Objective Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. Methods Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 mu g/ml (10 mu mol center dot L-1, n = 7) or 10 mu g/ml (40 mu mol center dot L-1, n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 mu g/ml, 500 mu mol center dot L-1, n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. Results Following a 3-h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 mu g/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 mu g/ml lacosamide, 83 mu g/ml valproate, and 2.5 mu g/ml lacosamide, respectively; p < .05). Significance Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.

Background Anti-epileptic drug therapy is a great challenge for the practitioners during pregnancy and lactation. Levetiracetam (LEV) is commonly prescribed to pregnant women, however, there are only few publications on its use during lactation with small number of participants. Objective To monitor LEV levels in breast-milk of epileptic mothers treated with LEV. Methods Breastfeeding women treated with LEV during pregnancy and after delivery were recruited. Milk sample was collected before administration of the drug and other samples were collected at time points of 1,3,6,9, and 12 hours after drug administration. Breastmilk and blood LEV levels were measured using HPLC. Results Fourteen breastfeeding women participated in the study: 9 infants were fully breastfed whereas 5 were partially breastfed. Maternal average daily dose of LEV was 2517 mg. Average infant´s age was 8 weeks (3–22w). Average infant´s weight 4368 gr (3300–7000 gr). Milk/Plasma LEV concentration ratio was 0.88 (0.23–1.1). Relative Infant Dose (RID) was 40% in partial breast feeding, and 61% in full breastfeeding. Estimated average daily dose that all infants received through milk was 158 mg/d (83–250 mg). The normalized dose for the average infant weight per day was 36 mg, which is 15% less than the maximal daily dose of LEV in infants (max. daily dose in infants 1–6 months in 42 mg/d). No adverse reactions were observed in the breastfeed infants. Conclusions Although the RID of LEV were found to be high, no adverse reactions were observed in the infants; Nevertheless, further studies are needed to elucidate the high variability of LEV excretion into breastmilk. Disclosure(s) Nothing to disclose

IntroductionThe importance of reporting adverse drug reactions (ADRs) is well known. However, the reporting rate is very low, and therefore, identifying new signal is challenging.ObjectiveTo create an interventional program in order to improve reporting rate and trying to identify new signal.Material and methodsThe interventional program was implemented at the Pediatric Division of Assaf Harofeh Medical Center and included presentations to the healthcare professionals, posters, creating new ADRs reporting methods and alerts.ResultsReporting rate of ADRs during the year before implementation of the program was negligible. During the study period (three months), the reporting rate increased dramatically. A new signal was reported; two neonates with apnea related to IVIG administration in the neonatology department. The distribution of reports was: 50% from the general pediatric department, 26% - pediatric neurology department, 21% and 6%, from the pediatric and neonatal intensive care units, respectively. Steroids and antibiotics were responsible for various ADRs, but not for a new signal.ConclusionThere is one case report in the literature on apnea related to IVIG administration. Adverse reactions in children are a major problem and sometimes can lead to morbidity mortality. Identifying new signal in pediatric patients is not common, and very challenging.Disclosure(s)Nothing to disclose

BackgroundLacosamide is indicated for various types of refractory epilepsy and as adjunctive therapy to other antiepileptic medications. Data on monitoring serum levels of lacosamide in pediatric patients is scarce.ObjectiveTo evaluate the correlation between serum levels of lacosamide and the tolerability in children with refractory epilepsy.MethodsThe medical records of 22 children with refractory epilepsy treated with lacosamide at Assaf Harofeh Medical Center were reviewed. Trough serum levels of lacosamide was measured using HPLC and correlated with its efficacy and safety.ResultsMean age of the children was 11 ± 4 (3–18) years. Median lacosamide daily dose was 9.3 (6.6–11) mg/kg and median plasma concentration was 7.1 (5.9–11.9) ug/ml. The therapeutic range of lacosamide serum concentration is 10 to 20 ug/ml. No change in seizures frequency was reported in 21.4% of children with lacosamide concentrations below 10 ug/ml. However, in 40% of the children, reduction of the seizures frequency was reported when serum concentration was above 10 ug/ml. No serious adverse events were reported during therapy. The prospective part of the study was initiated, and the first patients were recruited.ConclusionLarge studies, preferably prospective, on lacosamide serum monitoring including information on correlation with efficacy and safety are warranted.Disclosure(s)Nothing to disclose

IntroductionPolybrominated Diphenyl Ethers (PBDEs) are non-biodegradable flame retardants, accumulated in biological systems and acting as endocrine disruptors. Breast feeding is a major route of exposure in infancy. Taken together with the critical development of this age and the potential adverse effects of PBDEs, it is important to monitor these contaminants in breastmilk.ObjectiveTo evaluate the exposure of infants to PBDEsMethods343 families were recruited during 2013–2016 in Assaf Harofeh and Ichilov to create the AHI-EHF cohort. Maternal blood and urine, cord blood, breast milk and meconium were collected. Participants filled out questionnaires about socio-demographic status, medical history, exposures and life habits. Colostrum samples were collected from women at the maternity department. PBDEs in colostrum and Infant formulas levels were analyzed using GC-MSResults and discussionOut of 183 serum samples, only 11(6%) detectable levels of PBDEs. PBDEs were found in all colostrum samples. The average concentration of total PBDEs in breastmilk was 714ng/L. PBDEs levels were also measured in three infant formulas. Unlike breastmilk, infant formulas had of only 3 congeners and levels were relatively low. The average concentration of total PBDEs in infant formulas was 153ng/L. PBDEs, were found to be negatively correlated to anno-penile index (API) which serve as a marker for endocrine disruption.ConclusionsPBDEs levels in breast milk are higher than levels in some European countries, but lower than in North America. PBDEs might have negative influence on AGD in boys. Maternal exposure to PBDEs and the significance of it should be further investigated.Disclosure(s)Nothing to disclose

AIM:Empyema is a potential complication of community acquired pneumonia but factors predicting this complication are lacking.METHODS:A retrospective study of all previously healthy pediatric patients admitted between January 2007 and July 2009 with CAP. Patients with non-lobar pneumonia, RSV bronchiolitis, underlying chronic disease, or hospital-acquired pneumonia were excluded. Preadmission, clinical characteristics on admission, and outcome were compared between patients with and without empyema. Management strategies in patients with empyema were also compared.RESULTS:Overall 356 patients were included. Median age was 3.8 ± 3.54 years and 60.7% were males. A total of 43 patients (12%) were diagnosed with empyema. The development of empyema was independently associated, on multivariate analysis, with older age, female gender and antibiotic therapy prior to admission, and with dyspnea, thrombocytopenia and involvement of more than one lobe on chest radiograph on admission. Patients who developed empyema had a longer and more complicated course. Hypoxemia on admission was significantly less frequent in patients with empyema who were treated with antibiotic therapy alone, compared to those treated with chest tube or video-assisted thoracoscopic surgery.CONCLUSION:Early identification of dyspnea and thrombocytopenia in patients with community acquired pneumonia could alert physicians on the potential development of empyema. Antibiotic therapy alone may be sufficient in patients with empyema who are mildly hypoxemic on admission.

AIMAcute renal injury may occur after amphotericin B (AmB) administration. The hypothesized injury mechanism is renal vasoconstriction and direct toxic damage. Hyperbaric oxygen therapy (HBO) is indicated for treatment of many ischemic events but not for acute renal failure (ARF). The aim of this study was to investigate the role of HBO therapy in AmB induced ARF.METHODSARF was induced in 41 Sprague-Dawley rats by a single dose of 75 mg/kg AmB. The rats were randomly divided into two groups; one group was treated with daily HBO for 3 consecutive days. The control group received no HBO treatment. Parameters of renal function were taken on the 5th day after AmB administration.RESULTSForty-one rats were treated with AmB, 21 received HBO and 20 served as controls. Body weight loss following the administration of AmB was 13.5+14.7% in the HBO treated rats, as opposed to 24.6+5% in the control group (P=0.004). Serum creatinine and urea were 0.49+0.13 mg/dL and 200.63+87.82 mg/dL in the treatment group and 0.70+0.22 mg/dL and 368.01+169.35 mg/dL, respectively in the control (P=0.001).CONCLUSIONIn this model of AmB-induced ARF, HBO treatment alleviated renal injury as reflected by changes in serum creatinine and urea levels.

What is known and objective Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. Methods Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. Results and discussion The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. What is new and conclusion Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.

Background: Medication errors are a common cause of iatrogenic adverse drug events. The incidence and nature of medication errors during prehospital treatment have not been fully described.Objectives: The objectives of this study are to describe the incidence and characteristics of medication errors in adults during prehospital emergency treatment and in the emergency department (ED) and to identify risk factors for medication errors in those settings.Methods: This is a retrospective study of adult patients transferred by emergency medical services to the ED of a university-affiliated hospital in Israel. The drugs administered in the mobile intensive care unit and in the ED were reviewed by 2 reviewers, who independently decided whether an error had occurred. The primary outcome was the number of drug errors per patient. Secondary outcomes were the type and severity of the errors and variables associated with increased incidence of drug errors.Results: During the study period, 1837 patients were brought to the ED by mobile intensive care unit vehicles. Five hundred thirty-six patient charts (29%) were randomly selected for review; 65 charts (12.12%) could not be found; thus, 471 charts were reviewed. In the emergency vehicle, 188 patients (45.63%) received medications; of those, 12.76% (24 patients) were subject to a medication error. The number of drugs administered and long evacuation times were associated with higher risk for an error (P < .01 and P = .011, respectively). The presence of a physician in the emergency vehicle did not alter the risk of an error (P = .95). In the ED, 332 patients (72.6%) received medications. Of those, medication errors occurred in 120 patients (36.1%). The more medications administered, the higher the risk of error (P < .01). Less errors occurred in trauma patients (P = .041).Conclusion: More medication errors occur in the ED than in the emergency vehicles. Patients treated with multiple medications are more prone to medication errors. (C) 2012 Elsevier Inc. All rights reserved.

Data from the ongoing influenza A(H1N1) pandemic have shown that early antiviral treatment is crucial to reduce morbidity and mortality.1Jain S. Kamimoto L. Bramley A.M. Schmitz A.M. Benoit S.R. Louie J. et al.for the 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation TeamHospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009.N Engl J Med. 2009; 361 ([Epub 2009 Oct 8]): 1935-1944Crossref PubMed Scopus (1496) Google Scholar The numbers likely to receive oseltamivir over future influenza seasons make it imperative to be aware of any oseltamivir-related severe adverse effects, given that the winter is by now long over. We report two patients with suspected oseltamivir-induced bradycardia. A 39-year-old woman was admitted at 19 weeks of pregnancy for amnionitis confirmed by amniocentesis. Antibiotic treatment was initiated and termination of the pregnancy performed. The following evening, due to cough and suspected infiltrate on chest radiography, oseltamivir (75 mg twice daily) was started. Two days later, sinus bradycardia appeared, decreasing gradually to 40–45 bpm at rest (Figure 1). She was asymptomatic, with no additional dysrhythmias on electrocardiography and Holter monitoring two days later. Oseltamivir was discontinued for suspected oseltamivir-induced bradycardia; H1N1 PCR was subsequently negative. An overweight 24-year-old woman, hypertensive and on fluoxetine for an eating disorder, was hospitalized with a presumptive diagnosis of H1N1 influenza, subsequently validated by PCR. Oseltamivir 75 mg twice daily was initiated, with roxithromycin and bronchodilator inhalations. The next day, the oseltamivir dose was doubled due to increasing dyspnea, then reduced one day later to the standard dose. The admission heart rate was 79 bpm, decreasing to 45 bpm the following morning; she subsequently experienced repeated episodes of bradycardia, occasionally accompanied by dizziness or pre-syncope. Holter testing showed an average rate of 51 bpm, with multiple bradycardic episodes. Respiratory symptoms and fever had by then resolved; oseltamivir and fluoxetine were discontinued. Of the patients’ medications other than oseltamivir, none is known to be associated with bradycardia. Thyroid function, cardiac enzymes, and echocardiography were normal, and neither woman experienced hypoxia. While the Naranjo score2Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. et al.A method for estimating the probability of adverse drug reactions.Clin Phramacol Ther. 1981; 30: 239-245Crossref PubMed Scopus (8419) Google Scholar for both cases was 3 (possible adverse drug reaction), the appearance of bradycardia in conjunction with resolution of the admission diagnosis (amnionitis/influenza) in both women supports a drug reaction. Repeat cardiac Holter testing several weeks later was normal. While both mild and severe adverse effects have been reported for oseltamivir,3Dutkowski R. Thakrar B. Froehlich E. Suter P. Oo C. Ward P. Safety and pharmacology of oseltamivir in clinical use.Drug Saf. 2003; 26: 787-801Crossref PubMed Scopus (92) Google Scholar, 4Maxwell C. Tamiflu and neuropsychiatric disturbance in adolescents.BMJ. 2007; 334: 1232-1233Crossref PubMed Scopus (56) Google Scholar we could find no published reports of oseltamivir-induced bradycardia. Roche prescribing information mentions cardiac arrhythmias in the post-marketing assessment, but gives no further information.5Product information: Tamiflu® oseltamivir phosphate oral capsules, powder for oral suspension. Nutley, NJ: Roche Pharmaceuticals; 2008.Google Scholar We consider it probable that oseltamivir can cause bradycardia, an adverse event with potentially severe consequences; however, the lack of previous reports would indicate that it is relatively rare. Awareness of the possibility of oseltamivir-induced bradycardia will improve diagnosis if such an adverse effect exists; further post-marketing studies focusing on cardiac dysrhythmias are needed to validate the possibility. Conflict of interest: No conflict of interest to declare.

Aim:To determine whether implementation of criteria for performing a toxicology screen and increasing staff awareness improve detection of substance abuse among adolescents presenting to the emergency department.Methods:Patients 12 to 18 years of age presenting to one of three emergency departments in Israel were included in a prospective cohort study. In the 'study' hospital, a set of criteria for urine toxicology screen and measurements of ethanol serum level were implemented. No specific interventions were implemented in the two other hospitals. The main outcome measure was the rate of substance abuse detection.Results:The number of adolescents seen in the participating centres was 3200 at the study hospital, and 3493 and 2792 at the two other hospitals. High blood ethanol concentrations were found in 49 patients at the study hospital compared with 30 and 19 patients at the two other hospitals (p < 0.001).Illicit drugs were detected in 13, 4 and 1 patients, respectively (p = 0.002).Conclusions:Introducing structured guidelines for ordering toxicological screening increases the detection of alcohol and drug of abuse among adolescents presenting to paediatric emergency departments.

BACKGROUND Infantile exposure to macrolides has been associated with hypertrophic pyloric stenosis causing projectile vomiting, dehydration, electrolyte abnormalities, and in rare cases death possibly via macrolide interaction with gastric motilin receptors. Large population-based cohorts have suggested that exposure to macrolides via breastmilk may be associated with pyloric stenosis. METHODS In this prospective, controlled observational study designed to assess the safety of macrolides during lactation, we followed infants whose mothers contacted our Drug Consultation Center at the Assaf Harofeh Medical Center (Zerrifin, Israel) inquiring about safety of macrolides during lactation and compared them to a cohort of infants exposed to amoxicillin during breastfeeding. RESULTS Fifty-five infants exposed to macrolide antibiotics were compared to a control cohort of 36 infants exposed to amoxicillin via lactation. The infants in the macrolide group were all exposed to erythromycin and the newer macrolides: azithromycin, clarithromycin, and roxithromycin. The rate of adverse reactions the infant experienced while being exposed to both antibiotics was comparable. Seven (12.7%) infants in the macrolide group experienced adverse reactions versus three infants (8.3%) in the amoxicillin group (odds ratio = 1.6, 95% confidence interval, 0.38-6.65, p = 0.73). The adverse reactions in the infants exposed to macrolides were rash, diarrhea, loss of appetite, and somnolence, whereas the infants exposed to amoxicillin experienced rashes and somnolence. Factors such as gestational age, age and weight at exposure, maternal age, or type of macrolide were not associated with the infant's adverse reaction in multivariate regression analysis. CONCLUSIONS Rates and types of minor adverse reactions in breastfed infants exposed to a macrolide or amoxicillin in breastmilk were comparable. Macrolide exposure during breastfeeding was not associated with pyloric stenosis, although larger prospective studies are required to confirm our observation.

AIM:Nosocomial infections are of great concern in hospital settings, and even more so in the paediatric ward. Health professionals and their medical equipment have long been known to act as vectors of infectious diseases. This study aimed at evaluating the presence of bacterial pathogens on the stethoscopes of medical personnel in the paediatric division.METHODS:Forty-three stethoscopes belonging to senior physicians, residents, interns and medical students at the paediatric ward were sampled. Bacterial cultures and antibiotic sensitivity testing were carried out.RESULTS:All but six bacterial cultures were positive (85.7%). Staphylococcal species were the most common contaminants (47.5%). One case of methicillin-resistant Staphylococcus aureus was encountered. Gram-negative organisms were isolated in nine different samples (21%) including one case of Acinetobacter baumannii in the neonatal intensive care unit.CONCLUSION:Most stethoscopes harbour potential pathogens. The isolation of Gram-negative organisms pose a real risk of spreading potentially serious infections, especially in the setting of intensive care departments. Apparently, the current recommendations of regular disinfection of stethoscopes are not carried out by health personnel that participated in the study.