Chiara Mameli

Paediatric pharmacology: Remember the excipients

Excipients are largely used by pharmaceutical industry to guarantee preservation and stability and confer shape, volume and consistency to pharmaceutical preparations. They are particularly important in medicines intended for prescription in children since they often play a critical role in manufacturing of suitable paediatric formulations. It was generally believed that excipients were inert substances; on the contrary, it is actually well known that excipients are far from being inactive and much more interest is growing about safety issues associated with their extensive use by pharmaceutical industry in general, and for manufacturing of paediatric drugs in particular.

Adolescents with type 1 diabetes and risky behaviour

Aim:  The aim of the student is to assess whether adolescents with type 1 diabetes mellitus (T1DM) in Italy differ from their healthy peers in regard to risky behaviour.

PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes

Restoration of a PD-L1 defect in HSPCs reverses diabetes in NOD mice and thus may represent a potential cure for T1D. Stemming attacks on the pancreas In type 1 diabetes, autoreactive CD4 T cells attack and kill pancreatic β cells, disrupting insulin production. Many approaches have been taken to inhibit this process, but few have translated into real benefit for diabetic patients. Ben Nasr et al. demonstrate that hematopoietic stem and progenitor cells from NOD mice and diabetic patients express less PD-L1, which is a T cell inhibitory molecule. Induction of PD-L1 expression on stem cells reversed diabetes in NOD mice and inhibited human autoimmune responses in vitro. Either gene therapy or pharmacological modulation of PD-L1 on stem cells could be brought into the clinic, providing a new way to interrupt the autoimmune response and help people with diabetes. Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.

Serotype distribution and antimicrobial susceptibilities of nasopharyngeal isolates of Streptococcus pneumoniae from healthy children in the 13-valent pneumococcal conjugate vaccine era

Few epidemiological data are available since the introduction of 13-valent pneumococcal vaccine (PCV13) in 2010. We conducted a cross-sectional study to estimate the prevalence of Streptococcus pneumoniae (SP) nasopharyngeal carriage in healthy Italian infants and young children and to evaluate the impact of PCV13 on pneumococcal colonization. In the trimester September-December 2011 nasopharyngeal swabs were collected from healthy children aged 3-59 months presenting for routine well careat 16 primary care pediatricians in Milan. SP carriage isolates were serotyped and tested for antimicrobial resistance using EUCAST breakpoints. Among 1250 enrolled children, 618 had received at least 1 dose of PCV13, 292 at least 1 dose of PCV7, 94 a combination of the two vaccines and 246 were not vaccinated. The prevalence of SP carriage was 27% (95% confidence interval [CI] 25-30). At multivariable analysis, age≥25 months (prevalence ratio [PR]=0.74) and use of antibiotics in the previous 3 months (PR=0.67) were associated with lower SP carriage prevalence. Having siblings (PR=1.79 for 1 sibling and PR=2.23 for ≥2 siblings), day-care attendance (PR=2.27) and respiratory tract infections in the previous 3 months (PR=1.39) were associated with higher SP carriage prevalence. The immunization status for SP was not associated with SP carriage at univariable or at multivariable analysis. The most common carriage isolates were 6C, 19A and 23A. The prevalence of the six additional PCV13 serotypes carriage in children appropriately vaccinated with PCV13 was lower than in children appropriately vaccinated with PCV7 (0 vs. 0.060); the greater reduction in prevalence of carriage was observed for serotype 19A (0 vs. 0.041). Serotype 6C was the most common drug-resistant serotype (17.2%). Further epidemiological studies are needed to assess changes in circulating SP serotypes following the large-scale introduction of PCV13.

Gluten-Free Diet in Children: An Approach to a Nutritionally Adequate and Balanced Diet

Gluten-free diet (GFD) is the cornerstone treatment for celiac disease (CD). GFD implies a strict and lifelong elimination from the diet of gluten, the storage protein found in wheat, barley, rye and hybrids of these grains, such as kamut and triticale. The absence of gluten in natural and processed foods, despite being the key aspect of GFD, may lead to nutritional consequences, such as deficits and imbalances. The nutritional adequacy of GFD is particularly important in children, this the age being of maximal energy and nutrient requirements for growth, development and activity. In recent years, attention has focused on the nutritional quality of gluten-free products (GFPs) available in the market. It is well recognized that GFPs are considered of lower quality and poorer nutritional value compared to the gluten-containing counterparts. The present review focuses on the nutritional adequacy of GFD at the pediatric age, with the aim being to increase awareness of the potential complications associated with this diet, to identify strategies in order to avoid them and to promote a healthier diet and lifestyle in children with CD.

Adverse drug reactions in newborns, infants and toddlers: pediatric pharmacovigilance between present and future

Introduction: The detection, assessment, understanding and prevention of adverse drug reactions (ADRs) are the primary aims of pharmacovigilance activities. Pediatric patients, especially all newborns and infants, are particularly at risk for experiencing drug-related adverse events. Areas covered: This review briefly analyzes the physiological peculiarities of pharmacodynamic and pharmacokinetic aspects of drugs in newborns, infants and toddlers and children. It also deals with specific pediatric pharmacovigilance aspects, such as the frequent use of unlicensed and/or off-label drugs in neonatal intensive care units in European countries and in Australia. This review reports on European, American and Canadian data about the incidence and type of pediatric ADRs, particularly focusing on neonates, infants and toddlers. Expert opinion: The awareness of pediatricians about the importance of reporting ADRs should be stimulated, new reporting systems should be encouraged and pediatric pharmacovigilance activities should be improved, first, by intensifying active post-marketing surveillance methods.

Positional plagiocephaly: what the pediatrician needs to know. A review

IntroductionPositional or deformational plagiocephaly is the most common type of cranial asymmetry in infancy and has become more prevalent after the introduction of the “Back to Sleep” campaign in Western countries. However, the supine position cannot be considered as the only etiologic factor and different predisposing variables have been investigated in the last few years.DiscussionThe pediatrician should correctly diagnose this condition and exclude the possibility of craniosynostosis in any child with plagiocephaly in order to optimize management and reduce potential morbidity associated with different conditions other than positional ones. In addition, the pediatrician needs to be able to educate parents on methods to proactively decrease the likelihood of the development of occipital flattening, initiate appropriate management, and make referrals when necessary.

Timing of bolus in children with type 1 diabetes using continuous subcutaneous insulin infusion (TiBoDi Study).

BACKGROUND Continuous subcutaneous insulin infusion is considered a safe and effective way to administer insulin in pediatric patients with type 1 diabetes, but achieving satisfactory and stable glycemic control is difficult. Several factors contribute to control, including fine-tuning the basal infusion rate and bolus timing. We evaluated the most effective timing of a pump-delivered, preprandial bolus in children with type 1 diabetes. METHODS We assessed the response of 30 children with type 1 diabetes to a standard meal after different timing of a bolus dose. RESULTS The glucose levels for 3 h after the meal were lower (i.e., closer to the therapeutic target of <140 mg/dL) when the bolus doses were administered 15 min or immediately before the meal, rather than after the meal. However, these differences were not statistically significant, except at the 1-h postprandial time point: bolus just after meal, 177 +/- 71 mg/dL (9.83 +/- 3.94 mmol/L); 15 min before meal, 136 +/- 52 mg/dL (7.55 +/- 2.89 mmol/L) (P = 0.044); and just before meal, 130 +/- 54 mg/dL (7.22 +/- 3.00 mmol/L) (P = 0.024). The area under the curve (AUC) (in mg/min) did not differ significantly with different bolus times, but the SD of the AUC was the lowest with the bolus given 15 min before the meal. CONCLUSIONS These data support injection of the bolus before, rather than after, eating, even if the patient is hypoglycemic before meals.

Long-lasting immunogenicity of a virosomal vaccine in older children and young adults with type I diabetes mellitus

To evaluate the long-lasting immunogenicity and reactogenicity of a virosomal influenza vaccine in subjects with type I diabetes, a trial was conducted during the 2007-2008 influenza season in Milan, Northern Italy. One hundred five subjects aged 9-30 years were randomized to receive by intramuscular injection vaccination by a single dose (0.5 ml) of either a virosomal (Inflexal V) (n=52) or a standard subunit (Influvac) (n=53) vaccine. Serum hemagglutinin inhibition antibody titres were determined against the three recommended influenza-like strains, A/H1N1, A/H3N2 and B, at pre-vaccination, and 1 and 6 months post-vaccination. Geometric mean titres were increased in the two groups 1 and 6 months post-vaccination (P<0.001). One month post-vaccination both vaccines met the CPMP requirement for immunogenicity with high seroprotection rates (>95%) for strains A/H1N1 and A/H3N2, and a seroprotection of 73% and 70% in the virosomal and subunit vaccine for strain B. Mean fold increase ranged 2.8 (A/H3N2)-6.2 (A/H1N1) in the virosomal group and 2.3 (A/H3N2)-4.8 (A/H1N1) in the subunit group. Immunogenicity declined 6 months post-vaccination in both groups, and the CPMP requirement for immunogenicity was satisfied only in the virosomal group. In subjects without pre-existing antibodies to strain B (titre <10), the virosomal vaccine showed higher immune response than the subunit vaccine 6 months post-vaccination, with a geometric mean titre (95% CI) of 40.2 (30.7-54.6) vs. 21.2 (14.6-30.8). Reactogenicity was similar in the two vaccines. All reactions were transient and not severe. The results indicate that in older children and young adults with type I diabetes influenza vaccination with a virosomal or a standard subunit vaccine is safe and adequately immunogenic against the three influenza vaccine strains. In addition, the virosomal vaccine may show better long-lasting immune response than the standard subunit vaccine, especially in subjects without pre-existing antibodies to influenza strains.

An update on the assessment and management of metabolic syndrome, a growing medical emergency in paediatric populations

Graphical abstract Figure. No Caption available. ABSTRACT In the last decades the increasing rate of obesity in children and adolescents worldwide has led to the onset in paediatric age of metabolic syndrome, a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non‐alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA’s Adverse Event Reporting System database.