Teratogenicity, retinoids

The ability to form carbon—carbon bonds in a controlled manner around an alkene is the subject of continuing intense research [49,134—136], These compounds are stable and, due to the considerably different reactivities of the C—Zr and C—B bonds, allow for selective and sequential reactions with a variety of electrophiles. Temarotene 58 is a retinoid of interest [137] because it shows no sign of hypervitaminosis A and it is not teratogenic, presumably due to the lack of a polar group [138,139], The published synthesis of temarotene-type compounds is long and leads to mixtures of diastereo-isomers, from which the desired product is eventually isolated [140—142], However, the synthesis of temarotene 58 by the method of Srebnik et al. [130] is straightforward, as outlined in Scheme 7.18. 

Kistler A (1987) Limb bud cell cultures for estimating the teratogenic potential of compounds. Validation of the test system with retinoids. Arch Toxicol 60(6) 403 14... 

For early clinical trials, where it is unlikely there will be full reproductive toxicology data, any application should include a discussion of whether any effects on reproduction can be anticipated from the primary pharmacodynamics. The nature of the target receptor binding and any potential for binding to receptors involved in reproduction should be considered. For compounds in classes already known to be teratogenic such as cytotoxic anticancer products, retinoids, or histone deacetylase inhibitors, it can be reasonably expected that... 

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-... 

The chirality of the molecule should be determined and the potential for differences between animals and humans discussed. It is not uncommon for the enantiomers or different isomers of a molecule to have differing teratogenic potentials, for example as with retinoids, on which there is extensive published data, e.g., (4). 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

Systemically administered retinoids such as isotretinoin (1, Accutane ) have several disadvantages such as a relatively narrow therapeutic index and a variety of toxic effects including teratogenicity. Topically administered retinoids may avoid some of those drawbacks. For instance, tazarotene (2, Tazorac ) is a topical receptor-selective retenoid that normalizes differentiation and proliferation of keratinocytes. Its major metabolite, tazarotenic acid (11), binds to retinoic acid receptors (RARs) with high affinity. 

Much recent interest has been aroused by the fact that retinoid compounds, including both retinol and retinoic acid, reduce the incidence of experimentally induced cancer. In addition, 13-czs-retinoic acid taken orally is remarkably effective in treatment of severe cystic acne. s However, both vitamin A and retinoic acid in large doses are teratogenic, i.e., they cause fetal abnormalities. The use of 13-cis-retinoic acid during early phases of pregnancy led to a high incidence of major malformations in infants born.1 11 1... 

Tazarotene (Tazorac) is an acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy. 

Embryotoxicity/teratogenicity is the major drawback in the therapeutic use of retinoids. The exposure of the fetus during the first trimester with oral retinoids is known to produce characteristic malformations.93 There have also been case reports about malformations associated with retinoid embryopathy after the mother had used tretinoin topically during the first trimester of pregnancy 94-96... 

During the 1980s, two drugs used to treat different types of skin diseases were found to be teratogenic. The drugs, generic names are isotretoin and etretinate, respectively, and they are synthetic retinoids (i.e., derivatives of vitamin A). Isotretoin (Accutane) was prescribed for the treatment of acne while etretinate was prescribed for psoriasis. 

Hendrickx AG, Tzimas G, Korte R, Hummler H. Retinoid teratogenicity in the macaque verification of dosing regimen. J Med Primatol 1998 27(6) 310-8. 

G. Klopman and M. I. Dimayuga, J. Comput.-Aided Mol. Design, 4, 117 (1990). Computer Automated Structure Evaluation (CASE) of the Teratogenicity of Retinoids with the Aid of a Novel Geometry Index. 

Retinoids (e.g. retinoic acid) are involved in development and in metabolic regulation (e.g. through induction of expression of PEPCK, the rate limiting enzyme in gluconeogenesis). Retinoic acid derives from retinol, which in turn derives from ingestion of plant a-, 3- and "/-carotenes and other carotenes. Retinoic acid acts via retinoic acid receptors and retinoid X receptors note that these receptors can heterodimerize in the nucleus with other related hormone receptors such as PPA-Rs. The developmental importance of retinoic acid is underscored by the teratogenicity of retinoic acid and other vitamin A related compounds, notably some compounds developed for anti-acne properties. 

Studies with knockout mutant mice lacking one or another of the retinoid receptors suggest that there is some degree of redundancy or overlap between the receptor subtypes, and that RARy is especiallyimportant in the teratogenic actions of retinoids (Section 2.5.1.1 Mark et al., 1999 Maden, 2000) ... 

Soprano DR and Soprano KJ (1995) Retinoids as teratogens. Annual Reviews of Nutrition 15, 111-32. 

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