Teratogenicity of diphenylhydantoin in the New Zealand white rabbit

McClain, R.M.; Langhoff, Lasse

doi:10.1002/tera.1420210315

Cited by 59 publications

(10 citation statements)

References 28 publications

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“…Initially, it was shown that phalangeal hypoplasia was the most common defect seen when phenytoin was administered orally to pregnant rabbits from GD 7 to GD 18 (McClain and Langhoff, 1980). Subsequent studies showed the sensitive period for this defect was GD 14-16 and the digital defects were preceded by edema, dilated blood vessels, hemorrhage, and eventually mesenchymal necrosis (Danielson et al, 1992;Danielsson et al, 1992Danielsson et al, , 1995.…”

Section: Phenytoinmentioning

confidence: 93%

The effect of hypoxia in development

Webster

Abela

2007

Birth Defects Research Pt C

174

135

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There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects. Birth Defects Research (Part C) 81: [215][216][217][218][219][220][221][222][223][224][225][226][227][228] 2007. V C 2007 Wiley-Liss, Inc.

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Section: Phenytoinmentioning

confidence: 93%

The effect of hypoxia in development

Webster

Abela

2007

Birth Defects Research Pt C

174

135

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“…However, the rats seem to be less susceptible than mice and rabbits for teratogenic action by phenytoin. In the New Zealand White rabbit [45,46] both teratogenicity and fetal growth retardation were observed at the same free concentrations as been related to the same type of effects in human pregnancy [47,48]. Also in mice, teratogenicity has been observed after dosing regimens resulting in clinically relevant maternal concentrations [49][50][51][52].…”

Section: Pharmacological Effectsmentioning

confidence: 96%

Class III Antiarrhythmics and Phenytoin: Teratogenicity Due to Embryonic Cardiac Dysrhythmia and Reoxygenation Damage

Danielsson¹,

Sköld²,

Azarbayjani³

2001

CPD

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Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

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“…Common findings in rats, mice and rabbits include fetal growth retardation, CL(P), CP alone, heart defects such as ventricular septal defects, distal digital defects Fig. (3j) and behavioural changes [110,111,113,117,[120][121][122][123][124][125][126]. The similarity of these defects to those seen after exposure to almokalant and dofetilide has been used as additional evidence that these drugs have a common mechanism of teratogenicity [6,91,111,[114][115][116][117].…”

Section: (B) Other Defects In Ratsmentioning

confidence: 97%

The Relationship Between Cleft Lip, Maxillary Hypoplasia, Hypoxia and Phenytoin

Webster¹,

Howe²,

Abela³

et al. 2006

CPD

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Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.

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Teratogenicity of diphenylhydantoin in the New Zealand white rabbit

Cited by 59 publications

References 28 publications

The effect of hypoxia in development

The effect of hypoxia in development

Class III Antiarrhythmics and Phenytoin: Teratogenicity Due to Embryonic Cardiac Dysrhythmia and Reoxygenation Damage

The Relationship Between Cleft Lip, Maxillary Hypoplasia, Hypoxia and Phenytoin

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