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Treatment of Chagas disease with nifurtimox requires age- and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease. One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC 0-tlast and C max were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC 0-tlast : LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; C max : LS mean ratio, 101.7%; 90%CI, 89.4%-115.6%; n = 24). Exposure when giving the 4 × 30-mg dose as a slurry or as tablets was comparable, with an AUC 0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased C max ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC 0-tlast ratio fed/fasted , 172%; 90%CI, 154%-192%; C max ratio fed/fasted , 168%; 90%CI, 150%-187%). The data indicate that the 30- and 120-mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions., (© 2020 Eisai Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Context: The use of intravenous acetaminophen leads to meaningful health cost increases for paediatric institutions. Therefore, strict criteria for intravenous acetaminophen administration are needed., Objective: To undertake a systematic review of available evidence comparing oral versus intravenous acetaminophen use in children., Method: A systematic literature search was conducted on five databases. All prospective interventional studies comparing intravenous to oral acetaminophen in patients <18 years old were included. Data collection and analysis were done according to PRISMA guidelines., Results: Among 6,417 retrieved abstracts, 29 full-text articles were assessed of which 3 were retained. (1) Pharmacokinetic: Oral bioavailability (72% with a high inter-individual variability) was reported in 47 stable patients in a paediatric intensive care unit. (2) Analgesia: In a double-blind randomized controlled trial of 45 children, no difference in analgesia was found between oral and intravenous administration after cleft palate repair. (3) Fever: In an open-label prospective observational study of 200 children, temperature decreased faster after intravenous than oral administration but was similar 4 hours later., Conclusions: Available data are insufficient to guide clinicians with a rational choice of route of administration. Oral bioavailability should be studied in paediatric populations outside the intensive care unit. Despite the widespread use of intravenous acetaminophen, there is little evidence to suggest that it improves analgesia compared to the oral formulation. Similarly, fever weans faster but whether this translates into any meaningful clinical outcome is unknown. The lack of data plus the significantly higher costs of intravenous acetaminophen should motivate further research., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chagas disease reactivation in HIV-positive people is an opportunistic infection with 79 to 100% mortality. It commonly involves the central nervous system (CNS). Early treatment with trypanocidal drugs such as benznidazole (BNZ) is crucial for this severe manifestation of Trypanosoma cruzi infection. However, limited BNZ clinical pharmacology data are available, especially its concentration in the CNS. We report a series of HIV-positive patients undergoing treatment for T. cruzi meningoencephalitis, their clinical response, and cerebrospinal fluid (CSF) and plasma BNZ concentrations. Measurements were carried out using leftover samples originally obtained for routine medical care. A high-performance liquid chromatography/tandem mass spectrometry bioanalytical method designed for BNZ plasma measurements was adapted and validated for CSF samples. Six patients were enrolled in this study from 2015 to 2019. A total of 6 CSF and 19 plasma samples were obtained. Only three of the CSF samples had detectable BNZ levels, all under 1 µg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2 µg/ml, which is the putative trypanocidal level. We observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or not measurable in all patients, suggesting that the usual BNZ doses may be suboptimal in HIV-positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. These findings highlight the potential of therapeutic drug monitoring in BNZ treatment and suggest that the use of higher doses may be useful for Chagas disease CNS reactivations., (Copyright © 2021 American Society for Microbiology.)

Acetaminophen has become a novel treatment option for patent ductus arteriosus closure in premature infants. This raises concerns about whether acetaminophen should be avoided in late pregnancy, similar to nonsteroidal anti-inflammatory drugs, because of the risk of in utero ductus arteriosus closure. This article critically evaluated the literature reporting an association between acetaminophen use and in utero ductus arteriosus closure and provided a comparative pharmacokinetic analysis of fetal acetaminophen exposure in pregnancy vs drug levels in neonates, with the goal of making an expert recommendation regarding its safety. Here, 1 prospective cohort study and 12 case reports and series evaluating the risk of premature ductus arteriosus closure with prenatal acetaminophen use were reported and overall do not suggest causation. Pharmacokinetic studies showed that acetaminophen fetal transplacental exposures are well below the levels shown to close the ductus arteriosus in neonates. Short-term use of acetaminophen in the third trimester of pregnancy poses a negligible risk of premature ductus arteriosus closure and can still be considered safe in the third trimester of pregnancy at recommended doses., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF., Methods: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg -1  kg -1  day -1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft)., Results: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours -1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg -1  kg -1  day -1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective., Conclusions: The regimen of 30  mg -1  kg -1  day -1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy., (© 2019 Wiley Periodicals, Inc.)

This study shows the effects of tamoxifen, a known estrogen receptor antagonist used in the treatment of breast cancer, on the sphingolipid pathway of Trypanosoma cruzi, searching for potential chemotherapeutic targets. A dose-dependent epimastigote growth inhibition at increasing concentration of tamoxifen was determined. In blood trypomastigotes, treatment with 10 μM showed 90% lysis, while 86% inhibition of intracellular amastigote development was obtained using 50 μM. Lipid extracts from treated and non-treated metabolically labelled epimastigotes evidenced by thin layer chromatography different levels of sphingolipids and MALDI-TOF mass spectrometry analysis assured the identity of the labelled species. Comparison by HPLC-ESI mass spectrometry of lipids, notably exhibited a dramatic increase in the level of ceramide in tamoxifen-treated parasites and a restrained increase of ceramide-1P and sphingosine, indicating that the drug is acting on the enzymes involved in the final breakdown of ceramide. The ultrastructural analysis of treated parasites revealed characteristic morphology of cells undergoing an apoptotic-like death process. Flow cytometry confirmed cell death by an apoptotic-like machinery indicating that tamoxifen triggers this process by acting on the parasitic sphingolipid pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Exhaled nitric oxide (eNO) has been proposed for monitoring airway inflammation, diagnosis, and prediction of steroid responsiveness in asthma. However, its utility after elective suspension of asthma medication is still unclear. We aimed to determine the association between eNO values and the subsequent loss of asthma control (LAC) in asymptomatic asthmatic children after inhaled corticosteroids (ICS) withdrawal., Methods: We conducted a prospective observational cohort study. Forty-two children (23 boys), mean age 11 years, with clinically controlled asthma, according to GINA guidelines, and receiving low-dose of ICS (budesonide 200 μg/day or equivalent) were included immediately after the withdrawal of ICS. eNO, Asthma Control Test (ACT) and spirometry were monthly assessed, during 54 weeks or until the presence of at least one of the following criteria of LAC: 1) asthma exacerbation, 2) obstructive spirometric pattern, 3) ACT ≤ 19., Results: eNO baseline geometric mean (eNO b ), measured 4 weeks after discontinuation of ICS, was 23.7 ppb (SD: 1.16). An eNO b cutoff point of 21.8 ppb was determined to better discriminate between high and low eNO groups. Twenty-five subjects (71.4%) had LAC. High eNO b was associated to LAC (OR: 9.01; 95CI: 1.10-74.26). In addition, LAC occurred earlier in high eNO b than in low eNO b patients (8 vs 28 weeks, respectively; P = 0.017)., Conclusions: Our findings suggest that eNO predicts loss of asthma control and may contribute for clinical follow up decisions during childhood asthma after ICS withdrawal., (© 2019 Wiley Periodicals, Inc.)

Chagas disease (CD) is recognized as one of the major neglected global tropical diseases. Benznidazole (BNZ) is the drug of choice for the treatment of adults, young infants, and newborns with CD. However, the pharmacokinetics (PK) of BNZ have been poorly evaluated in all age groups, with consequent gaps in knowledge about PK-pharmacodynamic relationships in CD. The purpose of this study was to develop and validate a bioanalytical method to quantify BNZ levels in small-volume whole-blood samples collected as dried blood spots (DBS). The analysis was performed using high-performance liquid chromatography-positive electrospray tandem mass spectrometry. PK evaluation in healthy male volunteers was conducted to verify the correlation between DBS and plasma BNZ concentrations. The calibration curve was linear from 50 to 20,000 ng · ml -1 Intra- and interday precision and bias values were less than 14.87% ( n = 9) and 9.81% ( n = 27), respectively. The recovery rates ranged from 94 to 100% with no matrix effect. There was no hematocrit level effect in a range of 20 to 70%. The PK results obtained from DBS and plasma were comparable ( r 2 = 0.8295) and equivalent to previously published information on BNZ. BNZ in DBS was stable at room temperature for more than one year. This article describes the first microsampling method for measuring BNZ levels in DBS that has the potential to facilitate broad implementation of PK in clinical trials involving adult and pediatric patients in remote areas and helps to address existing knowledge gaps in the treatment of CD., (Copyright © 2018 Galindo Bedor et al.)

Background: No reliable tests or validated biomarkers exist to ensure parasitological cure following treatment of Chagas disease (CD) patients chronically infected with Trypanosoma cruzi . As seroreversion, the only marker of cure, happens more quickly in children, we investigated the correlation between previously identified biomarkers and seroreversion in children., Methods: Thirty CD children (age 1 month to 10 years) diagnosed as T. cruzi positive (time point S0) were treated with benznidazole (BZ) 5-8 mg/kg/d for 60 days. At least 2 serological tests were used to evaluate treatment efficacy from the end of treatment (S1) until seroreversion (S2). Thirty children (age 1 month to 10 years) and 15 adults were used as healthy controls (HCs). Immunoblot and a proteomic-based assay were used to validate previously identified fragments of apolipoprotein A-1 (ApoA1) and fibronectin (FBN) as CD biomarkers., Results: Correlation between seroreversion and absence of ApoA1 and FBN fragments by immunoblot was observed in 30/30 (100%) and 29/30 (96.6%) CD children, respectively. ApoA1 and FBN fragments were absent at the end of BZ treatment in 20/30 (66.6%) and 16/30 (53.3%) children, respectively. Absence of fragments in serum profiles was confirmed by mass spectrometry. Using intact protein analysis, a 28 109-Da protein identified as full-length ApoA1 by tandem mass spectrometry was detected in HC serum samples., Conclusions: These data confirm that ApoA1 and FBN fragments can discriminate between healthy and T. cruzi -infected samples. Correlation with seroreversion was shown for the first time; results suggest predictive capacity potentially superior to serology, making them potentially useful as surrogate biomarkers.

Introduction: Chagas disease (CD) is one of the most neglected public health problems in the Americas, where <1% of the estimated 6 million people with the infection have been diagnosed and treated. The goal of treatment is to eliminate the parasite, decrease the probability of cardiomyopathy and other complications during the chronic stage of infection, and interrupt the cycle of disease transmission by preventing congenital infection. Currently, only benznidazole (BZN) and nifurtimox are recognized by the World Health Organization as effective drugs for treatment of CD. In this paper, we provide an overview of the clinical pharmacology of BZN. Areas covered: This review covers the historical background, chemistry, mechanism of action, pharmacokinetics, preclinical research, resistance, clinical research, toxicology, adverse effects, and current regulatory status of BZN. Expert commentary: Ongoing investigations aim to optimize BZN therapy by adjusting the current standard regimen or by combining BZN with new chemical entities. These studies are assessing alternatives that improve safety while maintaining or increasing the efficacy of BZN. Timely diagnosis and antitrypanosomal treatment are critical components of programs to eliminate CD as a public health problem, and can dramatically reduce the heavy burden of morbidity and mortality caused by the disease.

Background: Risk assessment of the use of quetiapine during breastfeeding is challenging owing to a paucity of data., Methods: A pharmacokinetic study was conducted in lactating women who were taking quetiapine. The primary endpoint was to determine quetiapine concentration profiles in milk and estimated infant exposure levels. Multiple milk and a single blood quetiapine concentrations were determined using a highly sensitive liquid chromatography with tandem mass spectroscopy method., Results: Nine subjects receiving fast-release quetiapine (mean dose, 41 mg/d) were analyzed at steady state. The mean milk/plasma drug concentration ratio at 2-hour postdose was 0.47 (SD, 0.50; range, 0.13-1.67). The mean milk concentration of each patient was 5.7 ng/mL (SD, 4.5; range, 1.4-13.9 ng/mL). The mean infant quetiapine dose via milk per body weight relative to weight-adjusted maternal dose was 0.16 % (SD, 0.08; range, 0.04%-0.35%)., Conclusions: Infant exposure levels to quetiapine via milk are predicted to be very small.

Background: Postinfectious bronchiolitis obliterans (BO) is a chronic respiratory disease that usually follows a severe adenovirus infection., Objective: To determine the evolution of pulmonary function and clinical outcome of children with postinfectious BO during childhood., Methods: The study included patients diagnosed with postinfectious BO in whom at least two spirometries were performed within a minimum interval of 3 months., Results: 46 met the inclusion criteria. The mean (±SD) follow-up period was 12.5 (±3.5) years. 197 spirometries and 41 plethysmographies were performed. Initial (9±3 years old) lung function was as follows (z score, mean±SD): forced vital capacity (FVC) -3.8±1; forced expiratory volume in 1 s (FEV1) -4.4±1; FEV1/FVC -2.2±1; forced expiratory flow (FEF)(25-75) -3.7±1; total lung capacity (TLC) 120±26%; residual volume (RV) 309±108%; and RV/TLC 55±13. During childhood, FVC and FEV1 increased by a mean of 11%/year (95% CI 9.3% to 12.6%; p<0.0001) and 9%/year (95% CI 7.7% to 10.2%; p<0.0001), and the FEV1/FVC ratio decreased by 1.9%/year (95% CI 1% to 2.8; p<0.001). The z score for FVC, FEV1 and FEV1/FVC decreased by 0.07 z score/year (95% CI 0.1 to 0.01; p<0.05), 0.09 z score/year (95% CI 0.1 to 0.05; p<0.01) and 0.04 z score/year (95% CI 0.09 to 0.001; p<0.02), respectively. During the follow-up period, 69% of patients required at least one hospital readmission and five required mechanical ventilation. Nine patients developed a thoracic deformity, and seven whose bronchiectasis did not respond to clinical treatment underwent a lobectomy., Conclusions: After a 12 year follow-up period, pulmonary function remained severely impaired, showing an obstructive pattern with air trapping that slowly improved during childhood. An unequal growth of lung parenchyma over the airways suggests dysinaptic growth. Patients required frequent readmission due to recurrent respiratory infections, and hypoxaemia improved slowly over time., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Oral antibiotics use in infants in developing countries is challenging because liquid formulations are often unavailable. However, dissolving solid formulation of drugs in water poses a risk of gastrointestinal infection. Although mother's milk may be a potential vehicle, no evidence exists to indicate that antibiotics dissolved in human milk are bioequivalent to those dissolved in water. Therefore, we compared pharmacokinetic parameters of an orally administered antibiotic, amoxicillin, dissolved in human milk, to those of water-dissolved amoxicillin., Methods: A pharmacokinetic study was conducted in 16 healthy adult volunteers in a randomised crossover design. Marketed amoxicillin powder for suspension was dissolved in either human milk or water at a final concentration of 50 mg/mL, and 10 mL was given orally in a fasting state. Timed blood samples were obtained and plasma amoxicillin was quantified using liquid chromatography-mass spectrometry., Findings: Results showed that pharmacokinetic parameters, including area-under-the-curve, Cmax and half-life of the water-based and milk-based amoxicillin administration were not significantly different. 90% CIs of the ratios of these parameters in concomitant breast milk administration to those of water were within 89% and 116%, suggesting they are bioequivalent (defined as a range between 80% and 125%)., Interpretation: We conclude that oral administration of amoxicillin dissolved in human milk at 50 mg/mL results in pharmacokinetics profiles comparable to amoxicillin dissolved in water. Pharmaceutical interactions between amoxicillin and breast milk are unlikely, suggesting no need to modify dosing schedules.

Purpose: This review was conducted to examine the current status of paediatric medicines initiatives across the globe., Methods: The authors made a non-systematic descriptive review of current world situation., Results: Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment., Conclusions: Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Objectives: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)., Methods: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Children's Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes., Results: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes., Conclusions: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.

Background: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied., Objectives: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population., Methods: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight., Results: The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%., Conclusion: There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.

Background: Chagas disease is caused by infection with Trypanosoma cruzi. In adults, treatment with benznidazole is associated with a high incidence of adverse drug reactions (ADRs). However, in infants and children, treatment with benznidazole seems associated with a lower incidence and decreased severity of ADRs, but these effects have not been clearly characterized., Objective: We aimed to describe ADRs observed in infants and children treated with benznidazole., Patients and Methods: We conducted a prospective cohort study of infants and children in Argentina with Chagas disease treated with benznidazole., Results: A total of 107 infants and children diagnosed with asymptomatic Chagas disease (mean age: 6.9 years) were enrolled in the study. Sixty-two events (in 44 children) were considered benznidazole related. Mean ADR duration was 8.2 days. ADRs were mild (80.6%), moderate (16%), or severe (3.2%). Most (77.3%) ADRs were in children older than 7 years. Skin was the organ with the highest incidence of ADRs (21%), followed by the central nervous system (9%) and the gastrointestinal tract (8.5%). Also, the ADR rate was lower in infants and toddlers compared with older children (18% vs 53%) (P < .001)., Conclusions: Treatment with benznidazole was well tolerated in children. Most ADRs were mild and did not require treatment suspension. A strong association was observed between ADR incidence and patient age, and most ADRs occurred in children older than 7 years. We believe that anxiety over potential severe ADRs in children with Chagas disease is not justified and should not be an obstacle to using benznidazole.

Background: 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., Method: 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., Results: 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., Conclusion: These results strongly suggest more than one mechanistic pathway for different CBZ-induced hypersensitivity reactions in patients with different ethnic backgrounds.

Background: Unintentional poisoning with sulfonylurea hypoglycaemic drugs is a serious danger to infants and children, as the ingestion of relatively small amounts can be fatal. Although the administration of octreotide is considered effective in patients that remain hypoglycaemic despite glucose administration, experience in children is limited., Methods: A retrospective chart review of the clinical features of all children following sulfonylurea ingestion presenting between April 2001 and November 2008 at the Hospital for Sick Children in Toronto., Results: Ten children were identified with sulfonylurea exposure; six were classified as suspected ingestion and four had confirmed signs of sulfonylurea overdoses (mean age: 8.2 years; range 1.5 - 15). All four patients with confirmed ingestion were exposed to glyburide and developed severe hypoglycaemia; two were toddlers and two teenagers. Ingestion was accidental in the case of the toddlers, and suicidal attempts in the case of the adolescents. All patients were initially treated with glucose infusions. Both toddlers also received octreotide with favourable response and no rebound hypoglyacemia. The two teenagers were treated only with prolonged glucose infusions; in both cases rebound hypoglycaemia and increased glucose requirements were observed., Discussion: Glyburide-induced hypoglycaemia was pronounced in all patients identified. Treatment with octreotide proved effective in the 2 infants treated, agreeing with the limited experience reported to date in the literature, and suggesting that octreotide should be considered the treatment of choice in children.

A case of unusual reactions consisting of involuntary abnormal facial movements in a child following exposure to the 5-HT3 receptor antagonists for prophylaxis against chemotherapy-induced vomiting is presented. Potential mechanisms for these reactions are discussed.

Acute intoxication with acetylsalicylic acid is a severe event commonly seen in children resulting from wide availability of this drug without prescription. Cases of self-poisoning resulting from overdose continue to occur and, although far less common, they are often severe and life-threatening. We report a 14-year-old girl who presented to the emergency department with tachypnea and altered mental status as a result of acetylsalicylic acid overdose in a suicide attempt. We discuss her presentation and the pathophysiological considerations leading to the management decisions taken during her emergency department stay, highlighting the role of the clinician and therapeutic drug monitoring consultant. The use of rapid decontamination with multiple doses of charcoal, even when more than 4 hours have passed since ingestion, and the use of urinary alkalinization are stressed. Timely management can obviate the need for dialysis. Published cases of acetylsalicylic acid intoxication are reviewed.

We performed a meta-analysis to evaluate the association between ABCB1 C3435T polymorphisms and the prevalence of epilepsy, including all relevant human studies (until June 2009), in which patients with or without epilepsy had undergone genotyping for the ABCB1 gene. Odds ratios (ORs) were calculated using a random effects model. We identified 9 case-control studies that included a total of 3,996 patients (2,454 with epilepsy and 1,542 nonepileptic subjects). No association was found between ABCB1 C3435T polymorphisms and the risk of having epilepsy (odds ratio 1.07, 95% confidence interval 0.76-1.51; p = 0.34). ABCB1 genotyping for epileptic patients is not warranted.

Mycophenolate mofetil (MMF) has become a major therapeutic option in the management of patients undergoing transplantation, as well as in the treatment of autoimmune conditions. Case reports have suggested that MMF use during pregnancy is associated with a specific pattern of congenital malformations. Because many pregnancies are unplanned, it is imperative to assess the teratogenic risk of MMF. Using the Organization of Teratology Information Specialists network, we prospectively identified and followed pregnant women exposed to MMF during pregnancy to update this teratogenic potential. Ten cases were identified and all received the drug during embryogenesis at the recommended doses (500 to 1500 mg daily). There were four miscarriages and one elective abortion due to fear of teratogenesis. None of the five live births had malformations. It is possible that, similar to other human teratogens discovered first by case reports, the absolute risk from MMF may be smaller than originally calculated based on case reports. Because the major malformations phenotypic of MMF may be visualized in utero (e.g., microtia, cleft palate, congenital diaphragmatic hernia, and cardiac malformation), diagnostic imaging should be performed.

The authors reviewed the clinical, laboratory, and imaging data from cases of diarrhea-associated hemolytic uremic syndrome (HUS D+), diagnosed at our institution, from 2001 to 2008. The timing and utility of ultrasonographic features of HUS D+ were analyzed. The aim of the study was to determine factors that could aid in the early diagnosis of this disease. A total of 13 children with HUS D+ were identified out of 23 patients with HUS diagnosed during this time period. Evidence of Escherichia coli 0157:H7 was found in 9 cases (70%). Ultrasound studies were ordered in 10 patients (71%), all of which showed renal sonographic findings compatible with HUS. Ultrasound was performed at a mean of 13 days after onset of the diarrhea. Of note, 2 patients whose ultrasounds were performed at the beginning of their diarrheal illness manifested ultrasonographic features suggestive of HUS when there was only a mild increase in serum creatinine and no decrease in hemoglobin or platelets, suggesting that ultrasonography can identify renal involvement early in the course of the disease before other systemic signs appear. Early renal ultrasound may be a useful adjunct in the initial evaluation in children with bloody diarrhea. Evidence of increased renal echogenicity in a patient with bloody diarrhea could aid in early recognition of HUS when other diagnoses such as intussusceptions are being entertained, potentially allowing early intervention.

Introduction: Women with Chagas disease receiving treatment with nifurtimox are discouraged from breast feeding. Many patients who would receive treatment with nifurtimox live in extreme poverty, have limited access to resources such as clean water and baby formula and may not have safe alternatives to breast milk., Aim: We aimed to estimate, using limited available pharmacokinetics data, potential infant exposure to nifurtimox through breast milk., Methods: Original nifurtimox plasma concentrations were obtained from published studies. Pharmacokinetic parameters were estimated using non-linear mixed-effect modelling with NONMEM V.VI. A total of 1000 nifurtimox plasma-concentration profiles were simulated and used to calculate the amount of drug that an infant would be exposed to, if breast fed 150 ml/kg/day., Results: Breast milk concentrations on the basis of peak plasma levels (1361 ng/ml) and milk-plasma ratio were estimated. We calculated infant nifurtimox exposure of a breastfed infant of a mother treated with this drug to be below 10% of the maternal weight-adjusted dose, even if milk-plasma ratio were overestimated. Simulation led to similar estimates., Discussion: Risk for significant infant exposure to nifurtimox through breast milk seems small and below the level of exposure of infants with Chagas disease receiving nifurtimox treatment. This potential degree of exposure may not justify discontinuation of breast feeding.

Question: One of my pregnant patients came for a routine prenatal visit at 20 weeks' gestation. Near the end of the consultation, she asked me about "slapped cheek" disease and pregnancy, as her son had been diagnosed with fifth disease the previous week. What is the current guideline for pregnant women exposed to parvovirus B19?, Answer: The rate of vertical transmission during maternal parvovirus B19 infection is estimated at 33%, with fetal complications occurring in 3% of infected women. Fetal complications comprising hemolysis, anemia, and nonimmune hydrops fetalis and fetal loss are more frequent when maternal infection occurs before 20 weeks of gestation. The first step in the management of this patient would be to obtain immunoglobulin (Ig) M and IgG titres against parvovirus to evaluate if the patient has had previous immunity against the disease. If results are negative for IgG but positive for IgM (ie, primary infection), this patient would need close obstetrical monitoring for the following weeks, including serial ultrasounds to rule out fetal anemia and hydrops fetalis.

Question: I have a patient who has hyperthyroidism due to Graves disease. She was taking methimazole but discontinued when she found out she was pregnant. She is currently close to delivery and might require antithyroid therapy in the postpartum period. Can methimazole cross into human milk, and is breastfeeding safe for her infant?, Answer: The exposure of infants to methimazole or propylthiouracil through breast milk is minimal and not clinically significant. Women with hyperthyroidism using methimazole or propylthiouracil should not be discouraged from breastfeeding, as the benefits of breastfeeding largely outweigh the theoretical minimal risks.

Sulphonylurea ingestion is life-threatening in toddlers due to its strong and prolonged hypoglycemic effect, and is on the toddlers' "one pill can kill" list. Its administration to children may not be accidental. We discuss a case of non-accidental sulphonylurea ingestion by an 18-month-old girl, and the clinical reasoning process leading to identification of the causative agent for the patient's symptoms. A previously healthy 18 month-old girl presented to the Emergency Department with altered mental status and severe hypoglycaemia, which required intravenous hypertonic dextrose solutions to maintain euglycemia. A family history of type II diabetes prompted a search for sulphonylureas in the child's serum, which was positive. Further investigation led to the conclusion that the child's poisoning was the result of the mother's Munchausen-by-proxy syndrome. Sulphonylurea intoxication should be considered in previously healthy children presenting with hypoglycaemia. More than 20% of sulphonylurea poisonings reported in the literature correspond to Munchausen-by-proxy syndrome or homicide attempts. Initial management consists of rapid glucose infusion, but boluses should be avoided whenever possible to prevent rebound hyperinsulinism and worsening hypoglycemia. We stress the need to consider potential child abuse or neglect in a hypoglycaemic patient with sulphonylurea-using caregivers.

Question: My patient was taking glipizide (an oral sulfonylurea) for type 2 diabetes. Now she is pregnant and taking insulin instead. She is very anxious to return to her previous treatment immediately after delivery because of the pain and hurdles associated with the administration of insulin. Can sulfonylureas cross into human milk and, if so, is it safe for her to breastfeed her infant?, Answer: The exposure of infants to second-generation sulfonylureas (eg, glipizide, glyburide) through breast milk is expected to be minimal, based on the limited data available. Women with type 2 diabetes treated with sulfonylureas should not be discouraged from breastfeeding. The benefits of breastfeeding greatly outweigh the risks of these medications, if any. The baby should, however, be monitored for signs of hypoglycemia.

Chagas disease is a neglected parasitic disease endemic in the Americas. It mainly affects impoverished populations and the acute phase of the infection mostly affects children. Many cases have also been detected in nonendemic countries as a result of recent migratory trends. The chronic phase is relatively asymptomatic, but 30% of patients with chronic infection eventually develop cardiac and digestive complications that commonly lead to death or disability. Only two drugs are available for the treatment of Chagas disease, benznidazole and nifurtimox. These drugs have been shown to be effective in the treatment of both acute and early chronic phases in children, but the pharmacokinetics of these drugs have never been studied in this population. We have set out to conduct a pharmacokinetics study of benznidazole in a pediatric population with Chagas disease. The results of this study are expected to allow better estimation of the optimal doses and schedule of pharmacotherapy for Chagas disease in children.

Background: Hair testing is commonly used to confirm potential drug exposure in children living with drug users, as well as abstinence in their caregivers., Objective: To examine differences across pediatric age groups in the relationship between caregiver use of cocaine and cocaine exposure in children., Methods: We determined concentrations of cocaine and its metabolite, benzoylecgonine, in the hair of 19 child-caregiver pairs to estimate the pattern of exposure of the children according to age; concentrations in the caregivers' hair were used as a surrogate marker for the intensity of environmental exposure. Cocaine and benzoylecgonine concentrations in hair were determined by immunoassay., Results: A significant correlation was observed between cocaine concentrations in the hair of infants and their caregivers (Spearman rho = 0.87; p = 0.005; n = 8), and the absence of a correlation in older children. These results suggest that environmental exposure plays an important role in the accumulation of cocaine in the hair of infants., Conclusion: Measurement of cocaine hair concentrations can allow estimation of the degree of environmental drug exposure in young children. Infants seem to have a disproportionately increased risk for systemic exposure, compared with older children.

Question: One of my patients is currently using methadone for maintenance of opioid dependence. She wants to breastfeed. Is breastfeeding safe for her infant?, Answer: The exposure of infants to methadone through their mothers' breast milk is minimal. Women using methadone for treatment of opioid dependence should not be discouraged from breastfeeding. The benefits of breastfeeding largely outweigh any theoretical minimal risks.

Background: Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction., Methods: We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection., Results: Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites., Conclusions: We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.

According to epidemiological data, pregnant women have a two or three times higher risk of experiencing restless legs syndrome (RLS) than the general population. Current evidence suggests that dopaminergic dysfunction, impaired iron homeostasis, and genetic predisposition may be involved in the pathophysiology of RLS. Four classes of medications have been used for patients with RLS, but pregnancy elicits a therapeutic concern. Although two dopamine agonists, ropinirole and pramipexole, have been approved by the FDA for the treatment of RLS and are currently the first-line treatment for daily symptoms, there is very little information on the teratogenic risks of these new medications. Therefore, they are not currently recommended for use during pregnancy. Medications with a more extensive safety record in pregnancy include opioids; antiepileptics, such as carbamazepine and gabapentin; and certain benzodiazepines. Ruling out iron deficiency should be an integral part of a treatment plan for RLS in pregnancy. Before management with medication is introduced, every patient should be assessed for iron status with measurement of serum ferritin.

Background: Isotretinoin is a known teratogen. Pregnancy prevention programs aimed at minimizing isotretinoin exposure in pregnancy have been implemented in North America with limited success., Objective: To compare the management of fetal risk of isotretinoin in three countries, including information given to women, implementation of contraceptive methods, and pregnancy outcomes., Methods: Pregnant women exposed to isotretinoin who called teratogen information services (TIS) in Israel, Italy and Canada between July 1998 and October 2006 were interviewed at the time of initial consultation and after the expected day of delivery., Results: Fifty-three pregnant women exposed to isotretinoin contacted the TIS. Only 41% reported using a birth control method. Just one patient reported using two different forms. Forty-five percent of exposed pregnancies were terminated before delivery and 22% delivered healthy babies. Two babies were born with malformations., Conclusions: Since isotretinoin-exposed pregnancies still occur, there is a need for more effective strategies, which should take into account the cultural differences.

Background: Recurrent painful vaso-occlusive crises (VOC) are a hallmark of sickle cell disease (SCD), and narcotic analgesics are an effective component of therapy. However, the belief that these drugs can promote development of the acute chest syndrome (ACS) may lead to undertreatment of pain., Objective: The aim of this study was to explore the potential association between a dose-response effect of morphine exposure and the development of ACS in children with SCD who presented with VOC., Methods: A retrospective, self-matched, case-crossover design was used to study data from children with SCD who were treated with continuous-drip IV morphine (initial rate of 10 mug/kg . h) for VOC and subsequently developed ACS (index hospitalization) at a tertiary pediatric hospital in Toronto, Ontario, Canada, from April 1, 2000, to March 31, 2006. So that each child could serve as his or her own control for the analysis, a comparison hospitalization for VOC was identified for each child during which ACS did not develop (reference hospitalization). We determined the cumulative dose of morphine administered before ACS development (index interval) during the index hospitalization and the cumulative amount of morphine administered during the same time interval during the reference hospitalization (reference interval)., Results: Seventeen children (13 girls, 4 boys; index hospitalization: mean [SD] age, 8.9 [4.0] years; mean [SD] weight, 30.9 [15.2] kg; reference hospitalization: mean [SD] age, 8.6 [3.4] years; mean [SD] weight, 27.3 [11.2] kg) with SCD who met all inclusion criteria were identified. There was no significant difference in the cumulative morphine dose (mean [SD] amount, 1.24 [0.60] mg/kg) during the index interval compared with the amount administered during the reference interval (mean [SD] amount, 1.44 [0.84] mg/kg)., Conclusion: Among these children with SCD who presented with VOC, the administration of morphine was not found to be associated with a dose-response effect on the risk for ACS.

Although statins have been identified as potential teratogens on the basis of theoretical considerations and small case series, the available evidence is far from conclusive. In fact, epidemiological data collected to date suggest that statins are not major teratogens. The actual risk for an exposed pregnancy seems to be small, if present at all, and does not by itself warrant termination of pregnancy. Nevertheless, given the scarcity of available data, it is still advisable to avoid use of these drugs in patients who are planning pregnancy in order to reduce the risks as much as possible.

Question: One of my patients gave birth to a baby later diagnosed with HIV infection. I did not offer this patient HIV screening, as I thought she was at low risk. What are the recommendations for HIV testing and what might be the implications of not screening for HIV?, Answer: Although screening is currently recommended by all relevant authorities in Canada, more than 10% of women are not screened antenatally, increasing their babies' risk for infection. This rate represents a failure that is probably a combination of omission at times by clinicians, embarrassment about discussing the issue on the part of either the physician or the patient, and poor counseling. All Canadian women should receive appropriate antenatal counseling for HIV screening.

Question: An 18-year-old patient of mine, currently under treatment for attention deficit hyperactivity disorder (ADHD) with methylphenidate, just found out that she is pregnant. What are the risks for the baby when the mother uses ADHD medications during pregnancy?, Answer: Available evidence for amphetamines suggests no increased risk of malformations with use of therapeutic doses, and inadvertent exposure during pregnancy is unlikely to be harmful. Human data for methylphenidate and atomoxetine treatment in pregnancy are very limited. Documented cases do not suggest teratogenicity, but we cannot rule out this risk with the information available.

Exposure to drugs of abuse, particularly during pregnancy, is difficult to ascertain. Presently, there is sparse information on gestational exposure and fetal effects to potentially toxic drugs such as methamphetamine (MA) and cocaine; two of the most prevalent abused stimulants in North America. The Motherisk laboratory at the Hospital for Sick Children routinely carries out analysis of MA and cocaine in adult and infant hair. All mother-child pairs in whom at least one had cocaine and/or benzoylecgonine (BE), or MA detected in hair were identified from the Motherisk database. Eleven mother-infant pairs with positive hair for MA were identified. One infant (9%) had a negative MA result with a positive maternal result. There was not any positive infant hair with negative maternal hair for MA. MA concentrations in mothers and infants correlated positively and were not significantly different. Median cocaine concentrations were tenfold higher in hair of the mothers compared to the infants. Thirty-nine (40%) infants had negative cocaine and BE with positive maternal results. Mothers whose infants were cocaine positive had median cocaine significantly higher than those whose infants were negative. Infants' cocaine in hair was positively correlated with maternal cocaine and BE. Infants' BE correlated with maternal cocaine and BE concentrations. Fetal hair grows during the last trimester of pregnancy; therefore a positive neonatal hair result indicates maternal use after pregnancy is known, a strong indicator of maternal addiction. To our knowledge, this is the first report on fetal exposure to MA during pregnancy showing transplacental transfer of the drug, with accumulation in fetal hair. Transplacental exposure to cocaine of babies of addicted mothers is highly variable. Further research is needed to understand the mechanisms leading to placental defense against cocaine.

Background: Trastuzumab (Herceptin) is a monoclonal antibody used for the treatment of breast cancer. Experience with use of this agent during pregnancy, and its possible effects on the fetus, is limited., Case: We present a case of a patient with breast cancer who was treated with trastuzumab during the first 24 weeks of pregnancy. This treatment was associated with reversible maternal heart failure, which resolved slowly after the drug was discontinued, but with no adverse fetal effects and a normal infant examination at the age of 2 months. Updated literature review is discussed.

Question: One of my patients who was taking sibutramine to lose weight found out that she had unexpectedly conceived. The medication was stopped as soon as she found out, about 5 weeks into the pregnancy. Is the baby at risk? Should the pregnancy be aborted?, Answer: No data to date suggest that involuntary exposure to sibutramine during pregnancy carries major risk of congenital malformations. Nevertheless, this medication should be avoided whenever possible during pregnancy, as there is little information on its effects.

Cocaine use during pregnancy is difficult to ascertain, and maternal reports are likely to be inaccurate. Presently, the dose-response characteristics between maternal cocaine use and fetal exposure and adverse effects are unknown. Clinically, some babies are harmed, whereas others are not adversely affected. Taking advantage of the fact that cocaine and its metabolite benzoylecgonine (BE) accumulate and can be detected months after exposure in maternal and neonatal hair, an analytical test for cocaine and BE was developed by the authors. The aim of this study was to describe the characteristics of maternal and neonatal hair cocaine as biomarkers of fetal exposure. Of nearly 10,000 cases, all mother-child pairs in whom at least one had cocaine and/or BE detected in hair were identified. The relationship between maternal and neonatal levels was studied. When available, these data were also compared with meconium levels of cocaine. Median cocaine concentration was 10-fold higher in hair of the mothers compared with the neonates (3.56 ng/mg vs 0.31 ng/mg of hair). Infants' cocaine in hair was positively correlated with maternal cocaine and BE in hair (r2 = 0.41 and r2 = 0.22, respectively, P < 0.001 for both correlations). Infants' BE was also correlated with maternal cocaine and BE concentrations in hair (r2 = 0.50 and r2 = 0.27, P < 0.001 for both correlations). Thirty-nine (40%) babies had negative cocaine and BE results despite their mothers being positive. Mothers whose infants were cocaine-positive had a median hair cocaine concentration of 7.34 ng/mg, significantly higher than those whose infants were negative (1.25 ng/mg). Maternal cocaine levels below 0.24 ng/mg may serve as a relative threshold for detectable fetal exposure during the third trimester of pregnancy. Fetal hair grows in the last trimester. Hence, a positive neonatal hair indicates maternal use after pregnancy became known, a strong indicator of maternal addiction. Transplacental exposure to cocaine of babies of addicted mothers is highly variable. The dose-response relationship of both cocaine and BE between maternal and neonatal hair suggests that the placenta protects some fetuses but not others. More research is needed to understand the mechanisms leading to placental defense against cocaine.