines and 38% reporting the need to improve the palatability. The brand of flucloxacillin oral liquid significantly influenced the degree of difficulty associated with administration to children. A significant relationship was found between the concentration of flucloxacillin and the reported number of doses successfully administered. The use of food and drink to aid administration was more commonly stated in online forums (44%) compared to the survey data of parents/carers of children with CF (15.9%).

Conclusion: The administration of flucloxacillin oral liquid is perceived as a challenge by parent/carers because of palatability. For chronic use, a more concentrated oral liquid and certain brands are likely to improve acceptability.
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http://dx.doi.org/10.1111/ijpp.12308DOI Listing
October 2017

CHILDREN WITH CYSTIC FIBROSIS: UNDERSTANDING ISSUES RELATED TO ORAL ADMINISTRATION OF LIQUID FLUCLOXACILLIN.

Arch Dis Child 2016 09;101(9):e2

Pharmacy and Therapeutics, College of Medical and Dental Sciences, University of Birmingham.

Aim: Palatability of flucloxacillin is poor, yet is used long-term in the management of children with cystic fibrosis (CF). Strategies to aid administration of unpalatable medicines have been reported, however there has never been a systematic approach to gathering views of many parents/carers all administering the same medication to the same population of children. This study aimed to quantify the extent of flucloxacillin palatability issues for parents/cares of children with CF and identify parent/carer and healthcare professional (HCP) reported age-specific strategies to aid administration of flucloxacillin to children with CF.

Method: Passive analysis reviews of public online forums were conducted using search terms including, 'flucloxacillin' and 'taste' or 'palatability' or 'child' to identify evidence of tactics used by parents to aid administration of flucloxacillin to children, not only those with CF (strategies were only included if the age of the child was disclosed). A bespoke online questionnaire was developed and partially validated for parents/carers of children with CF to identify age-specific strategies to aid administration of flucloxacillin. Healthcare professionals (HCPs) were purposively selected for semi-structured interviews to further explore age-specific strategies to aid administration of flucloxacillin.

Results: 18 individual strategies were identified on 10 different public online forums to aid the administration of flucloxacillin to children. These included mixing with food/drink: milk was commonly used for children aged 6-20 months; honey, Nutella, jam, ice cream and squash for those aged 21-36 months. The use of an oral syringe to direct the medicine slowly into the back/side of the mouth, and pinching a child's nose was reported.253 parents/carers of children with CF completed the online survey and 11 HCPs were involved in the semi-structured interviews. 50.2% of parents/carers reported that administration of flucloxacillin was problematic, yet 89.3% reported that they administered 'most' or 'all doses' of flucloxacillin. 90.5% of parents/carers found administration of flucloxacillin more problematic than other medicines in pre-weaned babies. 162 of 253 parents/carers chose to comment on ways that administration of flucloxacillin could be improved/eased, with 38.3% of these respondents suggesting improved palatability was necessary. Mixing with food/drink was rarely reported by parents/carers of children with CF (15.9%) or HCPs (27.3%), contrary to data identified within online forums. This difference highlights that parents of children with CF are less likely to use food to aid administration compared to those using flucloxacillin for acute infections. A multi-methods approach to obtain information on manipulation of medicines by parents/carers would provide greater insights into explaining this finding.

Conclusion: The results from this study showed that flucloxacillin is unpalatable and that parents/carers use a range of strategies to improve acceptability of this product. Although food is an obvious strategy for making flucloxacillin more palatable when treating an acute infection; it may be that this doesn't work in longer term therapy (eg CF) and the wider population can learn from parents/carers with more experience with this medicine. Parents of children with CF and HCPs have provided useful age-specific strategies to ease administration of the known poorly tolerated medicine, liquid flucloxacillin.
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http://dx.doi.org/10.1136/archdischild-2016-311535.33DOI Listing
September 2016

Pharmacy and formulation support for paediatric clinical trials in England.

Int J Pharm 2016 Sep 30;511(2):1163-8. Epub 2016 Mar 30.

School of Pharmacy, Institute of Clinical Sciences, Robert Aitken Building, University of Birmingham, Edgbaston B15 2TT, UK. Electronic address:

Availability and sourcing of investigational drugs for paediatric clinical trials is known to be a challenge for investigator-led clinical trials. The National Institute of Health Research Clinical Research Network: Children (CRN: Children) provides support for formulations and pharmacy related issues to researchers planning and setting up paediatric clinical trials within England. This paper reviews pharmacy and formulation support provided to a consecutive series of investigator-led clinical studies supported by CRN:Children. Case studies are included to describe some of the unique pharmaceutical challenges encountered. 44 trials were reviewed and a total of 103 products were required to support these clinical trials. UK authorised products were suitable for use for 62 of these 103 products. In the remaining 41 cases, 4 could be sourced as an authorised product within the European Union and the remaining 37 required bespoke manufacture. Bespoke manufacture of an investigational drug or placebo is costly. Typical costs for the initial development and testing of a bespoke investigational drug or placebo were in the range of £30,000-100,000 per product. The estimated cost for 19 out of 45 trials was available; in summary, the costs on a per patient per day of therapy basis ranged from under £1 to almost £600; short studies involving multiple agents are obviously the most expensive. This range is dependent upon the need for bespoke manufacture and also the number of participants within the trial. The arrangements for investigational drug supply can greatly affect the study design, regulatory requirements, trial logistics, as well as the total cost of research. As investigational product related activities are often costly, necessitating months of advance planning, it is imperative that specialist inputs are sought from the very start of the study design and planning process.
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http://dx.doi.org/10.1016/j.ijpharm.2016.03.059DOI Listing
September 2016

Paediatric European Risperidone Studies (PERS): context, rationale, objectives, strategy, and challenges.

Eur Child Adolesc Psychiatry 2014 Dec 15;23(12):1149-60. Epub 2013 Dec 15.

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, RUNMC Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands,

In children and adolescents with conduct disorder (CD), pharmacotherapy is considered when non-pharmacological interventions do not improve symptoms and functional impairment. Risperidone, a second-generation antipsychotic is increasingly prescribed off-label in this indication, but its efficacy and tolerability is poorly studied in CD, especially in young people with normal intelligence. The Paediatric European Risperidone Studies (PERS) include a series of trials to assess short-term efficacy, tolerability and maintenance effects of risperidone in children and adolescents with CD and normal intelligence as well as long-term tolerability in a 2-year pharmacovigilance. In addition to its core studies, secondary PERS analyses will examine moderators of drug effects. As PERS is a large-scale academic project involving a collaborative network of expert centres from different countries, it is expected that results will lead to strengthen the evidence base for the use of risperidone in CD and improve standards of care. Challenging issues faced by the PERS consortium are described to facilitate future developments in paediatric neuropsychopharmacology.
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http://dx.doi.org/10.1007/s00787-013-0498-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246122PMC
December 2014

Blinding in pharmacological trials: the devil is in the details.

Arch Dis Child 2013 Sep 29;98(9):656-9. Epub 2013 Jul 29.

National Institute for Health Research-Medicines for Children Research Network-London & South East, Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, King's Health Partners, London, UK.

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http://dx.doi.org/10.1136/archdischild-2013-304037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833301PMC
September 2013

Fibroblast growth factor 23 and soluble klotho in children with chronic kidney disease.

Nephrol Dial Transplant 2013 Jan 23;28(1):153-61. Epub 2012 Nov 23.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, is elevated in chronic kidney disease (CKD). There are scarce data on the levels of its essential co-receptor klotho, and longitudinal changes in FGF23 levels are also unknown.

Methods: We examined FGF23 and soluble klotho (s-klotho) levels over 1 year in 154 children with CKD Stages 1-5 (CKD1-5), were on dialysis or who have received a transplantation.

Results: In children with CKD1-5 and who were receiving dialysis, FGF23 correlated inversely with the estimated glomerular filtration rate (eGFR) (P < 0.001), whereas a decrease in s-klotho was observed with a lower eGFR (P = 0.01). There was no correlation between FGF23 and serum phosphate (P) or parathyroid hormone (PTH) in our cohort wherein 89 and 66%, respectively, had normal levels. FGF23 increased by 6-fold over a 12-month period in children with eGFR of 15-29 mL/min/1.73 m(2), with an overall 5% annual increase in the CKD1-5 and dialysis cohort. High FGF23 levels were seen with high calcium (Ca) levels (P < 0.001). FGF23 levels were high when 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were deficient (P = 0.05 and P < 0.001, respectively). s-klotho levels correlated positively with 25(OH)D (P < 0.001) and negatively with PTH (P = 0.04) and age (P = 0.03). Multivariate regression analysis demonstrated a strong relationship between FGF23 and eGFR, whereas the association between s-klotho and eGFR as observed in univariate analysis was lost following the adjustment of confounders. In transplanted patients, FGF23 correlated with eGFR (P = 0.02) and 25(OH)D (P = 0.05).

Conclusions: This study shows increasing FGF23 and reduced s-klotho levels with progressive renal failure even in a population of children with well-controlled P levels. Novel associations between FGF23 and serum Ca as well as 25(OH)D warrant further investigation.
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http://dx.doi.org/10.1093/ndt/gfs411DOI Listing
January 2013

Ergocalciferol supplementation in children with CKD delays the onset of secondary hyperparathyroidism: a randomized trial.

Clin J Am Soc Nephrol 2012 Feb 19;7(2):216-23. Epub 2012 Jan 19.

Renal Unit, Ormond Street Hospital for Children NHS Trust and Institute of Child Health, London WC1N 3JH, UK.

Background And Objectives: Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism.

Design, Setting, Participants, & Measurements: A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism.

Results: Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median follow-up was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels >100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D.

Conclusions: Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.
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http://dx.doi.org/10.2215/CJN.04760511DOI Listing
February 2012

Can vitamin D slow down the progression of chronic kidney disease?

Pediatr Nephrol 2012 Dec 10;27(12):2167-73. Epub 2011 Dec 10.

Renal Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK.

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of renoprotective therapy, and the reduction of persistent RAAS activation is considered to be an important target in the treatment of chronic kidney disease (CKD). Vitamin D is a steroid hormone that controls a broad range of metabolic and cell regulatory functions. It acts as a transcription factor and can suppress the renin gene, thereby acting as a negative endocrine regulator of RAAS. RAAS activation can reduce renal Klotho expression, and the Klotho-fibroblast growth factor 23 interaction may further reduce the production of active vitamin D. Results from both clinical and experimental studies suggest that vitamin D therapy is associated with a reduction in blood pressure and left ventricular hypertrophy and improves cardiovascular outcomes. In addition, a reduction in angiotensin II through RAAS blockade may have anti-proteinuric and anti-fibrotic effects. Vitamin D has also been shown to modulate the immune system, regulate inflammatory responses, improve insulin sensitivity and reduce high-density lipoprotein cholesterol. Taken together, these pleiotropic effects of vitamin D may slow down the progression of CKD. In this review, we discuss the experimental and early clinical findings that suggest a renoprotective effect of vitamin D, thereby providing an additional rationale beyond mineral metabolism for the close monitoring of, and supplementation with vitamin D from the earliest stages of CKD.
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http://dx.doi.org/10.1007/s00467-011-2071-yDOI Listing
December 2012