Diazepam‐induced cleft palate in the mouse and lack of correlation with the H‐2 locus

Tocco, Donald R.; Renskers, Kevin J.; Zimmerman, Ernest F.

doi:10.1002/tera.1420350316

Cited by 15 publications

(2 citation statements)

References 20 publications

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“…Even common manifestations of maternal toxicity can impact development. For example, dietary deprivation during organogenesis in rabbits has been shown to cause resorptions and decreased fetal weight in rabbits (Matsuzawa et al, ; Clark et al, ) and deprivation of both food and water has been shown to cause cleft palate in mice (Tocco et al, ).…”

Section: Developmental Toxicity Studies In Animals and Their Interprementioning

confidence: 99%

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

Clark

2017

Birth Defects Research

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The World Health Organization currently recommends quinine1clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing 5 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine1pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine1pyrimethamine and artemether1lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios 2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above.

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Section: Developmental Toxicity Studies In Animals and Their Interprementioning

confidence: 99%

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

Clark

2017

Birth Defects Research

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“…However, some reports have linked diazepam to oral clefts, distal limb defects, microcephaly, and cardiovascular anomalies (reviewed in [53]). In addition, it is well established that high doses of diazepam lead to craniofacial malformations in rodents [54-57] and mice carrying targeted disruptions of the GABAergic pathway consistently develop a cleft palate, a rather common feature of Zellweger patients [58,59]. …”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system viathe diazepam binding inhibitor

Breitling

2004

BMC Pediatr

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BackgroundZellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses.HypothesisWe suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients.Testing the hypothesisUsing microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy.Implications of the hypothesisWe present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome.

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Corticosterone induction of cleft palate in mice dosed with orciprenaline sulfate

et al. 1988

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Orciprenaline sulfate is a beta-adrenoceptor stimulant chemically described as 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-isopropylaminoethane sulfate (Alupent). The drug has broncho-dilating activity and has been developed in numerous countries since 1961. The purpose of these studies was to investigate the teratogenic potential of orciprenaline and its mode of action in pregnant Jcl:ICR mice, when administered during the period of organogenesis and, more systematically, during the critical period of palate formation. Daily doses of 5, 50, and 500 mg/kg were given orally by gavage to mice on days 6-15, 11-13, or on day 12 of gestation. Additional studies were done to evaluate the maternal cardiotoxic action of orciprenaline and its effects on adrenal cortex and endogenous serum corticosterone. Five mg/kg triamcin-olone acetonide, a glucocorticoid, were given subcutaneously as a positive control causing 100% cleft palate. Myocardial necroses occurred in pregnant mice only after 500 mg/kg orciprenaline had been given, and a significant increase in cleft palate occurred if exposure took place during days 11-13 or day 12 of gestation. This increase in cleft palate can be explained by the teratogenic effect of an elevated maternal serum corticosterone level 1 hr after orciprenaline treatment, about three times the control value.

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Diazepam‐induced cleft palate in the mouse and lack of correlation with the H‐2 locus

Cited by 15 publications

References 20 publications

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system viathe diazepam binding inhibitor

Corticosterone induction of cleft palate in mice dosed with orciprenaline sulfate

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