Retinoid toxicity

Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, and mood alterations occur. Oral retinoids are potent teratogens and cause severe fetal malformations. Because of this, systemic retinoids should be used with great caution in females of childbearing potential. 

Pitha, J. and Szente, L. Rescue from hypervitaminosis A or potentiation of retinoid toxicity by different modes of cyclodextrin administration. Life Sci. 32, 719-723 (1983). 

Mawson A. Mefloquine use, psychosis, and violence a retinoid toxicity hypothesis. Med Sci Monit Int Med J Exp Chn Res 2013 19 579-83. Nevin RL. Limbic encephalopathy and central vestibulopathy caused by mefloquine a case report. Travel Med Infect Dis 2012 10 144r-51. Nevin RL. Mefloquine gap junction blockade and risk of pregnancy loss. Biol Reprod 2012 87(3) 65,1-9. 

Standeven AM, Johnson AT, Escobar M, Chandraratna RAS (1996) Specific antagonist of retinoid toxicity in mice. Toxicol Appl Pharmacol 138 169-175... 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Future generations of such receptor subtype-selective retinoids or also retinobenzoic acids [3] may provide clinicians with more specific and less toxic diugs for dermatologic therapy. 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

High daily doses of retinoids can lead to hyper-vitaminosis A manifesting itself as dermal toxicity such as erythematous dermatitis, bone pains, neurological symptoms and hepatosplenomegaly. A recent study shows a correlation between low bone mineral density and too high intake of vitamin A. 

Attractive alternative to oral retinoid therapy in psoriasis (e.g., etretinate), primarily due to less toxicity. Structural changes to the basic retinoid structure (e.g., conformational rigidity) are claimed to enhance therapeutic efficacy and reduce the local toxicity associated with topical tretinoin (retinoic acid). However, place in therapy should await direct comparisons vs standard regimens in terms of efficacy, toxicity, and cost... 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

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. 

Fontan B, Bonafe JL, Moatti JP. Toxic effects of the aromatic retinoid etretinate. Arch Dermatol 1983 119(3) 187—8. 

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