Talk:Abnormal Development - Drugs

2010

The effect of drugs with ion channel-blocking activity on the early embryonic rat heart

Birth Defects Res B Dev Reprod Toxicol. 2010 Oct;89(5):429-40.

Abela D, Ritchie H, Ababneh D, Gavin C, Nilsson MF, Khan MK, Carlsson K, Webster WS.

Department of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, Australia.

Abstract This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing. Birth Defects Res (Part B) 89:429-440, 2010. © 2010 Wiley-Liss, Inc.

PMID: 20973055

Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update

Postgrad Med. 2010 Jul;122(4):49-65.

Tuccori M, Montagnani S, Testi A, Ruggiero E, Mantarro S, Scollo C, Pergola A, Fornai M, Antonioli L, Colucci R, Corona T, Blandizzi C. Unit of Pharmacology, University Hospital of Pisa, Pisa, Italy. m.tuccori@ao-pisa.toscana.it Abstract General consensus exists about the need to avoid drug intake as much as possible during pregnancy due to the lack of thorough evidence about the safety of pharmacologic treatments during gestation for both mothers and fetuses. In this respect, the overall safety profile of selective serotonin reuptake inhibitors (SSRIs) in pregnancy remains unclear. This article reviews current evidence about the safety of each SSRI during pregnancy in order to describe their specific teratogenic potential, with a particular focus on major and cardiovascular malformations, and to verify whether such toxicity can be considered as a class effect. The literature review included controlled studies and meta-analyses (retrieved using PsychINFO, EMBASE, and Medline from January 1966 to May 2010) from which the risk of major and/or cardiovascular malformations associated with a specific SSRI (ie, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) could be estimated. Although there is evidence to support the association between birth defects and first-trimester exposure to paroxetine, findings from the studies reviewed suggest a teratogenic potential of the whole SSRI class, consistent with preclinical evidence. These teratogenic effects are mainly in the heart region, and they are often described as septal defects. It may be suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis. It is noteworthy that current evidence on SSRI teratogenicity stems from studies affected by several methodological weaknesses (ie, lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias). Accordingly, we are not yet able to rule out the possibility that positive associations, as determined in some studies, result from analyses of poor quality. PMID: 20675971

Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register

Seizure. 2010 Aug 24. [Epub ahead of print]

Vajda FJ, Graham JE, Hitchcock AA, O'Brien TJ, Lander CM, Eadie MJ. Department of Medicine and Neurology, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia. Abstract Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N=118), the incidences for LTG (N=243), carbamazepine (CBZ) (N=302) and VPA (N=224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs. Copyright © 2010. Published by Elsevier Ltd. PMID: 20739196

Are azole fungicides a teratogenic risk for human conceptus?

Toxicol Lett. 2010 Oct 5;198(2):106-11. Epub 2010 Jul 13.

Giavini E, Menegola E. Università degli studi di Milano, Dipartimento di Biologia, Via Celoria, 26, I-20133 Milano, Italy. erminio.giavini@unimi.it Abstract Azole fungicides are widely used in agriculture and in human mycosis. Their antifungal activity is based on their ability to inhibit CYP51, a key enzyme in the formation of fungal wall. Several azole fungicides tested in laboratory animals have been found to possess a common teratogenic potential to induce facial, axial skeleton, and limb defects. The mechanism of the teratogenic effect has been hypothesized to be related to the capability of these substances to alter embryonic retinoic acid catabolism. Although a number of human epidemiological studies were unable to demonstrate a definite relationship between azole exposure during pregnancy and birth defects, some case reports indicate a possible teratogenic effect of high doses of azoles in humans. Because of their common mechanism of action, azole fungicides should be regarded with caution for use in pregnant women. Copyright 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20633616