Valproic acid teratogenicity

Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14 R546-R551 Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276 36734-36741... 

For some agents for example valproic acid and ethanol, a threshold concentration must be reached before teratogenicity is induced and the effect is therefore related to the maximum plasma concentration For others such as retinoids and cyclophos-... 

Ritter, E.J., Scott, W.J., Jr, Randall, J.L. Ritter, J.M. (1987) Teratogenicity of di(2-ethylhexyl)phthlate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine. Teratology, 35, 41-46... 

Nau H (1985) Teratogenic valproic acid concentrations infusion by implanted minipumps vs. conventional injection Fegimen in the mouse. Toxicol Appl Pharmacol, 80 243-250. 

Some examples of carboxylic acids that have high teratogenic potency are illustrated in Figure 4.2 and include valproic acid (12), 2-ethylhexanoic acid (13), 2-propyl-... 

Propylpentanoic acid (valproic acid) (12) contains no chiral centers, but one of its mammalian metabolites is 2-propyl-4-pentenoic add (14), which has a chiral center at C-2. (S)-2-Propyl-4-pentenoic acid is a much more potent teratogen, at least in some assays, than (R)-2-propyl-4-pentenoic acid [56]. Similar observations have been made for the specific enantiomers of 2-propyl-4-pentynoic acid (15). (S)-2-Propyl-4-penty-noic acid is a much more potent teratogen than (R)-2-propyl-4-pentynoic acid [57]. 

Hauck, R.-S. and Nau, H. (1996) Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-ene-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol. Lett. 49 41-48. 

Exposure to retinoic acid, methylnitrosourea, and clomiphene during the early embryonic period, prior to the induction of the neural plate (before day 18 in the human), results in an increased incidence of neural tube defects and other malformations in experimental animal models (Bennett Finnell, 1998). In addition, exposure of rodents to teratogens such as retinoic acid, arsenic, and valproic acid during the period of neurulation results in neural tube defects such as spina bifida and encephaloceles (Adams Lammer, 1993 Bennett Finnell, 1998). Of these, therapeutic use of... 

The principles of teratology have been articulated by Wilson (104). The first principle is that teratogens act with specificity. A teratogen produces a specific abnormality or constellation of abnormalities. For example thalidomide produces phocomelia/ and valproic acid produces neural tube defects. This specificity also applies to species because drug effects may be seen in one species and not in another. The best example is cortisol which produces cleft palate in mice but not in humans. 

The consequences of trimethadione toxicity consist of hematologic side effects (neutropeifia, pancytopenia), hemeralopia (day blindness), photophobia, diplopia, dermatologic side effects (rash and erythema multiform), CNS side effects (drowsiness and tolerance), nephrotoxic syndrome (albuminuria), and teratogenic effects such as fetal trimethadione syndrome. From this it is apparent that trimethadione is only indicated for the control of absence seizures that are not responsive or have become refractory to treatment with less toxic substances such as ethosuximide or valproic acid. 

A rare complication is fulminant hepatitis. Children <2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury there were no deaths reported for patients >10 years old who received only valproate. Acute pancreatitis and hyperammonemia have been associated with the use of valproic acid. Valproic acid can produce teratogenic effects such as neural tube defects. 

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