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Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression : Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy

1 , 1 , 1

Birth Defects Research

Wiley

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      Pharmacological profile of antidepressants and related compounds at human monoamine transporters.

      Using radioligand binding assays, we determined the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites (desmethylcitalopram, desmethylsertraline, and norfluoxetine), some mood stabilizers, and assorted other compounds (some antiepileptics, Ca2+ channel antagonists, benzodiazepines, psychostimulants, antihistamines, and monoamines) for the human serotonin, norepinephrine, and dopamine transporters. Among the compounds that we tested, mazindol was the most potent at the human norepinephrine and dopamine transporters with KD's of 0.45 +/- 0.03 nM and 8.1 +/- 0.4 nM, respectively. Sertraline (KD = 25 +/- 2 nM) and nomifensine (56 +/- 3 nM) were the two most potent antidepressants at the human dopamine transporter. We showed significant correlations for antidepressant affinities at binding to serotonin (R = 0.93), norepinephrine (R = 0.97), and dopamine (R = 0.87) transporters in comparison to their respective values for inhibiting uptake of monoamines into rat brain synaptosomes. These data are useful in predicting some possible adverse effects and drug-drug interactions of antidepressants and related compounds.
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        Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors.

        Among many anticancer drugs collectively named "targeted or molecular therapies" epigenetic drugs are clearly promising. Differently from other agents targeting a single gene product, epigenetic drugs have chromatin as their target through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) therefore, yet unspecific, they may act upon most or all tumor types, as deregulation of the methylation and deacetylation machinery are a common hallmark of neoplasia. In the last years, valproic acid (VPA) as emerged as a promising drug for cancer treatment. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, and encouraging results in early clinical trials either alone or in combination with demethylating and/or cytotoxic agents. In addition, whole genome expression by microarray analysis from the primary tumors of patients treated with VPA show significant up-regulation of hundred of genes belonging to multiple pathways including ribosomal proteins, oxidative phosphorylation, MAPK signaling; focal adhesion, cell cycle, antigen processing and presentation, proteasome, apoptosis, PI3K, Wnt signaling, calcium signaling, TGF-beta signaling, and ubiquitin-mediated proteolysis among others. Despite in general, industry is not particularly interested in funding the clinical development of VPA, -at least in comparison to novel HDAC inhibitors-, existing preclinical and preliminary clinical data strongly suggest that VPA could be a drug that eventually will be used in combination therapies, either with classical cytotoxics, other molecular-targeted drugs or radiation in a number of solid tumors.
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          Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.

          Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Author and article information

            Affiliations
            [1 ]Laboratory of Teratology, Department of Medical Neurobiology; Hebrew University Hadassah Medical School; Jerusalem Israel
            Journal
            Birth Defects Research
            Birth Defects Research
            Wiley
            24721727
            July 17 2017
            July 17 2017
            July 17 2017
            : 109
            : 12
            : 933-956
            10.1002/bdr2.1079
            © 2017

            http://doi.wiley.com/10.1002/tdm_license_1.1

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