Teratogenicity of the IKr-blocker cisapride: relation to embryonic cardiac arrhythmia

Sköld, Anna‐Carin; Danielsson, Christian; Linder, Bengt; Danielsson, Bengt

doi:10.1016/s0890-6238(02)00042-4

Cited by 24 publications

(19 citation statements)

References 32 publications

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“…(ii) Monitoring of effects on embryonic heart rhythm using cultured rat embryos during the susceptible period in rats and exposing them to increasing concentrations of test drugs [42]. The results of in vivo studies in adult dogs/rabbits (or adult cardiac preparations) on proarrhythmic potential for IKr-blockers [3] may not be valid for the embryo, since the embryonic heart may have different susceptibilities to that of the adult heart.…”

Section: Discussionmentioning

confidence: 99%

“…Danielsson and colleagues in 2002 [42] undertook a study in rats to test if a single dose of cisapride administered on GD 13 in the rat would be teratogenic. This was based on the hypothesis that drugs with significant IKr inhibiting properties should show the same teratogenic profile as pure IKr-blockers such as dofetilide or almokalant.…”

Section: Single Dose Studies With Cisapride and Astemizolementioning

confidence: 99%

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New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential

Karlsson¹,

Danielsson²,

Nilsson³

et al. 2007

CPD

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Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Single Dose Studies With Cisapride and Astemizolementioning

confidence: 99%

New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential

Karlsson¹,

Danielsson²,

Nilsson³

et al. 2007

CPD

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“…Drugs inhibiting the hERG channel, deliberately (class III antiarrhythmic drugs) or as a side effect (e.g., cisapride), cause a very similar pattern of stage‐specific malformations as PHT, as well as concentration‐dependent embryonic bradycardia/arrhythmia during the same restricted period of development as PHT in rodents (reviewed in Danielsson et al,2001). Examination of the embryonic cardiac rhythm shows that I Kr blockers cause a relatively constant increase in length of the interval between individual heartbeats at lower exposure levels, while large variations in length between individual beats are recorded at higher concentrations (Sköld et al,2002; Danielsson et al,2003b).…”

Section: Introductionmentioning

confidence: 99%

“…In order to study the association between hERG‐channel–related arrhythmia and occurrence of hypoxia, the same examination was also performed at a later developmental stage when I Kr to a large extent is suppressed in favor of other cardiac repolarizing potassium channels (GD 15). A third aim of the study was to further characterize reported concentration‐dependent effects by PHT on embryonic heart rhythm by using a new technique (Sköld et al,2002). This technique made it possible to compare PHT‐induced rhythm disturbances with those observed by potent I Kr blockers.…”

Section: Introductionmentioning

confidence: 99%

Phenytoin teratogenicity: Hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism

Danielsson

Johansson

Danielsson

et al. 2005

Birth Defects Research Part A: Clinical and Molecular Teratolog

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“…The pattern is particularly characterized by orofacial clefts, limb reduction defects and cardiovascular defects [6]. Some similar features are seen with other less selective HERG inhibitors such as phenytoin, ibutilide [148], cisapride [149] and astemizole [150]. It is likely that all of these drugs cause embryo/fetal bradycardia and that the defects are a consequence of the resultant hypoxia followed by edema and hemorrhage [6, 7, 90-92, 113-117, 151].…”

Section: Is There a Fetal Hypoxia Syndrome?mentioning

confidence: 99%

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 the IKr-blocker cisapride: relation to embryonic cardiac arrhythmia

Cited by 24 publications

References 32 publications

New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential

New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential

Phenytoin teratogenicity: Hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism

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

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