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Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long-term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin-1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence-based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF.

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 AUC0-tlast and Cmax were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC0-tlast: LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; Cmax: 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 AUC0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased Cmax ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC0-tlast ratiofed/fasted, 172%; 90%CI, 154%-192%; Cmax ratiofed/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. Fil: Stass, Heino. No especifíca; Fil: Feleder, Ethel. No especifíca; Fil: Garcia Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina Fil: Nagelschmitz, Johannes. No especifíca; Fil: Weimann, Boris. No especifíca; Fil: Yerino, Gustavo. No especifíca; Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina

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 1mg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2mg/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. Fil: Fernandez, Marisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; Argentina Fil: Marson, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina Fil: Mastrantonio Garrido, Guido Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina Fil: Corti, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Fleitas, Ulises Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina Fil: Lloveras, Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Lista, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Priarone, Maria M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Dominguez, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Garcia-Bournissen, Facundo. Western University; Canadá

Nifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, data on NF safety are scarce, and many physicians defer or refuse NF treatment because of concerns about drug tolerance. In a retrospective study of adverse drug reactions (ADRs) associated with NF treatment of ChD, children received NF doses of 10 to 15 mg/kg/day for 60 to 90 days, and adults received 8 to 10 mg/kg/day for 30 days. A total of 215 children (median age, 2.6 years; range, 0 to 17 years) and 105 adults (median age, 34 years; range, 18 to 57 years) were enrolled. Overall, 127/320 (39.7%) patients developed ADRs, with an incidence of 64/105 adults and 63/215 children (odds ratio [OR] = 3.7; 95% confidence interval [CI], 2.2 to 6.3). We observed 215 ADRs, 131 in adults (median, 2 events/patient; interquartile range for the 25th to 75th percentiles [IQR25-75], 1 to 3) and 84 in children (median, 1 event/patient; IQR25-75 = 1 to 1.5) (Padjusted, 0.001). ADRs were mainly mild and moderate. Severe ADRs were infrequent (1.2% in children and 0.9% in adults). Nutritional, central nervous, and digestive systems were the most frequently affected, without differences between groups. Treatment was discontinued in 31/320 (9.7%) patients without differences between groups. However, ADR-related discontinuations occurred more frequently in adults than in children (OR = 5.5, 95% CI = 1.5 to 24). Our study supports the safety of NF for ChD treatment. Delaying NF treatment due to safety concerns does not seem to be supported by the evidence. (This study has been registered in ClinicalTrials.gov under identifier NCT04274101). Fil: Berenstein, Ariel José. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Falk, Nicolás Ariel. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: González, Nicolas. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Garcia Bournissen, Facundo. Western University; Canadá Fil: Ballering, Griselda Edith. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Freilij, Hector León. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina

Dear Editor,Nivolumab, a humanized IgG4 monoclonal antibody, blocks the programmed cell death protein-1 (PD-1) leading to lymphocyte activation against many chemotherapy-resistant tumors [1]. Women...

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.

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 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.

BACKGROUND: The benefits of early cystic fibrosis (CF) detection using newborn screening (NBS) has led to widespread use in NBS programs. Since 2002, a two-stage immunoreactive trypsinogen (IRT/IRT) screening strategy has been used as a CFNBS method in all public maternity units in the City of Buenos Aires, Argentina. However, novel screening strategies may be more efficient. The aim of this study is to prospectively compare two CFNBS strategies: IRT/IRT and IRT/PAP (pancreatitis-associated protein). METHODS: A two-year prospective study was performed. IRT was measured in dried blood samples collected 48-72 h after birth. When an IRT value was abnormal, PAP was determined, and a second visit was scheduled to obtain another sample for IRT before 25 days of life. Newborns with a positive CFNBS were referred for a confirmatory sweat test. RESULTS: There were 69,827 births in the City of Buenos Aires during the period studied; 918 (1.31%) had an abnormal IRT. A total of 207 children (22.5%) failed to return for the second IRT, but only two PAP (0.2%) were not performed. IRT/IRT was more likely to lead to a referral for sweat testing than IRT/PAP (odds ratio 2.3 [95% confidence interval 1.8-2.9], p

Background Treatment with nifurtimox (NF) for Chagas disease is discouraged during breast-feeding because no information on NF transfer into breast milk is available. NF is safe and effective for paediatric and adult Chagas disease. We evaluated the degree of NF transfer into breast milk in lactating women with Chagas disease. Patients and methods Prospective study of a cohort of lactating women with Chagas disease. Patients were treated with NF for 1 month. NF was measured in plasma and milk by high performance liquid chromatography (HPLC). Breastfed infants were evaluated at admission, 7th and 30th day of treatment (and monthly thereafter, for 6 months). Results Lactating women with chronic Chagas disease (N = 10) were enrolled (median age 28 years, range 17–36). Median NF dose was 9.75 mg/kg/day three times a day (TID). Six mothers had mild adverse drug reactions (ADRs), but no ADRs were observed in any of the breastfed infants. No interruption of breastfeeding was observed. Median NF concentrations were 2.15 mg/L (Inter quartil range (IQR) 1.32–4.55) in milk and 0.30 mg/L (IQR 0.20–0.95) in plasma. Median NF milk/plasma ratio was 16 (range 8.75–30.25). Median relative infant NF dose (assuming a daily breastmilk intake of 150 mL/kg/day) was 6.7% of the maternal dose/kg/day (IQR 2.35–7.19%). Conclusions The low concentrations of NF in breast milk and the normal clinical evaluation of the breastfed babies imply that maternal NF treatment for Chagas disease during breastfeeding is unlikely to lead to clinically relevant exposures in the breastfed infants. Trial registration Clinical trial registry name and registration number: ClinicalTrials.gov NCT01744405., Author summary It is not known whether Nifurtimox, a drug for Chagas disease, is significantly transferred into breast milk, and no clinical trials were conducted to evaluate this topic. Treatment with nifurtimox is safe and effective in children and newborns with Chagas disease. Treatment of young women before pregnancy prevents congenital transmission of Chagas disease. This is the first study to measure nifurtimox concentrations in breast milk. We found that presence of nifurtimox into breast milk is limited, and that breastfed babies had normal clinical evaluations with no observable adverse events. None of the mothers had to discontinue breastfeeding due to adverse events. The exposure of nifurtimox through breast milk during the treatment of mothers with Chagas disease does not seem to pose significant risks for the breastfed infants.

Chagas disease is a parasitic disease endemic to Latin America that, if left untreated, can lead to severe long-term organ damage, particularly in the heart and gastrointestinal tract. Treatment with benznidazole or nifurtimox has been shown to be effective in the acute phase and during childhood, and limited evidence suggest a beneficial effect later in life too. However, both drugs require prolonged treatments (30–60 days) and are associated to significant adverse events that increase in severity and prevalence with age. Prompt pediatric diagnosis and treatment are vital for an effective use of these medications.

Background:Few studies have focused on Familial Mediterranean Fever (FMF)-related AA amyloidosis and cardiovascular disease event risk. Systemic inflammation stimulates the development and progression of atherosclerosis which is accelerated by vascular endothelial inflammation and enhanced oxidative stress. Excessive reactive oxygen species (ROS) generation has been reported in FMF, which correlated with attack severity. ROS may also be involved in amyloid formation, and in the pathogenesis of progressive renal injury.Objectives:In this non-randomized, 24 weeks open label interventional study, we aimed to evaluate the effect of a combination of natural products on parameters related to inflammation, endothelial dysfunction and oxidative stress in a cohort of FMF patients with AA amyloidosis.Methods:Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL) were given to patients with FMF related AA amyloidosis. We included patients with biopsy proven AA amyloidosis, older than 18 years who have normal estimated glomerular filtration rate (eGFR) and proteinuria [>3500mg/day]. Flow-mediated dilatation (FMD), asymmetric dimethylarginine (ADMA), hs-CRP, serum PTX3, Carotis intima media thickness (CIMT), malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels were studied in baseline and after 24 weeks.Results:67 FMF-related amyloidosis [52 male (77.6%); median recruitment age 36 years (range 21-66)] were enrolled. M694V mutation was the most common mutation found (74%), with 50.7% of the patients in homozygosity. All patients were treated with colchicine, and most of them (83.6%) has been on colchicine treatment at the time of enrollment. Serum ADMA, MDA, PTX3, hsCRP, cholesterol, and proteinuria were significantly decreased compared to baseline, while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies (Table 1). The change of the inflammatory markers PTX3, and hsCRP were negatively correlated with the change in FMD and positively correlated with the change of proteinuria, ADMA, MDA, cholesterol and CIMT.Conclusion:24 weeks of AAL, AIC and AOL combined supplementation was significantly associated with reduction in serum inflammatory markers (PTX3 and hsCRP), improved endothelial functions (FMD, ADMA), and oxidative state (MDA). Our findings highlight the link among the three pathogenetic mechanisms including inflammation, endothelial function and oxidative status in progression of atherosclerosis and renal injury in patients with FMF related AA amyloidosis. Efficient control of these three mechanisms can have long term benefits from the cardiovascular and renal perspective of the patients with AA amyloidosis.References:[1]Romano M et al. Sci Rep, 2020[2]Yilmaz M et al. Sci Rep, 2020Table 1.Comparison of clinical and laboratory characteristics at the baseline and after 24 weeks of AAL, AIC and AOL supplementationBaselineMean (SD)24th weekMean (SD)DeltaMean (SD)pTotal Cholesterol (mg/dl)221.2 (60.3)155.8 (35.4**)-65.3 (55.5)eGFR (ml/min/ 1.73 m2)110.2 (12.8)104.1 (11.2**)-6.1 (11.9)Malondialdehyde (MDA) (nmol/ml)4.2 (1.8)1.8 (0.5**)-2.2 (1.8)CuZn-SOD (U/ml)431.5 (154.7)538.1 (146.4**)159.7 (211.8)GSH-Px (U/ml)47.8 (13.2)74.1 (20.3**)26.3 (21.1)ADMA (µmol/l)4.5 (2.6)1.3 (0.6**)-3.2 (2.5)FMD (%)5.0 (0.7)6.4 (0.8**)1.3 (0.9)CIMT (mm)0.9 (0.2)0.7 (0.1)-0.2 (0.2)Proteinuria (mg/24h)6855.3 (3116.9)4079.9 (2359.6)-2775.3 (2874.5)hs-CRP (mg/l)25.5 (4.4-48.0)3.0 (1.0-9.1)*-20.8 (11.2)PTX3 (ng/ml)13.4 (2.3-67.0)2.3 (0.4-14.5)*-17.5(17.5)Disclosure of Interests:None declared

Background Acetaminophen is the most commonly used drug in children. In 2019, an IV formulation became available in Canada, but with a price tag >500 times higher than oral acetaminophen. Acetaminophen use has been growing in the US since its approval in 2011, leading to a significant health cost increase. Therefore, strict criteria for IV acetaminophen administration are needed to guide clinicians with a rational choice for route of administration and contain costs. Objectives To undertake a systematic review of available evidence comparing oral versus IV acetaminophen use in children. Design/Methods A systematic literature search was conducted on 5 databases until October 2019. All prospective interventional studies comparing IV to oral acetaminophen in patients Results Among 6417 abstracts, 29 full text articles were assessed, of which only 3 were retained. Indication for acetaminophen use in these studies was: analgesia (2 studies) and fever (1 study). Studies focused on: - Pharmacokinetics: In 2019, the first determination of oral bioavailability (F) of acetaminophen in children was reported in 47 stable PICU patients (microtracer study design with a population pharmacokinetic study). It showed an F=72% with a high inter-individual variability (range: 11%-91%). - Pharmacodynamics studies: • Analgesia: Analgesic efficacy after cleft palate repair was compared in 45 children (median age: 8 month) divided in three arms receiving either oral (15mg/kg every 6h), IV (12.5mg/kg every 6h) or placebo in a double-blind randomized controlled trial. No difference in pain scores and opioids requirements was found between the oral and IV acetaminophen groups. • Fever: An open-label prospective observational study reported the effect of IV (15mg/kg) versus oral acetaminophen (15mg/kg) on the evolution of temperature in children with fever >39.5°C in hospital and outpatient settings. Two hundred patients (mean age 6.7 years) were included in each arm. Temperature decreased quicker with IV administration but 4 hours after administration, temperature was similar in each group. Conclusion Despite the widespread use of IV 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. Available data is insufficient to guide clinicians with a rational choice of route of administration, but the significantly higher costs do not seem justified by the small (if any) benefits of IV vs oral acetaminophen.

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., 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 (r2 = 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.

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. Fil: Ruiz Lancheros, Elizabeth. National Reference Centre For Parasitology; Canadá Fil: Rasoolizadeh, Asieh. National Reference Centre For Parasitology; Canadá Fil: Chatelain, Eric. No especifíca; Fil: Garcia Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Ndao, Momar. National Reference Centre For Parasitology; Canadá

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.

Aims Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration–time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk.

Background: Benznidazole (BNZ) is safe and effective for the treatment of paediatric Chagas disease. Treatment of adults is also effective in many cases, but discouraged in breastfeeding women because no information on BNZ transfer into breast milk is available. We aimed to evaluate the degree of BNZ transfer into breast milk in lactating women with Chagas disease. Patients and methods: Prospective cohort study of lactating women with Chagas disease treated with BNZ administered for 30 days. Patients and their breastfed infants were evaluated at admission, the 7th and 30th day of treatment (and monthly thereafter, for 6 months). BNZ was measured in plasma and milk by high performance liquid chromatography. The protocol was registered in ClinicalTrials.gov (#NCT01547533). Results: 12 lactating women with chronic Chagas disease were enrolled (median age 28.5 years, range 20–34). Median BNZ dose was 5.65 mg/kg/day twice daily. Five mothers had adverse drug events (45%), but no adverse drug reactions or any untoward outcomes were observed in the breastfed infants. Median milk BNZ concentration was 3.8 mg/L (range 0.3–5.9) and 6.26 mg/L (range 0.3–12.6) in plasma. Median BNZ milk to plasma ratio was 0.52 (range 0.3–2.79). Median relative BNZ dose received by the infant (assuming a daily breast milk intake of 150 mL/kg/day) was 12.3% of the maternal dose per kg (range 5.5%–17%). Conclusions: The limited transference of BNZ into breast milk and the reassuring normal clinical evaluation of the breastfed babies suggest that maternal BNZ treatment for Chagas disease during breast feeding is unlikely to present a risk for the breastfed infant. Fil: García Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moroni, Martín Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Marson, María Elena. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Moscatelli, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Mastrantonio Garrido, Guido Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina Fil: Bisio, Margarita María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Cornou, Maria Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Ballering, Griselda. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Altcheh, Jaime Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina

Fil: Marson, Maria Elena. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Area de Toxicologia; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

To estimate the proportion of abstracts presented at National Pediatric Research Meetings that are fully-published and describe their design and factors that influence nonpublication.Descriptive and analytical study including all abstracts presented at National Pediatric Research Meetings (1998-2011). One author per study was identified and asked to complete a survey on its design, publication and factors associated with non-publication.Out of 746 abstracts that were submitted, the authors of 522 (70%) completed the survey. Among these, 84.3% were observational studies and 15.7%, experimental; 34% had received funding. Two hundred and seventeen abstracts were published subsequently (41.5%, 95% confidence interval [CI]: 37.3-45.9). Funded studies had better chances of being published (odds ratio [OR]: 2, 95% CI: 1.4-2.9, p 〈 0.001). Lack of time, insufficient sample size, and problems with funding were referred as the most common reasons for failure to publish.Among allabstracts presented at National Pediatric Research Meetings, 41.5% were fully published. Lack of time was the most common reason for unpublished studies.Estimar la proporción de trabajos presentados en Encuentros Nacionales de Investigación Pediátrica que posteriormente fueron publicados en forma completa; describir sus diseños y factores involucrados con la no publicación.Estudio descriptivo y analítico, que incluyó todos los trabajos presentados en Encuentros N acionales de Investigación Pediátrica (1998-2011). Se identificó un investigador por estudio y se lo encuestó sobre el diseño, la publicación y los factores asociados a la no publicación.Sobre 746 trabajos presentados, respondieron la encuesta los autores de 522 (70%). El 84,3% eran estudios observacionales y 15,7%, experimentales; 34% recibieron financiación. Fueron publicados posteriormente 217 trabajos (41,5%, IC 95%: 37,3-45,9). Aquellos con financiación tuvieron mayor probabilidad de publicarse (OR 2; IC 95%: 1,4-2,9; p 〈 0,001). Las causas de no publicación más frecuentes fueron la falta de tiempo, el tamaño muestral insuficiente y la dificultad con el financiamiento.El 41,5% de trabajos presentados en Encuentros Nacionales de Investigación Pediátrica alcanzaron la publicaciónen texto completo. La falta de tiempo fue la principal causa para no hacerlo.

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.

Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. To date, there has not been any attempt at a systematic evaluation of this model. The aim of this study was to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a pharmacokinetic model to account for nonplacental pharmacokinetic parameters in the perfusion results. In general, the fetal-to-maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery of the infant. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R² = 0.85, P < 0.0001). Placental perfusion experiments can be used to predict placental drug transfer when adjusting for extra parameters and can be useful for assessing drug therapy risks and benefits in pregnancy.

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.

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.

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.

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.

Summary Background: Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system. Methods: We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model. Results: We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78–1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89–1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51–1.89, p = 0.96). Conclusions: We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.

Urologic medical conditions are not frequently encountered during pregnancy. Still, urologists often are asked to treat pregnant patients for conditions that require prescriptions. In the generally healthy population of pregnant women, the use of pharmaceutical agents is usually reserved for women who have either infections or necessary surgical procedures. This article addresses the implications for pregnancy of common urologic conditions in generally healthy pregnant women, namely simple urinary tract infections that demand nitrofurantoin and complex urinary tract infections that necessitate fluoroquinolones treatment. It also examines the implications of nonobstetric surgical intervention.

This paper may be read to imply that all positive RIA and ELISA samples were confirmed with GC–MS. It is my understanding that some, but not all, positive samples were confirmed with GC/MS. This had no impact on the results of following the disappearance of cocaine. The paper’s conclusions remain the same. The authors would like to apologise for any inconvenience caused.

The primary objective of this study was to estimate the prevalence of this disease in women of childbearing age and children treated at health centres in underserviced areas of the city of Buenos Aires. Demographic and Chagas disease status data were collected. Samples for Chagas disease serology were obtained on filter paper and the reactive results were confirmed with conventional samples. A total of 1,786 subjects were screened and 73 positive screening results were obtained: 17 were from children and 56 were from women. The Trypanosoma cruzi infection risk was greater in those individuals who had relatives with Chagas disease, who remember seeing kissing bugs, who were of Bolivian nationality or were born in the Argentine province of Santiago del Estero. The overall prevalence of Chagas disease was 4.08%. Due to migration, Chagas disease is currently predominantly urban. The observed prevalence requires health programme activities that are aimed at urban children and their mothers. Most children were infected congenitally, which reinforces the need for Chagas disease screening of all pregnant women and their babies in Argentina. The active search for new cases is important because the appropriate treatment in children has a high cure rate. Fil: Moscatelli, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Berenstein, Ada. Community Action Centre 15. Primary Care Centre; Argentina Fil: Tarlovsky, Ana. Community Action Centre 11. Primary Care Centre; Argentina Fil: Siniawski, Susana. Community Action Centre 15. Primary Care Centre; Argentina Fil: Biancardi, Miguel Angel. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Ballering, Griselda. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Schwarcz, Marta. Interamerican Open University. Centre of Studies on Human Science and Health; Argentina Fil: Hernandez, Susana. Interamerican Open University. Centre of Studies on Human Science and Health; Argentina Fil: García Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Cozzi, Andrés Espejo. Interamerican Open University. Centre of Studies on Human Science and Health; Argentina Fil: Freilij, Hector León. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina

It is currently unknown whether treatment of Chagas disease decreases the risk of congenital transmission from previously treated mothers to their infants. In a cohort of women with Chagas disease previously treated with benznidazole, no congenital transmission of the disease was observed in their newborns. This finding provides support for the treatment of Chagas disease as early as possible.

Neglected diseases (NDs), also known as neglected tropical diseases, are a group of chronic diseases that disproportionately affect the poorest populations in the world.

Introduction: One of the causes of long-term morbidity associated with the treatment of acute lymphoblastic leukemia (ALL) is late neurotoxicity manifesting as impairment of higher cognitive functions. Cranial radiation therapy (CRT) and chemotherapeutic agents, particularly methotrexate (MTX), are often suggested to be major contributing factors for its development. Homocysteinemia that arises as a result of MTX-induced folate depletion was proposed to play a role in MTX-related neurotoxicity. Several enzymes are essential to maintain the homocysteine levels. Their different functional forms, associated with common genetic polymorphisms, may modulate homocysteine levels and thereby influence MTX-associated neurotoxicity. Objectives: To test this hypothesis we assessed whether the variants of the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine β-synthase (CBS) and endothelial nitric acid synthase (eNOS, NOS3) genes, acting either independently or in conjunction with other risk factors, influenced the cognitive functioning in ALL patients. The influence of the genes was measured by estimating the change in IQ scores over a period of 4 years post ALL diagnosis. Results: Two variants, the CBS 844ins68 polymorphism and NOS3 894T homozygosity, were associated with a change in IQ scores (p = 0.01 and 0.007, respectively). A multivariate model obtained through step-wise selection pointed to the importance of the NOS3 894TT genotype only. This effect appears to be dependent on CRT; IQ decline was apparent among individuals with the 894TT genotype who received radiation therapy (p = 0.03). Furthermore, additional factors affecting IQ were identified, including the treatment administered (i.e., CRT; p = 0.02) and a younger age at diagnosis (p = 0.003), and the modifying effect of the treatment protocols was also noted (p = 0.04). Conclusion: The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.

The WHO has identified 17 neglected diseases, affecting over a billion people worldwide, many of which can be effectively controlled by relatively simple measures. However, these are but a fraction of the full spectrum of neglected diseases and conditions affecting the most impoverished and marginalised populations of the world. These neglected diseases and conditions include, among many others, reproductive health issues, sexually transmitted diseases, micronutrient deficits and poisonings. Largely ignored, children comprise an important part of the voiceless victims of these diseases. Currently available treatments for neglected diseases and conditions have a number of shortcomings for children, including lack of paediatric formulations and absence of paediatric specific data. These problems force dosing decisions to be based on adult data, leading to a greater risk of toxicity, or therapeutic failure due to underdosing. Considering that toxicology is an area where sizeable clinical studies are extremely rare, it is easy to understand that clinical research in paediatric toxicology is a highly deserted area, particularly for acute poisonings and understandably (but not justifiably) worse for neglected diseases and conditions. When toxicology studies do enrol children it is usually as part of the general population, but rarely in sufficient numbers to achieve the power required for paediatric subgroup analysis. Scorpion envenomation is one of these neglected conditions for which clinical trials are uncommon, and most rare in children. However, mortality is currently concentrated in the paediatric population. To date, studies have provided strong evidence of the effectiveness of prazosin, …

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. Fil: Yazdani Brojeni, Parvaneh. University Of Toronto. Hospital For Sick Children; Canadá Fil: García Bournissen, Facundo. University Of Toronto. Hospital For Sick Children; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fujii, Hisaki. University Of Toronto. Hospital For Sick Children; Canadá Fil: Tanoshima, Reo. University Of Toronto. Hospital For Sick Children; Canadá Fil: Ito, Shinya. University Of Toronto. Hospital For Sick Children; Canadá

Hair testing is commonly used to confirm potential drug exposure in children living with drug users, as well as abstinence in their caregivers. To examine differences across pediatric age groups in the relationship between caregiver use of cocaine and cocaine exposure in children. We determined concentrations of cocaine and its metabolite, benzoylecgonine, in the hair of 19 childcaregiver 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. 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. 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.

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.

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.

BACKGROUND: Due to migration, Chagas disease is a significant public health problem in Latin America, and in other nonendemic regions. The 2 drugs currently available for the treatment, nifurtimox and benznidazole (BNZ), are associated with a high risk of toxicity in therapeutic doses. Excretion of drug into human breast milk is a potential source of unwanted exposure and pharmacologic effects in the nursing infant. However, this phenomenon was not evaluated until now, and measurement techniques for both drugs in milk were not developed. METHODS: In this work, we described the development of a simple and fast method to quantify BNZ in human milk using a pretreatment that involves acid protein precipitation followed by tandem microfiltration, and reverse phase high-performance liquid chromatography/ultraviolet analysis. It is simple because it takes only 3 steps to obtain a clean extracted solution that is ready to inject into the high-performance liquid chromatography equipment. It is fast because a complete analysis of a sample takes only 36 minutes. RESULTS: Although the human breast milk composition is very variable, and lipids are one of the most difficult compounds to clean up on a milk sample, the procedure has proven to be robust and sensitive with a limit of detection of 0.3 μg/mL and quantization of 0.9 μg/mL. Despite a 70% recovery value, which could be considered a relatively low result, this recovery is reproducible (coefficient of variation

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

This review was conducted to examine the current status of paediatric medicines initiatives across the globe.The authors made a non-systematic descriptive review of current world situation.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.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.

Objective To examine the health and well-being of children residing in residences where drug production is occurring. Study design Starting in January 2006, children identified by police and the Children’s Aids Society in the York region of Ontario, Canada, were referred to the Motherisk Program at the Hospital for Sick Children for pediatric assessment of their general health and well-being, with specific focus on illicit-drug exposure. We used a standard protocol to collect all available medical and environmental history, conducted physical and neurologic examinations, and collected hair for analysis of illicit drugs. Results In total, 75 children, at the mean age of 6.5 years, were referred to us after being removed from homes where marijuana was grown (80%) or other operations linked to drug production were occurring (20%). Overall, rates of health issues in this cohort fell below reference values for Canadian children. Of the hair tests, 32% were positive for illicit substances. In the majority there were no clinical symptoms related to these drugs. Conclusion The majority of children removed from drug-producing homes were healthy and drug free. Comprehensive evaluations should be performed on a case-by-case basis in order to determine what is ultimately in the best interest of the child.

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.

The objective of this study was to utilize a case report to review the use of physostigmine for jimsonweed intoxication. A 15-year-old girl was found at school hallucinating and incoherent. Upon presentation to the emergency department, she was found to be tachycardic and confused with dilated pupils and dry, flushed, hot skin. She was admitted to our institution. Hallucinations and symptoms resolved after the use of physostigmine. She subsequently admitted to ingesting 'moonflower seeds,' which are derived from Jimsonweed (Datura stramonium). She was discharged when she got well. Jimsonweed is known to contain high concentrations of anticholinergic substances; hence, ingestion can result in the anticholinergic toxidrome. Signs and symptoms include hallucinations, tachycardia, dilated pupils, and disorientation. In our patient, the use of the physostigmine as an antidote resulted in a favorable outcome without any complications. Ingestion of the Datura species can result in severe toxicity. Each plant varies in the concentrations of alkaloid substances. For this reason, it is very important for individuals to become educated on the toxicities and potential risks associated with recreational use of these plants. The use of physostigmine can help in both the diagnosis and management of patients intoxicated with these substances.

Increase in use of atypical antipsychotics has been paralleled by an increase in the incidence of intentional and nonintentional overdose. Pediatric cases are uncommon, but may be severe. We describe a case of a child presenting with severe extrapiramidal symptoms, initially interpreted as seizures, caused by a nonintentional intoxication with risperidone, and review management options and the literature.

About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the beta(2)-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the beta(2)-adrenergic receptor (beta(2)AR), induce resistance to the smooth-muscle relaxing effect of beta(2)-adrenergic agonists.We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled beta(2)-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined asor = 15% improvement in forced expiratory volume in 1 second (FEV(1)) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the beta(2)AR. Individual and summary odds ratios were calculated using a random effects model.We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative beta(2)-bronchodilator response, defined as15% improvement in FEV(1) and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled beta(2)-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the beta(2)AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the beta(2)AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to beta(2)-agonists and polymorphism at amino acid position 27 of the beta(2)AR (OR = 1.04; 95% CI [0.76,1.42]).Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the beta(2)-adrenergic receptor. Genetic typing for beta(2)AR polymorphism may help identify children with drug-resistant asthma.

Genetic polymorphisms of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and SLCO1B1 coding organic anion-transporter polypeptide 1B1, are independent risk factors known to increase irinotecan toxicity in adults. Although combined occurrence of polymorphisms in these 2 genes is likely to influence susceptibility to irinotecan toxicity, data are scarce, especially in children. We report an 11-year-old female with severe and prolonged neutropenia after irinotecan-based chemotherapy. The patient's genotyping revealed polymorphisms in both UGT1A1 and SLCO1B1. To our knowledge, this is the first case report of combined genotyping of both UGT1A1 and SLCO1B1 in a child with severe irinotecan toxicity.

A new strain of influenza A virus (novel influenza A H1N1) that originated in swine has rapidly spread from the initial outbreak in Mexico and the southern United States to Canada and many countries in Europe and Asia. Consequently, the World Health Organization raised the level of alert for an