Country-wise Listing - Israel

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S.NO Title & Authors Name page
Treating Symptoms of Morning Sickness: The First Dual Release Combination of Doxylamine-Pyridoxine
Gideon Koren*, Manon Vrandrick
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Modified release tablet preparations are sought when there is a need to provide clinical solutions which are not achieved optimally with the standard release products. Nausea and vomiting of pregnancy (NVP) affect most pregnancies. Symptomatic treatment aims to improve woman’s quality of life, and counteract dehydration, electrolyte imbalance, need for hospitalization and attendant risk of maternal and fetal complications. Until recently, the only agent approved by Canada, USA, South Korea. Israel and Singapore has been the delayed release combination of doxylamine and pyridoxine (Diclectin®/ Diclegis®).
All other countries worldwide do not presently have a pregnancy- approved anti emetic drug.
Due to its delayed release properties, Diclectin®/ Diclegis® begins to exert its antiemetic effect 6-8 hours after ingestion, and hence symptom relief may be delayed and necessitate the use of an immediate release medication. In November 2016 the FDA approved Bonjesta®, a novel, dual- release combination of doxylamine and pyridoxine, whereby a rapid release phase is followed by a delayed release phase, thus overcoming the time delay in action of the delayed release combination of doxylamine and pyridoxine.

In this article we review the unique properties of this new drug in the context of other medications where modified- release forms have been effective.

Preventing Inappropriate Hydroxyurea Dosing in Children by Introducing a Child-Appropriate Preparation
Gideon Koren*, Michael Lishner, Ami Ballin
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Hydroxyurea (HU) is the only FDA- approved disease- modifying drug for sickle cell disease, by inducing the production of fetal hemoglobin and thus decreasing the sickling of red blood cells. Till recently HU was available only in adult doses of 1000 mg. This meant that to aim at the standard dose of 20 mg/kg/d, most young children had to be overdosed, or the doses had to be fluctuated daily to achieve the aimed mean dose. Because adherence improves with unchanged daily dose, and due to the more than 10 fold variability in HU pharmacokinetics in children, there was an urgent need for a pediatric formulation of HU.
This issue has been solved with FDA approval of the French-originated orphan HU, Siklos, a preparation of 50 and 100 mg, which prevents the risk of inappropriate dosing in children.

High Dose Folic Acid during Pregnancy and the Risk of Autism - The Birth Order Bias: A Nested Case-Control Study
Sarah Sharman Moser*, Michael Davidovich, Ran S Rotem, Gabriel Chodick, Varda Shalev and Gideon Koren
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Background: There has been a dramatic increase in the prevalence of autism worldwide, concurring with growing use of folic acid for the prevention of neural tube defects. A recent study suggested increased risk of autism at high gestational dose levels of folic acid, raising public anxiety and fears of using folic acid. Our objective was to examine whether gestational use of folic acid is associated with increased risk of autism, with focus on high doses. Methods: This was a nested case- control study in a large health fund insuring 2 million citizens. Among 504,028 children born into Maccabi from 2000 to 2010 (inclusive) singleton children with autism (n=2009) were matched with up to 10 non autistic controls (n=19,886). The main dependent outcome measure was the diagnosis of autism, and the independent variable was the mean gestational dose of folic acid compared between cases of autism and controls after appropriate matching. Results: Significantly more autistic children were first born, and birth order effect was independently and significantly associated with folic acid use; Mothers purchased significantly more folic acid during the first pregnancy than during later pregnancies (P<0.001). In multivariate analysis, accounting for birth order and other confounders, folic acid use was not associated with increased autistic risk, and no dose -response trends were observed. Compared with mothers of the lowest average daily folate dose, the odds ratio for autism among mothers of highest daily dose (3 mg) was 0.99 (95% confidence interval: 0.59-1.67). The lack of association was further confirmed in sensitivity analysis restricted to first-born children only. Conclusions: Folic acid supplementation is not associated with a risk for autism even at high doses. A new type of bias, the birth order bias, has to be recognized and accounted for. The results are of public health importance given that folic acid is needed to prevent neural tube defects, sometime at high doses.