Children’s views on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

Objectives: To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods: Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results: A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions: This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications Health care professionals should consider the views of children in decisions that affect their health.

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

Inhaled recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) has shown potential for treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs have limited clinical efficacy. Encapsulation of rSLPI within 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]:Cholesterol liposomes (DOPS-rSLPI) protects rSLPI against Cat L inactivation in vitro. We aimed to determine the effect of liposomes on rSLPI pharmacokinetics and activity in vitro and after local delivery to the airways in vivo.

Development and validation of a dried blood spot LC-MS/MS assay to quantify ranitidine in paediatric samples.

A novel approach has been developed to determine ranitidine in paediatric samples using dried blood spots (DBS) on Guthrie cards (Whatman 903). A selective and sensitive HPLC-MS/MS assay has been developed and validated using small volumes of blood (30µl). A 6mm disc was punched from each DBS and extracted with methanolic solution of the internal standard (IS) nizatidine. This was further subjected to solid phase extraction (SPE), followed by reversed phase HPLC separation, using a XBridge™ C18 column and mobile phase 10mM ammonium acetate/methanol (98:2 v/v) with a flow rate of 0.3mL/min. This was combined with multiple reaction monitoring (MRM) mass detection using electrospray ionisation (ESI). The calibration curve for ranitidine was found linear over the range 10-500ng/mL (r=0.996). The limit of quantification (LOQ) of the method was validated at 10ng/mL. Accuracy and precision values for within and between days were

The 'Unified airway': The RCPCH care pathway for asthma/or rhinitis

Abstract Aims The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies: the asthma/rhinitis care pathway is the third such pathway. Asthma and rhinitis have been considered together. These conditions co-exist commonly, have remarkably similar immuno-pathology and an integrated management approach benefits symptom control. Method The asthma/rhinitis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and was approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. Results The pathway entry points are defined by symptom type and severity at presentation. Acute severe rhinitis and life-threatening asthma are presented as distinct entry routes to the pathway, recognising that initial care of these conditions requires presentation-specific treatments. However, the pathway emphasises that ideal long term care should take account of both conditions in order to achieve maximal improvements in disease control and quality of life. Conclusions The pathway recommends that acute presentations of asthma and/or rhinitis should be treated separately. Where both conditions exist, ongoing management should address the upper and lower airways. The authors recommend that this pathway is implemented locally by a multidisciplinary team (MDT) with a focus on creating networks. The MDT within these networks should work with patients to develop and agree on care plans that are age and culturally appropriate.

Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma.

Rationale Upregulation of glucocorticoid receptor ß (GRß) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRß has been proposed as a dominant negative isoform of glucocorticoid receptor a (GRa) but it has also been suggested that GRß can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway.


Objectives To examine GRß, GRa, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers.


Methods Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRß antibody.


Measurements and main results Protein and mRNA expression for GRa and HDAC2 did not differ between groups. GRß mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRß antibody detected an additional ‘cross-reacting’ protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers.


Conclusions GRß mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRß and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRß literature may be explained in part by clathrin cross-reactivity with commercial antibodies.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

Objectives: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate in paediatric patients. Patients and Methods: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analysed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. Results: A one-compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (L/hr) = 11.4 × (WT /70.0)(0.75) and V/F (L) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 L/hr and 21.4 L, respectively, resulting in an elimination half-life of 11.2 hr. Conclusions: The range of estimated CL/F in the study population was 0.67-7.38 L/hr. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in critically ill paediatric patients (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of weaning by protocol for invasively ventilated critically ill children.

To compare the total duration of invasive mechanical ventilation of critically ill children who are weaned using protocols versus usual (non-protocolized) practice.
To ascertain any differences between protocolized weaning and usual care in terms of mortality, adverse events, ICU length of stay, and quality of life.

Perceptions and attitudes of Jordanian paediatricians towards off-label paediatric prescribing

Objective To assess current experiences and attitudes of hospital based paediatricians towards off-label medicine prescribing. Setting Paediatric hospital wards and out-patient clinics. Design A prospective, questionnaire based study. Results A 30 item questionnaire was sent to 300 hospital based paediatricians and 250 (83%) were returned completed. Over 69% of responders were familiar with the term off-label medicines. However, only 28% were knowingly prescribing off-label medicines to children. The majority of respondents (90%) expressed concerns about the safety and efficacy of off-label medicines. Only 15% had observed Adverse Drug Reactions, and 31% a treatment failure. The vast majority of respondents (83%) did not obtain informed consent or tell parents they were prescribing off label medicines to their children. Conclusions Off-label prescribing of medicines to children is a familiar concept to the majority of paediatricians in Jordan although only a smaller number are aware that it is common in their practice. Respondents showed concern about off label prescribing, although the majority do not consider it necessary to inform parents. More comprehensive research is needed in this area in Jordan and other Middle Eastern countries.

Determination of diclofenac from paediatric urine samples by stir bar sorptive extraction (SBSE)-HPLC-UV technique

A novel stir bar sorptive extraction (SBSE) method coupled with high performance liquid chromatography (HPLC) and UV detection for the extraction of diclofenac (DIC) from paediatric urine samples has been developed and validated. Selectivity and sensitivity being the prime objectives of the bioanalytical method for clinical samples, an optimised SBSE protocol was developed that selectively extracted DIC from various concurrently administered drugs. The validated assay was found to be linear (r=0.9999) over a concentration range of 100-2000 ng mL(-1). SBSE showed consistent recoveries (similar to 70%) of DIC across the validated linearity range. Overall, the method exhibited excellent accuracy and precision across all QC concentrations, tested over three days. Calculated LOD and LOQ were found to be 12.03 ng mL(-1) and 36.37 ng mL(-1), respectively, however, for the experimental purposes, 100 ngmL(-1) was considered as the validated LOQ(accuracy and precision at this LQC was