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Objectives There are long-held concerns that analgesia in patients with acute abdominal pain may obscure the physical examination and lead to missing a diagnosis of appendicitis. Despite evidence to the contrary, analgesia continues to be underutilized and suboptimally dosed in children with acute abdominal pain. The objective of this systematic review and meta-analysis was to determine if opioids provide analgesia without an increase in side effects and appendicitis-related complications. Methods Trials were identified through electronic searches of MEDLINE (1946–2013), EMBASE (1980–2013), Cochrane Central Register of Controlled Trials (2013), CINAHL (1981–2013), and Google Scholar (2013). All randomized controlled trials (RCTs) of children aged 0–18 years with acute abdominal pain that compared any opioid analgesic to placebo were included. The methodologic qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration's Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system, respectively. Results Six RCTs met inclusion criteria, and each compared a single-dose parenteral opioid to a placebo, providing data on 342 children aged 5 to 18 years. The pooled mean pre/post difference in self-reported pain scores was 19.61 mm (95% confidence interval [CI] = –1.16 to 40.37 mm) lower in those receiving opioid analgesia. There was no significant increase in the risk of perforation or abscess associated with opioids in cases of appendicitis (relative risk [RR] = 1.03, 95% CI = 0.55 to 1.93). The risk of side effects was significantly greater in patients who received opioids (RR = 6.06, 95% CI = 1.10 to 33.49). Subtherapeutic dosing of opioids was detected in all six trials. Conclusions The use of opioids in undifferentiated acute abdominal pain in children is associated with no difference in pain scores and an increased risk of mild side effects. However, there is no increased risk of perforation or abscess. The overall quality of evidence is low, suggesting the need for larger, high-quality trials that are powered to detect both serious complications of appendicitis and determine the most efficacious opioid dosing for children.

Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children.

Pharmacogenomics is the study of how genetic variants affect the way in which an individual or subgroup responds to drugs. This developing field aims to inform individual drug therapy and to minimize adverse drug reactions (ADRs). It also promises great benefits in the drug development process. Innovation in pharmacogenomics and its translation into clinical practice is desirable, but appropriate regulation of the safety and effectiveness of pharmacogenomics testing is necessary. This article will describe the current regulatory framework applicable to pharmacogenomic tests in Canada, the United States and Europe. In particular, it will examine the different regulatory pathways for pharmacogenomic tests marketed as test kits and for laboratory-developed tests (LDTs). Recent and upcoming changes to the regulation of pharmacogenomic tests will also be discussed. For example, FDA's proposal to regulate LDTs could have a major impact on the development and availability of pharmacogenomic tests. This review will lead to an evaluation of the issues raised by the regulatory framework and the impact of regulatory changes in relation to meeting the goals of ensuring public safety and promoting the advancement of pharmacogenomics. Regulatory policies which successfully achieve the dual objectives of ensuring public safety and promoting innovation in health technology are imperative in order to reap the benefits of this emerging field.

Azithromycin is an antibiotic that is commonly prescribed for upper and lower respiratory tract infections in children. While it has proven benefits, some concerns regarding azithromycin use have arisen in recent years. This practice point considers azithromycin therapy for acute respiratory infections in otherwise healthy children. Pharmacokinetics, spectrum of activity, the problem of resistant bacteria and clinical aspects are considered, along with recommendations for use and contraindications. Azithromycin should be avoided in patients with a significant risk of bacteremia. It is associated with pneumococcal resistance and, with stated exceptions, is generally not recommended for the treatment of acute pharyngitis, acute otitis media or pneumococcal community-acquired pneumonia in the paediatric population.L’azithromycine est un antibiotique souvent prescrit chez les enfants en présence d’infections des voies respiratoires supérieures et inférieures. Elle a des avantages démontrés, mais plusieurs préoccupations ont surgi ces dernières années au sujet de son utilisation. Le présent point de pratique permet d’évaluer le traitement d’infections respiratoires aiguës à l’azithromycine chez des enfants autrement en santé. La pharmacocinétique, le spectre d’activités, le problème de bactéries résistantes et les aspects cliniques sont évalués, de même que les recommandations relatives à l’utilisation et les contre-indications. Il faudrait éviter l’azithromycine chez les patients présentant un risque marqué de bactériémie. Ce médicament s’associe à une résistance pneumococcique et, sauf dans des exceptions définies, il n’est généralement pas recommandé pour traiter la pharyngite aiguë, l’otite moyenne aiguë ou la pneumonie pneumococcique d’origine non nosocomiale au sein de la population d’âge pédiatrique.

Ondansetron is a useful adjunct for the treatment of acute gastroenteritis in the paediatric ED. The use of ondansetron is associated with many benefits including decreased emesis, decreased need for intravenous fluids, decreased rate of admission, decreased length of stay, decreased revisit rates and increased cost savings (15-18). There may be value in giving patients a second as-needed home dose of ondansetron as part of ED discharge planning, with the appropriate patient education, in anticipation of recurrent emesis. This practice may further reduce ED revisit rates and also prevent morbidity and hospitalization associated with severe dehydration for patients who do eventually return to the ED, especially those in rural communities where timely treatment and access to an ED is difficult. The decision to dispense ondansetron should be made clinically by the ED physician for patients who have failed ORT whose symptoms are predominantly emesis as opposed to diarrhea, and when the discharging physician is reasonably certain of a diagnosis of acute gastroenteritis and not something more sinister. There is currently no consensus on the role of ED-provided ondansetron for out-of-hospital use for paediatric patients with acute gastroenteritis. Future studies are needed to determine the potential impact on morbidity and the health care economy. ©2014 Pulsus Group Inc. All rights reserved.

Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision making process for children, notably in areas such as childhood cancer where the benefits and risks of therapy are considerable.

Objective To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B15:02 and HLA-A31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B15:02 or HLA-A31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? Methods A systematic literature search was performed for HLA-B15:02 and HLA-A31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. Results Patients carrying HLA-B15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B15:02 is rare among Caucasians or Japanese; no HLA-B15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. Significance This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B15:02 and HLA-A31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. © 2014 International League Against Epilepsy.

Background: Adverse drug reactions are common problems for children and adults. Among the most serious are hypersensitivity reactions. The pathogenesis of these reactions has not been understood, but recently there have been new insights into the mechanism(s) responsible for these complex adverse drug reactions. Objectives: The goals of this paper were to review potential mechanisms for hypersensitivity adverse drug reactions and to relate these mechanisms to the care of children with hypersensitivity reactions. Methods: A search for original research in the pathogenesis of hypersensitivity adverse drug reactions was done using MEDLINE from 1985 to 2001. Other databases were not consulted. The research reviewed was confined to that described in English. Results: Hypersensitivity adverse drug reactions appear to be initiated by metabolism of the parent drug to reactive intermediates. The ongoing propagation of these reactions appears to be mediated by immunity. The mechanism(s) involved in the immunopathogenesis of drug hypersensitivity reactions mediated by reactive drug metabolites remains unclear, but may include changes in T-cell responses mediated by changes in T-cell signaling. Conclusions: Hypersensitivity adverse drug reactions are important challenges for health care workers caring for children. Health care workers need to be vigilant for the development of hypersensitivity adverse drug reactions and be aware that these reactions may continue to evolve clinically despite discontinuation of the drug in question.

Insofar as it exerted its immunosuppressive effect by inhibiting cytokine expression, we assessed the effect of FK506 (Tacrolimus) on cytokine-stimulated T-cell activation. Human T cells, treated with FK506, or controls were stimulated with the mitogens PHA + PMA, Con A, and the "CD3-bypass" stimulation regimen, PMA + ionomycin. T-cell proliferation was quantitated by measuring the uptake of tritiated thymidine, and mRNA expression was assessed by RT-PCR. FK506, in a concentration-dependent fashion, inhibited T-cell proliferation and steady-state mRNA expression of IL-2 and IL-7; half-maximal suppression was obtained at 10(-7) to 5 x 10(-8) M. We tested whether FK506 antiproliferative effect could be overcome with exogenously reconstituted rIL-2 and/or rIL-7. Neither rIL-2 nor rlL-7, individually in conjunction with suboptimal concentrations of PHA or Con A, or in combination without any costimulus, was capable of abrogating FK506 antiproliferative effect, indicating that FK506 also acted by inhibiting cytokine-stimulated T-cell activation. To confirm this, T cells were treated with FK506 and stimulated by rIL-2 and rIL-7, individually in conjunction with suboptimal concentration of PHA and Con A. In addition, T cells were stimulated with rIL-2 and rIL-7 without any costimuli. FK506 inhibited T-cell activation stimulated by rIL-2 and by rIL-7, individually and in combination. This confirms that, in exerting its antiproliferative effect, FK506 acts at two levels, by inhibiting cytokine availability and by suppressing cytokine effect on target cells, and explains the beneficial effect of FK506 in attenuating ongoing immune responses.

Background Hair cortisol analysis has been shown to be an effective measure of chronic stress. Cortisol is assumed to incorporate into hair via serum, sebum, and sweat sources; however, the extent to which sweat contributes to hair cortisol content is unknown. Methods Sweat and saliva samples were collected from 17 subjects after a period of intensive exercise and analyzed by salivary enzyme-linked immunosorbent assay (ELISA). Subsequently, an in vitro test on exposure of hair to hydrocortisone was conducted. Residual hair samples were immersed in a 50-ng/mL hydrocortisone solution for periods lasting 15 minutes to 24 hours, followed by a wash or no-wash condition. Hair cortisol content was determined using our modified protocol for a salivary ELISA. Results Postexercise control sweat cortisol concentrations ranged from 8.16 to 141.7 ng/mL and correlated significantly with the log-transformed time of day. Sweat cortisol levels significantly correlated with salivary cortisol concentrations. In vitro hair exposure to a 50-ng/mL hydrocortisone solution (mimicking sweat) for 60 minutes or more resulted in significantly increased hair cortisol concentrations. Washing with isopropanol did not affect immersion-increased hair cortisol concentrations. Conclusions Human sweat contains cortisol in concentrations comparable with salivary cortisol levels. This study suggests that perfuse sweating after intense exercise may increase cortisol concentrations detected in hair. This increase likely cannot be effectively decreased with conventional washing procedures and should be considered carefully in studies using hair cortisol as a biomarker of chronic stress.

Glucocorticoids (GCs) exert their immunosuppressive/antiproliferative effects largely through inhibition of cytokine expression, and paradoxically upregulate the expression of (proinflammatory) cytokine receptors on select nonlymphoid cells. Clinically, withdrawal of GCs was frequently associated with worsening of the outcome of heightened immunity disorders, thereby implicating enhanced cytokine and cytokine receptor expression as a possible consequence of acute/short-term GCs withdrawal. In view of the significance of this complication of GC therapy, we addressed the effect of GC withdrawal on cytokine receptor expression and subsequent T-cell effector function, using the proliferation of human T cells as biological readout. To mimic GC withdrawal, T cells were treated with GCs or controls, stimulated, and incubated for 16–20 h at 37°C, washed, and reactivated for a further 4–48 h. Surface marker expression was assessed by FACS analysis, and proliferation was determined by measuring the cellular uptake of tritiated thymidine. Dexamethasone (DEX) and prednisolone (PRED), in a concentration-dependent manner, inhibited T-cell proliferation induced by anti-CD28 Ab + PMA. However, pretreatment of T cells activated with mitogens, cross-linking antibodies, or PMA + ionomycin (“CD3-bypass” stimulation regimen), but not resting T cells, with DEX or PRED resulted in a marked increase in IL-1R, IL-2Rα, and IL-6R expression, which was accompanied by a significant enhancement in T-cell proliferation. This effect of GCs was neither stimulus specific nor did it result from alteration in cell viability, and was paralleled by augmentation in cytokine (rIL-2) effects on DEX-pretreated and preactivated T cells. Taken together, our results underline the dual effects of GCs in regulating T-cell activation and cytokine expression. In essence, GCs directly inhibited T-cell proliferation by suppressing cytokine production, and, by enhancing cytokine receptor expression, pretreatment with GCs augmented T-cell proliferation.

Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders and they exert their effects by several mechanisms, the most significant of which is inhibition of cytokine production and action. Recent reports suggested that GCs inhibit cytokine expression indirectly through promotion of a T helper cell type 2 (Th2) cytokine-secreting profile, thereby resulting in preferential blockade of pro-inflammatory monokine and T helper cell type 1 (Th1) cytokine expression. The target of GCs appeared to be monocytes macrophages, whereby altered regulation of interleukin (IL)-1/IL-1 receptor antagonist (IL-1ra), coupled with profound blockade of IL-12 synthesis and inhibition of interferon (IFN)-gamma-induced major histocompatibility complex (MHC) class II expression, lead to a preferential cognate stimulation of Th2 cells at the expense of Th1 cells. It is possible that this may have involved the expansion of a Th2-cell pool or, in addition, frank stimulation of uncommitted naive CD4 + T cells toward the Th2 lineage. In addition, GCs may have blocked Th1 cytokine expression, thereby inhibiting ongoing Th1 cytokine secretion, and consequently provided for the unimpeded production of Th2 cytokines. Collectively, this indicates that, in exerting their anti-proliferative effects, GCs act indirectly by altering Th1/Th2 cytokine balance, blocking the (pro-inflammatory) Th1 program and favoring the (anti-inflammatory) Th2 program.

A growing antivaccine movement in Canada and elsewhere is hearing more about an unproven homeopathic therapy, 'nosodes', as an alternative to routine vaccines. The present statement defines nosodes and describes limitations for their use in children. There is scant evidence in the medical literature for either the efficacy or safety of nosodes, which have not been well studied for the prevention of any infectious disease in humans. Recommendations to change the labelling on these products to reflect such limitations are made.Un mouvement croissant d’opposition à la vaccination au Canada et ailleurs parle de plus en plus d’un traitement homéopathique non démontré, les « nosodes », pour remplacer les vaccins systématiques. Le présent document de principes contient la définition de ce que sont les nosodes et décrit les limites de leur utilisation chez les enfants. Les publications scientifiques offrent peu de données probantes sur l’efficacité ou l’innocuité des nosodes, qui n’ont pas fait l’objet d’études approfondies sur leur capacité à prévenir les maladies infectieuses chez les humains. La Société canadienne de pédiatrie recommande donc de modifier l’étiquetage de ces produits pour en refléter les limites.

Trois evolutions de la sante publique : l’hygiene publique, les antibiotiques et la vaccination, ont radicalement change un monde dans lequel, il n’y a pas si longtemps, les maladies infectieuses etaient la principale cause de deces pendant l’enfance.(1) La vaccination reussit particulierement a prevenir des maladies qui ne sont pas dotees d’un traitement efficace.(2) Cependant, malgre l’efficacite et l’innocuite demontrees des vaccins, un mouvement oppose a la vaccination vehement a pris de l’expansion ces dernieres annees et incite de nombreux parents a remplacer la vaccination par autre chose. Les « nosodes » (du grec nosos, maladie) sont des preparations biologiques utilisees en homeopathie pour prevenir les maladies. C’est le docteur Samuel Hahnemann (1755–1843), inventeur de l’homeopathie, qui en a propose le concept.(3) Les nosodes designent une categorie precise de traitement homeopathique derive d’un element de maladie ou de tissus pathologiques, definis comme « un remede homeopathique fabrique a partir du produit d’une maladie infectieuse extrait directement de la bacterie ou du virus ou, moins directement, d’un tissu suppose contenir cette bacterie ou ce virus ».(3) La preparation de nosodes est composee de dilutions successives d’une matiere biologique, generalement par un facteur de 100, qui est ensuite administree pour prevenir ou traiter un probleme de sante. Les nosodes, tres utilises en homeopathie veterinaire, le sont desormais dans un cadre therapeutique chez les humains. Le modele conceptuel de la maniere dont les nosodes previennent une maladie infectieuse differe considerablement des modeles medicaux actuels sur le mode d’acquisition de l’immunite et sur la reponse du systeme immunitaire humain aux attaques infectieuses. Tres peu de recherches appuient l’efficacite des nosodes dans les publications scientifiques. Selon une etude realisee en 1997 sur des souris exposees a une dose potentiellement mortelle de Francisella tularensis, le groupe traite a l’aide de nosodes mourait plus rapidement, mais presentait une diminution modeste de la mortalite par rapport aux sujets temoins.(4) Une etude de cohorte a grande echelle faisant appel a une preparation de nosodes pour soigner une epidemie potentielle de leptospirose a Cuba semblait s’associer a une diminution des taux d’infection, meme si cette etude comportait de multiples facteurs confusionnels et n’a toujours pas ete repliquee.(5–7) Des etudes chez les animaux evaluant l’efficacite potentielle des nosodes pour traiter une infection par le Plasmodium berghei semblent egalement demontrer une survie prolongee dans un modele murin.(8,9) L’analyse Cochrane d’une preparation aviaire de nosodes pour traiter l’influenza a conclu que les donnees pour en soutenir l’efficacite etaient de faible qualite.(10) En revanche, les donnees probantes demontrant a la fois l’innocuite et l’efficacite de tous les vaccins administres systematiquement aux enfants canadiens abondent. Les vaccins previennent presque tous les cas de rougeole, de rubeole, d’oreillons, de diphterie, de tetanos, de polio et d’hepatite B. Chaque annee au Canada, les campagnes publiques de vaccination permettent egalement de prevenir de nombreux cas de varicelle, de coqueluche, de meningite et d’infections bacteriennes invasives. Les nosodes n’ont jamais fait l’objet d’etudes sur la prevention de ces infections.(11) Le Reglement sur les produits de sante naturels de Sante Canada approuve l’utilisation des nosodes chez les humains. Au moment de la publication, 179 produits differents etaient approuves a la vente, y compris 82 dont l’etiquette indiquait qu’ils pouvaient etre utilises pour prevenir les infections courantes et importantes. Cependant, comme on l’a precise plus haut, aucune donnee scientifique ni medicale n’appuie l’efficacite des nosodes pour la prevention des maladies infectieuses. Il est important de faire connaitre les meilleures donnees probantes aux parents canadiens afin qu’ils puissent prendre des decisions eclairees sur la sante de leur enfant. Selon la reglementation actuelle, l’etiquetage des nosodes doit inclure le libelle suivant : « Ce produit n’est pas une alternative a la vaccination ». La Societe canadienne de pediatrie (SCP) ne croit pas que cette reserve rend pleinement compte du fait que, de toute evidence, les nosodes ne sont ni efficaces ni securitaires pour remplacer la vaccination. La SCP recommande que le libelle des nosodes soit modifie pour se lire comme suit : « Il n’est pas demontre que ce produit previent les infections. Sante Canada recommande de faire administrer a votre enfant tous les vaccins systematiques, meme s’il utilise ce produit. » En plus des modifications au libelle, la SCP recommande que Sante Canada lance une campagne d’education publique pour favoriser l’utilisation des vaccins et pour fournir aux Canadiens les meilleures donnees probantes sur les avantages demontres de la vaccination et sur les risques associes au refus des vaccins.

Objectives A lymphocyte-based in vitro rechallenge technique was used to examine the potential for cross-reactivity between loracarbef and cefaclor in children who had had adverse reactions to cefaclor. Study design The study cohort included 10 patients (2.2 ± 1.1 years old) with a serum sickness-like reaction to cefaclor, five patients (4.1 ± 4.6 years old) with immediate-type hypersensitivity reactions to the drug, and five patients (1.5 ± 0.9 years old) who had a delayed hypersensitivity reaction to cefaclor without joint involvement (i.e., not a serum sickness-like reaction). Peripheral blood mononuclear cells were isolated from each patient and were exposed to cefaclor, loracarbef, and the metabolites of each generated with phenobarbital-induced murine hepatic microsomes. Results Among patients with cefaclor-associated serum sickness-like reactions, lymphocyte killing (expressed as percentage cell kill above baseline) in the presence of cefaclor metabolites (83.6% ± 42.2%) was significantly (p < 0.02) higher than that observed among the patients with either immediate-type (1.1% ± 2.4%) or delayed hypersensitivity (0%) reactions. In contrast, loracarbef did not produce significant in vitro cytotoxicity among any of the patient subgroups. Our in vitro evidence was supported at therapeutic rechallenge with loracarbef among three children with cefaclor-associated serum sickness-like reactions who tolerated a full course of therapy without adverse reactions. Conclusion The metabolite-mediated cytotoxicity associated with cefaclor among patients who had had serum sickness-like reactions after therapeutic administration of the drug was not shared with loracarbef. The extent to which the apparent lack of in vitro cross-reactivity between cefaclor and loracarbef may be predictive of clinical cross-reactivity is not known. Clinical Pharmacology & Therapeutics (1998) 63, 686–693; doi

OBJECTIVE:To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a focus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed.DATA SOURCES:Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology.DATA EXTRACTION:Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens.DATA SYNTHESIS:Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs.CONCLUSIONS:Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.

OBJECTIVE To determine the effect(s) of reactive sulfonamide metabolites on antibody production by human lymphocytes. METHODS Human peripheral blood cells (PBMCs) were isolated from control volunteers and incubated with the hydroxylamine of sulfamethoxazole (SMX H/A), a reactive metabolite of the most commonly used sulfonamide, in increasing concentrations. PBMCs were then stimulated to produce antibody with pokeweed mitogen. After incubation for 8 days, concentrations of IgG and IgM were determined in supernatant using an ELISA assay. RESULTS Production of both IgG and IgM was significantly suppressed by sub-lethal concentrations of SMX H/A in a concentration-dependent fashion (p < 0.05). Suppression was more marked for IgM production (maximal decline to 80% of baseline antibody production) than for IgG production (maximal decline to 57% of baseline antibody production). No suppression was seen when cells were incubated with sulfamethoxazole in concentrations up to 400 microM. This suppression was not related to changes in cell viability; at a concentration of 25 microM of SMX H/A, IgM and IgG concentration were reduced by 47 +/- 8.7% and 73 +/- 7.2%, while cell viability (percentage of live cells) was 93 +/- 5%. Suppression was time-dependent, increasing over the incubation periods to reach a plateau after 2 h of incubation. CONCLUSION Sulfonamide reactive metabolites, in concentrations which are achieved during therapy, suppress antibody production by PWM-stimulated human cells. This may explain, in part, the alterations in immunity associated with hypersensitivity reactions to the sulfonamides. This may also have implications for patients receiving sulfonamide therapy and concurrent immunosuppressive therapy.

Because of an increasing number of reports of adverse reactions associated with pharmaceutical excipients, in 1985 the Committee on Drugs issued a position statement1recommending that the Food and Drug Administration mandate labeling of over-the-counter and prescription formulations to include a qualitative list of inactive ingredients. However, labeling of inactive ingredients remains voluntary. Adverse reactions continue to be reported, although some are no longer considered clinically significant, and other new reactions have emerged. The original statement, therefore, has been updated and its information expanded.

Since 1985 molecular biology techniques have made possible the synthetic synthesis of pure human growth hormone in potentially unlimited amounts. With this increased availability, its use in patients other than children with growth hormone deficiency has been associated with clinical and ethical questions. This statement presents an analysis of the current status of the use of human growth hormone in children.

Gingival enlargement is a fibrotic condition that can arise from systemic administration of the dihydropyridine calcium channel blocker nifedipine. Periostin, a transforming growth factor-beta (TGF-β)-inducible matricellular protein, has been associated with fibrosis in numerous tissues, but its expression has never been examined in nifedipine-influenced gingival enlargement (NIGE). The objective of this study was to assess if periostin up-regulation is associated with NIGE and whether nifedipine induces periostin expression in gingival fibroblasts. In NIGE tissue (n = 6), periostin is overexpressed in the gingival connective tissue compared with healthy control tissue (n = 6). The transcription factor p-SMAD2/3, which is associated with canonical TGF-β signaling, localizes to the nuclei in both HGFs and oral epithelial cells in NIGE tissues, but not in control healthy tissue. In vitro culture of HGFs with 30 and 100 ng/mL of nifedipine significantly increased periostin mRNA and protein levels, which correlated with increased levels of active TGF-β and increased phosphorylation and nuclear localization of SMAD3. Blocking of canonical TGF-β signaling through inhibition of the TGF-β receptor I with SB431542 significantly reduced nifedipine-induced SMAD3 phosphorylation and periostin expression. Our results demonstrate that nifedipine up-regulates periostin in HGFs in a TGF-β−dependent manner.

Nephrotoxicity is a serious side effect associated with ifosfamide use. It can affect up to 30% of children who are treated with this chemotherapeutic drug, and treatment may necessitate lifelong supplementations, renal dialysis, renal transplant, and in severe cases may result in death. The antioxidant n-acetylcysteine is a promising strategy for mitigating this renal toxicity. It is currently used in children for acetaminophen overdose in the 21-hour IV protocol, a dose which has also been suggested to provide renal protection against ifosfamide. Of significance, both in vitro and in vivo studies suggest n-acetylcysteine does not interfere with the antitumor actions of ifosfamide. Most importantly, n-acetylcysteine has successfully protected against ifosfamide-induced nephrotoxicity in both cell and rodent models, as well as in several paediatric cases, suggesting it should be evaluated as a treatment option for children on ifosfamide who present with renal dysfunction. The purpose of this paper is to outline strategies and recommendations for treating patients at risk or suffering from nephrotoxicity during ifosfamide therapy. These recommendations may be used when deciding who to treat, how and when to treat, as well as several considerations when exact recommendations cannot be met. They have been created to increase both the quality of care and quality of life of paediatric oncology patients.

Glucocorticoids (GCS) profoundly inhibit several aspects of T cell immunity largely through inhibition of cytokine expression at the transcriptional and posttranscriptional levels. GCS were also reported to act indirectly by inducing transforming growth factor-β expression, which in turn blocks T cell immunity. In exerting their antiproliferative effects, GCS diffuse into target cells where they bind their cytoplasmic receptor, which in turn translocates to the nucleus where it inhibits transcription of cytokine genes through direct binding to the glucocorticoid response elements (GRE), which are located in the promoter region of cytokine genes or, alternatively, through antagonism of the action of transcription factors required for optimal transcriptional activation. In contrast to their inhibitory effects on cytokine expression, GCS upregulate cytokine receptor expression that correlates with enhanced cytokine effects on target cells. In this review, we summarize the current state of knowledge of the mechanism of action of GCS, including the phenomenon of steroid-induced rebound, which ensues upon GCS withdrawal.

Drug hypersensitivity reactions (DHRs) are rare but potentially fatal adverse drug reactions (ADRs). A reliable test to diagnose DHRs would be a major advance in the clinical care for patients and in the evaluation of ADRs during drug development as well as for mechanistic studies of drug hypersensitivity. Available in vitro tests including the lymphocyte toxicity assay (LTA) have been used but are time-consuming, cumbersome, and expensive. We have developed a novel diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA). The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamides. We recruited 66 individuals (36 DHS-sulfa patients and 30 healthy controls) to participate in the study. Blood samples were obtained and LTA and iPTA were performed in parallel. There was concentration-dependent toxicity in the cells of patients when incubated with the reactive hydroxylamine metabolite of sulfamethoxazole for both the LTA and iPTA (P .05). The iPTA was more sensitive than conventional LTA test in detecting susceptibility of patient cells to in vitro toxicity (P .05). The novel iPTA has considerable potential as an investigative tool for DHS as it is more sensitive and cheaper, requiring no special reagents.

Among the many challenges facing the newly created states formed in Eastern Europe and Central Asia after the collapse of the Soviet Union is the development of medical education and health care independent of many of their former ties to Moscow. Ukraine, the largest of these states following the Russian Republic, is facing many of these challenges. Paediatric clinical pharmacology is markedly underdeveloped in the Ukraine. There is little clinical pharmacology content in undergraduate medical education and essentially none in postgraduate training. Underdevelopment of paediatric clinical pharmacology also increases difficulties faced because of lack of a domestic pharmaceutical industry. This situation compounds the difficulty of how physicians in Ukraine can best learn to choose and apply rational individualized therapy.

Serum sickness-like reactions most commonly occur secondary to drug administration. We describe a serum sickness-like reaction that was possibly associated with meropenem therapy.

Although the past century has seen the most remarkable advances in medical management in history, the benefits of the therapeutic revolution have not been equally shared (1). As child health care workers appreciate, and as noted elsewhere in this issue of Paediatrics & Child Health, there is no evidence-based support for the efficacy, optimal dosing and safety of the majority of drugs commonly used in children. Academic paediatrics has let therapeutics for children evolve by default, driven by inferences from adult medicine and emotional rather than evidence-based prescribing practice. Given the increasing number and complexity of new therapies entering clinical practice, this usual state of affairs is clearly unacceptable for now and certainly for the future.

Despite the important role of drug therapy in children, there is often a lack of readily available information regarding the indications and dosing regimens for medications in paediatrics.To collect data on where family physicians obtain this prescribing information.A structured questionnaire was mailed to 500 family physicians in Ontario.Questionnaires were returned by 261 (52%) family physicians, 217 (83%) of whom identified themselves as currently involved in the care of children. Most (87%) reported that the Compendium of Pharmaceuticals and Specialties (CPS) was the source that they most commonly consulted for drug information in children. The available sources of information on prescribing for children were thought to be not adequate by 40% and not readily available by 27%. Sixty-one per cent reported being moderately confident (in doubt part of the time) about their decisions regarding drug prescribing in this age group. The majority (70%) had learned most of what they know about prescribing in paediatrics during practice, while 69% and 62% reported they had little or no teaching during undergraduate and postgraduate (internship or residency) medical education, respectively.Although it is recognized that for a number of drugs used in children the CPS does not reflect the current standard of care in paediatrics, it is currently the source most commonly referred to by family physicians. Further work should be done in the provision of useful information on paediatric drug therapy to family physicians.

The prevalence of opioid abuse is increasing in North America. Opioid abuse during pregnancy can cause medical, obstetric and psychosocial complications. Neonates exposed to opioids in utero often develop the neonatal abstinence syndrome. Methadone maintenance therapy is the treatment of choice for maternal opioid dependency. There have been unsupported concerns that infants cared for by mothers treated with methadone have higher mortality rates during the first year of life than in the general population.To compare the mortality rates of infants exposed to methadone in utero to those of general population in Ontario, Canada.We utilized several provincial and national databases including those of the Office of the Chief Coroner of Ontario, the Canadian Institute for Health Information, and the Ontario Infant Mortality Rate Report. Reference organ weights were obtained from the peer reviewed literature.The Office of the Chief Coroner of Ontario has reported 8 deaths in children under one associated with in utero methadone exposure between January 1, 2006 and December 31, 2010. Over the same period there have been a total of 1103 cases of neonatal abstinence syndrome recorded in the province. The mean infant mortality rate in Ontario for children under the age of 1year over the same period was 5.2 per 1000 live births. The odds ratio for mortality among children with neonatal abstinence syndrome was not different from that in the general population [OR 1.45 (95% confidence interval 0.471-4.459)] (p=0.56).The available data do not support the concerns that children under the age of one year, born to mothers on methadone maintenance therapy (MMT) are at an increased risk for mortality.

In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.

Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives. Copyright © 2012 by the American Academy of Pediatrics.

Objective Although the use of anesthetic creams before intravenous (IV) insertion has been shown to be both safe and effective in decreasing pain during IV cannulation, the use of any single agent based on efficacy is not yet considered the standard of care in children. We sought to compare a commonly used preparation, 4% liposomal lidocaine (Maxilene), with 4% amethocaine (Ametop), a newer agent with reportedly good efficacy and an intrinsic vasodilatory effect. Methods A total of 60 children aged 5 to 12 years were randomized to receive topically either 4% amethocaine or 4% liposomal lidocaine before IV cannulation. The primary outcome variable was the child's rating of pain using the Faces Pain Scale - Revised. Secondary outcomes included success rate on first IV cannulation attempt, cannulation difficulty ratings by the nurses, and adverse skin reactions. Results We found no statistically significant differences in self-reported scores in the Faces Pain Scale-Revised with the use of 4% amethocaine versus 4% lidocaine before IV cannulation. There was a trend toward fewer IV cannulation attempts in the 4% amethocaine group. Adverse skin reactions were uncommon, and there were no statistically significant differences between groups. Discussion This study demonstrates that there is no difference between 4% amethocaine and 4% liposomal lidocaine in reducing pain associated with IV cannulation in children. Amethocaine confers no advantage in improving IV cannulation success rate over lidocaine. Both agents are associated with few local adverse skin reactions.

The drug development process is a carefully regulated, very expensive, long and complex process designed to bring safe and effective drugs to the market. The process begins with preclinical studies that identify and evaluate promising compounds that are then studied in a series of carefully regulated steps to bring the products from the laboratory to the clinic. This process is closely regulated, even after approval is given for the drug to be marketed. The classical drug development process can be applied to drugs derived from plants, with the acknowledgement that there are both special opportunities and special challenges in using the drug regulatory process to bring drugs derived from plants to market. The drug development and regulatory process is facing a number of challenges, many of which are not unique to drugs derived from plants but rather reflect the changing nature of biomedical science and drug regulation. Some of these changes may in fact facilitate the development of plant-derived therapeutic agents, and recent successes in this area point to the considerable promise for development of drugs from plants.

Summary Armed conflict has a major impact on child health throughout the world. One in six children worldwide lives in an area of armed conflict and civilians are more likely to die than soldiers as a result of the conflict. In stark contrast to the effect on children, the international arms trade results in huge profits for the large corporations involved in producing arms, weapons and munitions. Armed conflict is not inevitable but is an important health issue that should be prevented.

Purpose Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. Patients and Methods We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. Results We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10−5 for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate–binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. Conclusion We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

A body of convincing evidence demonstrates that periconceptional folic acid supplements are associated with a reduction in the risk for first occurrences of neural tube defect and for recurrence of neural tube defects among women with a previously affected pregnancy. The mechanism(s) of this protective effect are unknown, and although the effect can be seen with folate doses between 0.4 and 4 mg, the optimal dose remains unknown. The optimal method of ensuring that all women of child-bearing age receive this dose of folate remains in question; supplementation offers the advantage of targeting only the population at risk, whereas food fortification offers the advantage of ensuring compliance in virtually all of the population at risk. The use of periconceptional folic acid can be expected to reduce, but not abolish, the incidence of neural tube defects. Research into the mechanism(s) of the protective effects of folic acid and the underlying biology of neural tube defects is required to address the problem of how to develop therapeutic strategies to further reduce the impact of neural tube defects.

We sought to describe demographic characteristics of and pattern of contraception use by Canadian women prescribed synthetic retinoids who voluntarily contacted the Motherisk Program in Toronto and to describe the degree of use of the Pregnancy Prevention Program (PPP) for retinoids. Prospectively gathered intake data from isotretinoin-exposed women was statistically compared to that from matched controls selected from our database. Intake data is qualitatively reported for etretinate-exposed women. We included women who voluntarily contacted the Motherisk Program from November 1, 1988, to January 30, 1991, for counseling about reproductive risks of isotretinoin or etretinate. Primary outcome parameters were maternal age, race, marital status, socioeconomic status; gravity, parity, previous miscarriages and elective abortions, maternal tobacco and ethanol exposure, contraception use, and use of PPP (educational components used, patient recollection of warnings). The 26 isotretinoin-exposed women were younger than controls (25.2 [SD 6.7] years vs 28.9 [SD 5.1] years, P = 0.03), tended to be adolescent (30.8% vs. 3.8%, P = 0.014) and sought counselling later in gestation (10.1 [SD 8] weeks vs. 6 [SD 4.2] weeks, P = 0.01). Twenty (77%) knew the drug was teratogenic, yet 10 (38.5%) used no contraception, 6 (23.1%) experienced method failure, and 2 (8%) stopped contraception during isotretinoin therapy. In conclusion, although cognizant of the teratogenicity of isotretinoin, more than one-third of the women in this study used no birth control or experienced contraception failure. In this same group, however, compliance with contraception use appeared to increase in those who saw more of the PPP.

RESUMELes enfants ont toujours ete des « orphelins therapeutiques ». De nombreux medicaments n’ont pas fait l’objet d’etudes aupres des enfants et des adolescents ou leur utilisation n’est pas autorisee officiellement aupres d’eux, ce qui cree un defi constant en matiere d’elaboration et de definition de pharmacotherapies a la securite et l’efficacite optimales au sein du groupe d’âge pediatrique. Depuis dix ans, des reseaux ont germe aux Etats-Unis et en Europe afin d’accroitre la recherche sur les medicaments dans ce groupe, mais aucune evolution comparable ne s’observe au Canada. Le present document de principes expose le contexte de la situation canadienne et contient des recommandations qui tiennent compte de deux besoins pressants : plus de recherches sur les medicaments axees sur les enfants et les adolescents canadiens, y compris un financement dedie a de telles recherches, et plus d’effectifs pour mener des etudes ciblees. Ces initiatives devraient etre entreprises en collaboration, sur les scenes nationale et internationale, et inclure des demarches strategiques et novatrices afin de regler les problemes et enjeux ethiques uniques que presente la recherche sur les medicaments au sein de cette population.

Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed.

Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 µmol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2-mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide.

Cutaneous adverse drug reactions (CADRs) are the most prevalent adverse drug reactions (ADRs) in hospitalized children, with an estimated rate of 2-3%. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) is a pan-Canadian active surveillance network identifying genomic biomarkers of risk for serious ADRs. The purpose of this paper is to describe the characteristics of paediatric CADR cases reported to the CPNDS from February 2005 to December 2008. The CPNDS database was mined and details of CADRs and key clinical data from cases were extracted. Reports were individually analyzed and classified in two main groups: severe and non-severe CADRs, with subcategories. In total, 326 CADR cases were included in the study; 214 (65.6%) severe and 112 (34.4%) non-severe CADRs. Overall L-asparaginase (n=56, 16%), amoxicillin (n=29, 8.3%), cotrimoxazole (n=25, 7.2%), carbamazepine (n=17, 4.9%) and lamotrigine (n=13, 3.7%) accounted for 40% of all suspected medications. We have demonstrated the ability to comprehensively collect clinical data on a wide range of severe and non-severe CADRs to drugs commonly used in the care of children. Our study provides additional real world evidence to promote the proactive detection, collection, reporting and assessment of CADRs in children.

Stevens-Johnson (SJS) and Toxic Epidermal Necrolysis (TEN) are two uncommon mucocutaneous diseases usually considered as severe drug reactions and are characterized by different grades of epidermal necrosis. Several treatment modalities have been proposed with variable results but the lack of controlled studies makes difficult to analyze them objectively especially in children. All publications describing management for SJS and TEN in children were searched in MEDLINE, EMBASE, and the Cochrane Library. Reports included were divided in two categories: A, studies with 5 or more patients and observational studies; and B, reports with less than 5 patients. A formal meta-analysis was not feasible. Description was made using central tendency measures. From 1389 references only 31 references with a total of 128 cases were included, 88 category A and 40 category B. The 4 main treatment modalities were: intravenous immunoglobulin (IVIG), steroids (prednisolone, methylprednisolone, dexamethasone), dressings with or without surgical debridement, and support treatment alone. Miscellaneous treatments: Of 12 patients, 3 received ulinastatin, 4 patients plasmapheresis, 2 patients IV pentoxifylline and the last three patients received different treatment each (cyclosporine, methylprednisone/G-CSF and methylprednisolone/IVIG). Patients receiving IVIG and steroids showed similar findings while patients treated with dressing and support treatment alone, reported both longer time to achieve remission and hospitalization stays and appear to be associated with more complications and deaths. There is scant quality literature about management of SJS and TEN in children. Steroids and IVIG seem to improve the outcome of SJS and TEN patients but results from different reports are variable. Patients treated only with care support seem to have higher morbidity and mortality. Further studies are necessary to define optimal management.

Due to ethical concerns and constraints inherent to research in children, the conduct of clinical trials in children has often been difficult. The views of medical professionals and trainees towards conducting clinical trials in children have been largely unexplored and are potentially important towards working to increase the number of appropriate trials conducted in children.To explore the views of Canadian medical school trainees towards paediatric clinical trials and to compare these views with that of an earlier pilot study conducted amongst Canadian and British health care professionals.Participants were given a questionnaire which consisted of direct questions as well as scenarios with ethical dilemmas. Responders were asked to state whether they would enter children in the trial documented in the scenario and to justify their reasons.89 questionnaires were collected (74% response rate). 42% had formal teaching regarding paediatric ethical dilemmas but only 2% had formal teaching on pharmaceutical testing in children. The students were divided on whether children should only participate in trials where they receive direct benefit. Most students (85%; 95% CI: 77% to 91%) were comfortable with non-inferiority trials even with post-hoc consent. Only a third (33%; 95% CI: 24% to 43%) agreed with the use of placebo in an analgesia trial.Teaching on the ethics of paediatric clinical trials still appears to be lacking amongst medical trainees. However, there does seem to be increased willingness on the part of trainees compared to practicing medical professionals in enrolling children in clinical trials.

Drug hypersensitivity syndrome (DHS) can present in several clinical forms ranging from simple maculopapular skin rash to severe bullous reactions and multi-system dysfunction. Genetic analysis of DHS patients has revealed a striking association between carbamazepine (CBZ)-induced severe bullous reactions, such as Steven-Johnson Syndrome, and toxic epidermal necrolysis in individuals from Southeast Asia who carry a specific HLA allele (HLA-B*1502). This ethnic-specific relationship with a disease phenotype has raised the question of the commonality of the pathogenesis mechanisms of these diseases. The aim of this study was to investigate the genetic and metabolic bases of DHS development to help predict patient susceptibility.A case of carbamazepine-induced Steven-Johnson Syndrome reaction in a HLA-B*1502 positive child of Han Chinese origin, a carbamazepine-induced DHS case in a Caucasian patient and 3 healthy controls were investigated. We performed two types of in vitro toxicity assay, the lymphocyte toxicity assay (LTA) and the novel in vitro platelet toxicity assay (iPTA) on cells taken from the Chinese child 3 and 9 months after recovery from the reaction and from two healthy volunteers. We also tested the Caucasian patient, who developed CBZ-induced DHS, 3 months after the reaction.Both LTA and iPTA tests were negative 3 and 9 months after the reaction on samples from the Chinese child whereas the tests were positive in the Caucasian patient.These results strongly suggest more than one mechanistic pathway for different CBZ-induced hypersensitivity reactions in patients with different ethnic backgrounds.

We assessed a 2-year 4-month-old boy found to have a persistently elevated serum creatinine (peak 926 μmol/L) as measured by the Jaffe reaction after ingesting an unknown quantity of fuel for a model car, which commonly contains nitromethane. The patient was otherwise clinically well and the remaining investigations were unremarkable. When creatinine concentrations were measured with specific enzymatic testing on these same blood samples, all values were within normal limits. Nitromethane has been shown to interfere with the determination of serum creatinine through the Jaffe reaction. Because many ingestions present only rarely, it is not possible for the emergency department clinician to be aware of all toxin factors affecting patient management. This case illustrates the importance of analysis of laboratory results in the context of the patient's clinical status.