Paediatric formulations : pharmaceutical development and clinical evaluation

Drug development for children has long been a neglected area compared to adult drug development. There are many ‘older’ medicines that have an important place in the treatment of children, but often no suitable dosage form is available. There is a great need for well-studied, child-friendly, oral drugs, which preferably have a large dose flexibility. In collaboration with the Laboratory of Dutch Pharmacists (LNA), we developed two liquid formulations, taking into account the limited amount of excipients that can be safely used, and specific aspects such as taste (acceptance). Amlodipine and lorazepam were chosen as model compounds for water-soluble and non-water-soluble drugs. Subsequently the formulations were studied in adult volunteers and in paediatric patients, in which pharmacokinetics (PK), pharmacodynamics (PD), side effects and acceptance were investigated. In recent years, the importance of suitable dosage forms for children has been increasingly recognized. Pharmacy preparations play an important role here because of the lack of commercial products. Optimization and standardization of these preparations is necessary to guarantee good quality

Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam

Aims: This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations. Methods: Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state. Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus. Results: Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted- vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state. Conclusion: The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients.</p

Measuring working memory load effects on electrophysiological markers of attention orienting during a simulated drive

Intersection accidents result in a significant proportion of road fatalities, and attention allocation likely plays a role. Attention allocation may depend on (limited) working memory (WM) capacity. Driving is often combined with tasks increasing WM load, consequently impairing attention orienting. This study (n = 22) investigated WM load effects on event-related potentials (ERPs) related to attention orienting. A simulated driving environment allowed continuous lane-keeping measurement. Participants were asked to orient attention covertly towards the side indicated by an arrow, and to respond only to moving cars appearing on the attended side by pressing a button. WM load was manipulated using a concurrent memory task. ERPs showed typical attentional modulation (cue: contralateral negativity, LDAP; car: N1, P1, SN and P3) under low and high load conditions. With increased WM load, lane-keeping performance improved, while dual task performance degraded (memory task: increased error rate; orienting task: increased false alarms, smaller P3). Practitioner Summary: Intersection driver-support systems aim to improve traffic safety and flow. However, in-vehicle systems induce WM load, increasing the tendency to yield. Traffic flow reduces if drivers stop at inappropriate times, reducing the effectiveness of systems. Consequently, driver-support systems could include WM load measurement during driving in the development phase

Oral lorazepam can be substituted for intravenous midazolam when weaning paediatric intensive care patients off sedation

Aim: Intravenous sedatives used in the paediatric intensive care unit (PICU) need to be tapered after prolonged use to prevent ia

ADVANCE AUSTRALIA FAIR? (IN)EQUALITY, PROSPERITY AND SUSTAINABILITY IN SHAPING AUSTRALIA’S FUTURE

Scholarships & Prizes Office. University of Sydne

Availability of age-appropriate paediatric formulations in the Netherlands: The need in daily clinical practice remains

Objectives: To quantify the availability of authorised, age-appropriate paediatric medicines in clinical practice in the Netherlands and to identify gaps by assessing dispensing practice in a paediatric hospital. Methods: The availability of age-appropriate formulations was assessed by conducting a survey on the use of pharmacy compounded medicines among the paediatric hospitals in the Netherlands, and by analysing dispensing data of oral medication from the inpatient pharmacy of the largest paediatric hospital in the Netherlands. The age-appropriateness of the dispensed formulations was assessed on two aspects: dose-capability and acceptability. Liquid drug products that are unsuitable due to the presence of potentially harmful excipients, were identified based on the dosage in clinical practice. Results: For 129 out of 139 drug substances included in the survey (93%), at least one of the eight respondents stated to use a pharmacy compounded product to meet the needs of their paediatric patients. The age-appropriateness of medicines dispensed from the inpatient pharmacy increased with age, and was higher for non-intensive care unit (ICU) patients than for ICU patients. We identified 15 drug products causing excipient exposure above the European Medicines Agency-recommended values. Conclusions: This study confirms there is still a large need for age-appropriate formu

Clostridioides difficile infection with isolates of cryptic clade C-II: a genomic analysis of polymerase chain reaction ribotype 151

Objectives: We report a patient case of pseudomembranous colitis associated with a monotoxinproducing Clostridioides difficile belonging to the very rarely diagnosed polymerase chain reaction (PCR) ribotype (RT) 151. To understand why this isolate was not identified using a routine commercial test, we performed a genomic analysis of RT151. Methods: Illumina short-read sequencing was performed on n = 11 RT151s from various geographical regions to study their genomic characteristics and relatedness. Subsequently, we used PacBio circular consensus sequencing to determine the complete genome sequence of isolates belonging to cryptic clades CeI and C-II, which includes the patient isolate. Results: We found that 1) RT151s are polyphyletic with isolates falling into clades 1 and cryptic clades C eI and C-II; 2) RT151 contains both nontoxigenic and toxigenic isolates and 3) RT151 C-II isolates contained monotoxin pathogenicity loci. The isolate from our patient case report contains a novelpathogenicity loci insertion site, lacked tcdA and had a divergent tcdB sequence that might explain the failure of the diagnostic test. Discussion: This study shows that RT151 encompasses both typical and cryptic clades and provides conclusive evidence for C. difficile infection due to clade C-II isolates that was hitherto lacking. Vigilance towards C. difficile infection as a result of cryptic clade isolates is warranted. Quinten R. Ducarmon, Clin Microbiol Infect 2023;29:538.e1-538.e6 (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).Molecular basis of bacterial pathogenesis, virulence factors and antibiotic resistanc

Manipulation of oral medication for children by parents and nurses occurs frequently and is often not supported by instructions

Aim: Due to a lack of age-appropriate formulations, administration of drugs to children remains a challenge. This study aimed to identify the problems experienced in both the outpatient setting and the clinical setting. Methods: Between June 2017 and January 2018, we performed a cross-sectional, prospective study at the Sophia Children’s Hospital, The Netherlands. The study comprised of a structured interview on drug manipulations with parents visiting the outpatient clinic, and an observational study of drug manipulations by nurses at the wards. Results: A total of 201 questionnaires were collected, accounting for 571 drugs and 169 manipulations (30%). Drug substances that were most often mentioned as manipulated were macrogol (n = 23), esomeprazole (n = 15), paracetamol (n = 8), methylphenidate (n = 7) and melatonin (n = 7). Of all manipulated medicines, 93/169 (55%) were manipulated according to the instructions or recommendations of the Summary of Product Characteristics (SmPC) or patient information leaflet. During the observational study, manipulation was performed by 21/35 of observed nurses (60%), of whom 11 deviated from the hospital protocol for manipulation or SmPC (52%). Conclusion: Manipulation was a widely used method to administer drugs to children. Validated information regarding manipulation of drugs for both parents and nursing staff is needed

Functional Characterization of N297A, A Murine Surrogate for low-Fc Binding Anti-Human CD3 Antibodies

Several low- or non-FcR binding anti-human CD3 monoclonal antibodies have been under investigation for the treatment of autoimmune diseases. To model the mechanism of action of these anti-human CD3 mAbs in the murine system, an Fc-modified anti-mouse CD3 antibody (N297A) was generated. N297A exhibited similar biological effects as Fc-modified anti-human CD3 antibodies including rapid, reversible reduction in peripheral leukocyte numbers, differential modulation of activated versus resting T cells, and reduced levels of induced cytokine release compared to the non-Fc-modified parent antibody. In an in vivo model of colitis induced by adoptive transfer of IL–10-deficient cells, administration of N297A significantly reduced body weight loss. As N297A shared many functional characteristics of non-FcR binding anti-human CD3 mAbs both in vitro and in vivo, it provides a means to model the mechanisms of action of Fc-modified anti-human CD3 antibodies in mouse

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS