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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.

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.Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX.Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model.A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

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.

The immunosuppressant azathioprine is increasingly being used in pregnancy. The human placenta is considered a relative barrier to the major metabolite, 6-mercaptopurine (6-MP), and likely explains the lack of proven teratogenicity in humans. The aim of this study was to determine how the human placenta restricts 6-MP transfer using the human placental perfusion model. After addition of 50 ng/ml (n=4) and 500 ng/ml (n=3) 6-MP into the maternal circulation, there was a biphasic decline in its concentration and a delay in fetal circulation appearance. Under equilibrative conditions, the fetal-to-maternal concentration ratio was >1.0 as a result of ion trapping. Binding to placental tissue and maternal pharmacokinetic parameters are the main factors that restrict placental transfer of 6-MP. Active transport is unlikely to play a significant role and drug interactions involving, or polymorphisms in, placental drug efflux transporters are not likely to put the fetus at risk of higher 6-MP exposure.

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.

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

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.

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.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.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.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%.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.

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.

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.

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.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.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.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.

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?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.

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

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?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.

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.

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 causating 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.

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.

One of my patients is currently using methadone for maintenance of opioid dependence. She wants to breastfeed. Is breastfeeding safe for her infant?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.

Methods that employ detection of drugs of abuse in hair are important for monitoring compliance with drug abstinence. Understanding the mechanisms and timeline of drug disappearance from hair is critical for clinical and forensic application of hair testing. We aimed to evaluate the kinetics of disappearance of cocaine and its metabolite, benzoylecgonine (BE), from hair after discontinuation of drug use. Methods The Motherisk laboratory at the Hospital for Sick Children in Toronto routinely receives hair samples for toxicology analysis. Cocaine and BE hair results were obtained from the Motherisk Database for calculation of half-life of these compounds in hair. Subjects were included in the study if they had gradually decreasing concentrations of cocaine and/or BE in sequential hair samples, with higher levels in the 1–3 cm distal segments (i.e. earlier in time) and low or non-measurable levels in the segment closest to the scalp (i.e. closer to the date of sampling). Elimination half-life of cocaine and BE in hair was calculated using standard kinetics calculations. The study was anonymous, and received ethics approval by the Ethics Review Board of our institution. Results 137 subjects met the inclusion criteria for the study. The median half-life of cocaine in hair was 1.5 months (95% CI 1.2–1.8) in females and 1.5 months (95% CI 1.1–1.8) in males. The median half-life of BE was 1.5 months (95% CI 1.1–2) in females and 1.5 months (95% CI 0.8–1.8) in males. Half lives of cocaine or BE were not statistically different between males and females (Mann–Whitney U-test; P = 0.93 for cocaine, P = 0.99 for BE). Half lives of cocaine and BE were strongly correlated (Spearman rank rho = 0.73; P Conclusion Cocaine and BE could be detected in hair of former drug users for several months after abstinence. The calculated half-life of over 1 month for cocaine implies that, assuming first order elimination, approximately 3–4 months have to pass for hair testing to become negative in the segment proximal to the scalp. This finding should be incorporated in interpreting compliance with abstinence of former drug users, and suggests that caution has to be exerted when evaluating potential breaches of abstinence.

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 Paco 2 , Pao 2 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 Paco 2 was significantly higher (P < 0.05) in the amitriptyline group. Postmorphine Paco 2 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 Paco 2 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 Paco 2 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.

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.

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?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.

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, P0.001 for both correlations). Infants' BE was also correlated with maternal cocaine and BE concentrations in hair (r2 = 0.50 and r2 = 0.27, P0.001 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.

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.

Vitamin B6 is often prescribed for the treatment of nausea and vomiting of pregnancy (NVP), at much higher doses than initially recommended. Large doses of vitamin B6 have been associated with cases of neuropathy. We set out to assess whether higher than standard doses of vitamin B6 during the first trimester of pregnancy were associated with a risk of maternal adverse events, major malformations, miscarriages or low birth weight. This was a prospective comparative observational study. The study group included women who were exposed to >50 mg/day of vitamin B6 during the first trimester; the control group included pregnant women with a non-teratogen exposure. A total of 192 pregnancies were followed-up. The mean dose of B6 used in the study group was 132.3 mg/day (median 110 mg/day, range 50 - 510 mg/day), for a mean period of 9 +/- 4.2 weeks. In this group (n = 96), there were 91 live births, one major malformation and the mean birth weight was 3,542 +/- 512 g. There were no statistical differences in the study endpoints between the vitamin B6 and the control groups. Within the limits of our sample size, higher than standard doses of vitamin B6 do not appear to be associated with an increased risk for major malformations.

Background: Methamphetamine misuse is a serious health problem of epidemic proportions. Use of this drug, particularly during pregnancy, is difficult to ascertain. Sparse information is available on gestational exposure. Objectives: To quantify methamphetamine accumulation in hair, identify the use of methamphetamine with other drugs of abuse and characterise correlations between concentrations of methamphetamine in maternal and neonatal hair. Subjects and methods: Motherisk laboratory at the Hospital for Sick Children routinely carries out analysis of methamphetamine in hair. Mothers and infants with positive results for methamphetamine in hair were identified. Drugs present in hair were analysed by ELISA and positive results were confirmed by gas chromatgraphy/mass spectrometry. Results: 396 people positive for methamphetamine in their hair were identified from our database. Almost 85% of them were positive for at least one other drug of abuse, mostly cocaine. Eleven mother–baby pairs with hair positive for methamphetamine were identified. Methamphetamine levels in hair ranged between 0.13 and 51.97 ng/mg in the mothers and between 0 and 22.73 ng/mg in the neonates. Methamphetamine levels in mothers and neonates correlated significantly. One (9%) neonate was negative for methamphetamine even though the mother was positive. Conclusion: To our knowledge, this is the first report on fetal exposure to methamphetamine during pregnancy, showing transplacental transfer of the drug, with accumulation in fetal hair. Hair measurement for methamphetamine in neonates is a useful screening method to detect intra-uterine exposure to the drug. The data also indicate that positive exposure to methamphetamine strongly suggests that the person is a polydrug user, which may have important implications for fetal safety.

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.

A pregnant patient who underwent magnetic resonance imaging (MRI) because of an acute abdomen, was told that MRI contrast agents (ie, gadolinium-based contrast agents) are contraindicated during pregnancy. What is the risk to her baby?Current radiology practices and recommendations discourage the use of gadolinium-based contrast agents during pregnancy because their safety for the fetus has not yet been proven. In line, however, with the European Society of Radiology guidelines and based on the available evidence, gadolinium-based contrast agents appear to be safe in pregnancy. Gadolinium use should be considered when the diagnostic study is important for the health of the mother.

Due to legal, ethical and monetary problems, drug studies in pregnancy are rare. Numerous pharmacokinetic and pharmacodynamic changes occur in pregnancy that can affect the efficacy and safety of drugs, and these are difficult to predict without appropriate studies. Drugs potentially useful and safe in pregnancy have to either not cross the placenta and/or be harmless to the fetus at clinically relevant concentrations. The first characteristic can be predicted using in vitro models such as the placenta perfusion model. In the case of glibenclamide (glyburide), in vitro experiments showed minimal maternal-fetal transfer, leading to completion of a successful clinical trial of this drug in gestational diabetes. Insulin, the main drug used in diabetes during pregnancy, has also been shown not to cross the placenta in vitro, as has insulin lispro. Animal insulin may cross the placenta when complexed with anti-insulin antibodies. Other sulphonylurea drugs (tolbutamide and chlorpropamide) have been shown to cross the placenta both in vitro and in vivo and to produce toxicity in the fetus. This review summarises the pharmacokinetic data available for hypoglycaemic drugs during pregnancy, as well as the potential role for the in vitro placenta perfusion model in the preclinical evaluation of drugs with potential usefulness in pregnancy.

Introduction: Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce. Patients and Methods: Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387). Results: Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs). Discussion: Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted. Trial Registration: ClinicalTrails.gov NCT00699387., Facultad de Ciencias Exactas