Thalidomide and Congenital Abnormalities

Lenz, W; Pfeiffer, RudolfA.; Kosenow, W; Hayman, D.J

doi:10.1016/s0140-6736(62)92665-x

Cited by 387 publications

(125 citation statements)

References 0 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…The use of medications during pregnancy may expose the developing fetus to risks like miscarriage, intrauterine growth retardation, malformations and mortality. In this respect, the historical saga of thalidomide, a sedative used in the treatment of hyperemesis gravidarum, but later found to be responsible for a string of birth defects readily comes to mind [10][11][12][13]. Many herbal remedies have been reported to impair fetal development following usage in pregnancy [14][15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Embryotoxic and Teratogenic Potentials of Salacia lehmbachii in Rats

Essiet¹,

Akuodor²,

Essien³

2017

IOSRJPBS

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Embryotoxic and Teratogenic Potentials of Salacia lehmbachii in Rats

Essiet¹,

Akuodor²,

Essien³

2017

IOSRJPBS

View full text Add to dashboard Cite

“…It was developed by Chemie Grunenthal in the 1950s as a sedative that appeared so nontoxic in rodent models that a LD50 could not be established. In 1961, McBride (1) and Lenz (2) described the association between limb defects in babies and maternal thalidomide usage. Although humans are exquisitely sensitive to the teratogenic effects of thalidomide, experiments in rodents failed to reveal similar effects (3,4).…”

mentioning

confidence: 99%

Thalidomide Is an Inhibitor of Angiogenesis

Amato¹,

Loughnan²,

Flynn³

et al. 1996

Retina

204

240

View full text Add to dashboard Cite

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of aniogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antaniogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization ofthafidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally adminsered drug for the treatment of many diverse dease dependent on angiogenesis.Thalidomide is a potent teratogen. It was developed by Chemie Grunenthal in the 1950s as a sedative that appeared so nontoxic in rodent models that a LD50 could not be established. In 1961, McBride (1) and Lenz (2) described the association between limb defects in babies and maternal thalidomide usage. Although humans are exquisitely sensitive to the teratogenic effects of thalidomide, experiments in rodents failed to reveal similar effects (3, 4). Teratogenic effects could be experimentally reproduced by the administration of thalidomide to pregnant rabbits at an oral dose of 100-300 mg per kg per day (5, 6). Over the past 30 years, the mechanism of thalidomide's teratogenicity has been extensively studied but has remained unsolved (7).We now postulate that the limb defects seen with thalidomide were secondary to an inhibition of blood vessel growth in the developing fetal limb bud. The limb bud is unique in requiring a complex interaction of both angiogenesis and vasculogenesis during development (8). Vasculogenesis is the formation of a capillary bed from endothelial cells that have differentiated from mesenchymal precursors. Angiogenesis is the formation of new blood vessels from sprouts ofpreexisting vessels. Therefore, the limb bud would be a particularly vulnerable target to a teratogen that inhibited endothelial cell function. We chose to examine the effect of thalidomide on growing vasculature in the chicken chorioallantoic membrane and in the rabbit cornea. MATERIALS AND METHODSChicken chorioallantoic membrane (CAM) assays were performed as described (9, 10) and the effects on the developing vasculature were recorded at 48 h after implantation of the 0.5% carboxymethylcellulose pellet containing various drugs. Corneal

show abstract

“…Thalidomide was identified as a human teratogen 20 years ago (1)(2)(3). Compared to other teratogens, thalidomide's selective toxicity in the embryo, particularly for the developing limbs, and its relative lack oftoxicity in the adult is striking (4).…”

mentioning

confidence: 99%

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

Gordon¹,

Spielberg²,

Blake³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

145

View full text Add to dashboard Cite

It was postulated that thalidomide causes birth defects by being metabolized to a toxic electrophilic intermediate. This hypothesis was tested by using an in vitro assay in which drug toxicity to human lymphocytes was assessed in the presence of a hepatic microsomal drug metabolizing system. Maternal hepatic microsomes from pregnant rabbits mediated the production of a metabolite that was toxic to lymphocytes. Toxicity was enhanced by inhibitors of epoxide hydrolase (EC 3.3.2.3) and abolished by adding the purified enzyme to the incubation medium. The metabolite thus appears to be an arene oxide, consistent with the previously reported isolation of phenolic metabolites of thalidomide from the urine of treated animals. Two teratogenic analogs of thalidomide (phthalimidophthalimide and phthalimidinoglutarimide) were also toxic in the system; two nonteratogenic analogs (phthalimide and hexahydrothalidomide) were not toxic, even in the presence of epoxide hydrolase inhibitors. The toxic metabolite of thalidomide was not produced by rat liver microsomes (the rat is not sensitive to thalidomide teratogenesis) but was produced by hepatic preparations from maternal rabbits, and rabbit, monkey, and human (all sensitive species) fetuses. A toxic arene oxide therefore may be involved in the teratogenicity of thalidomide.Thalidomide was identified as a human teratogen 20 years ago (1-3). Compared to other teratogens, thalidomide's selective toxicity in the embryo, particularly for the developing limbs, and its relative lack oftoxicity in the adult is striking (4). Despite intensive investigation, however, the mechanism of the fetal toxicity of the drug remains unknown.An interesting early observation was that rats were resistant to the teratogenic effects of thalidomide but rabbits and monkeys were sensitive (5-7). Differences in species susceptibility could result from differences in biotransformation of the compound. It was noted that rabbit liver homogenates enhanced the rate of disappearance of the drug from incubation mixtures whereas rat liver homogenates did not (8). Similarly, in vivo, more thalidomide metabolites were bound to liver macromolecules in the rabbit than in the rat, suggesting that a metabolite might interact covalently with macromolecules important in morphogenesis. Furthermore, after thalidomide treatment, 4-and 5-hydroxylated metabolites of thalidomide were recovered from the urine of rabbits but not from rats (9).The presence ofphenolic derivatives ofthalidomide suggests that the drug might undergo oxidative metabolism via an arene oxide intermediate. Arene oxides have been implicated as mutagens, cytotoxins, and teratogens (10-12). Thus, birth defects caused by the anticonvulsant phenytoin may result from an arene oxide metabolite which covalently binds to critical structures in the developing fetus (12). Therefore, we have attempted to look for a possible toxic arene oxide metabolite ofthalidomide. We have used an in vitro assay system in which human lymphocytes are the target of metabol...

show abstract

Thalidomide and Congenital Abnormalities

Cited by 387 publications

References 0 publications

Embryotoxic and Teratogenic Potentials of Salacia lehmbachii in Rats

Embryotoxic and Teratogenic Potentials of Salacia lehmbachii in Rats

Thalidomide Is an Inhibitor of Angiogenesis

Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite.

Contact Info

Product

Resources

About