Fumaric acid esters

Diels-Alder reactions of the type shown in Table 15.1, that is, Diels-Alder reactions between electron-poor dienophiles and electron-rich dienes, are referred to as Diels-Alder reactions with normal electron demand. The overwhelming majority of known Diels-Alder reactions exhibit such a normal electron demand. Typical dienophiles include acrolein, methyl vinyl ketone, acrylic acid esters, acrylonitrile, fumaric acid esters (irans-butenedioic... 

Vinyls, finyl esters are usually used in waterborne coatings in the form of copolymer dispersions. Typical vinyl esters are vinyl acetate, vinyl propionate, vinyl laurate, and vinyl versatate. Acrylic, maleic, and fumaric acid esters are used as copolymers, finyl acetate is lower in cost compared to (meth) acrylic esters. Although vinyl acetate coatings are inferior to acrylics in both photochemical stability and resistance to hydrolysis, this does not prevent them from being used for exterior... 

In 83 patients with severe psoriasis vulgaris, the fumaric acid ester formulations Fumaderm initial and Fumaderm caused adverse effects in 62%, mainly flushing and gastrointestinal complaints, which decreased in frequency during the course of the study (6). 

In 66 patients with severe psoriasis who took fumaric acid esters for up to 14 years, there were adverse events in 73%, usually mild and mainly consisting of flushing (55%), diarrhea (42%), nausea (14%), tiredness (14%), and stomach complaints (12%) (8). There was a relative lymphocytopenia in 76%, resulting in permanent withdrawal in four patients. There were transient eosinophUia in 14%, and moderate Uver enzyme rises were observed in 25%. 

Fumaric acid esters are used to treat a variety of skin disorders, including psoriasis (1), cutaneous sarcoidosis (2), necrobiosis lipoidica diabeticorum (3), and disseminated granuloma annulare (4). 

Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters results of a prospective multicentre study. German Multicentre Study. Br J Dermatol 1998 138(3) 456-60. 

Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol 2003 149(2) 363-9. 

Ducker P, Pfeiff B. Zwei Falle von Nebenwirkungen einer Fumarsaureester—Lokaltherapie. [Two cases of side effects of a fumaric acid ester—local therapy.] Z Hautkr 1990 65(8) 734-6. 

Deegan AP, Kirby B, Rogers S, Grotty TB, McDonnell TJ. Organising pneumonia associated with fumaric acid ester treatment for psoriasis. Clin Respir J 2010 4(4) 248-51. 

Tumorigenicity Fumaric acid esters have been used in the treatment of psoriasis since 1959, after Schweckendiek s description. They induce a shift from the T-helper 1 (Th-1) cytokine response to a Th-2 cytokine response and subsequent lymphopenia with low CD3 and CD4 counts. Low CD4 counts reflect the degree of immunosuppression and, in organ transplant recipients increase the risk of skin cancers, such as squamous cell carcinoma [25 ]. 

This patient had had high UV exposure over his lifetime, including both PUVA and sunhght, which would have put him at high risk of skin cancer. In addition, he had lymphopenia and a reduction in CD subsets after taking a fumaric acid ester, resulting in profound immunosuppression. 

Jennings L, Murphy GM. Squamous cell carcinoma as a complication of fumaric acid ester immunosuppression. J Eur Acad Dermatol Venereol 2009 23(12) 1445-69. 

Reich K, Thad D, Mrowietz U, Kamps A, Neureither M, Luger T (2009) Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis a retrospective study (FUTURE). J Dtsch Dermatol Ges 7(7) 603-611... 

AUopurinol (50), isotretinion (51), fumaric acid esters (52), mycophenolate mofetil (53), and Tranilast (54) have been reported to be effective for sarcoidal skin disease. Resolution of sarcoidal skin lesions has occurred after radiation therapy (55), ultraviolet A1 therapy (56), phototherapy, and photodynamic therapy (57). 

Georgiou S, Monastirli A, Pasmatzi E, et al. Cutaneous sarcoidosis complete remission after oral isotretinoin therapy. Acta Derm Venereol 1998 78 457-459. Breuer K, Gutzmer R, Voelker B, et al. Therapy of noninfectious granulomatous skin diseases with fumaric acid esters. Br J Dermatol 2005 152 1290-1295. Kouba DJ, Mimouni D, Rencic A, et al. Mucocutaneous sarcoidosis treated with mycophenolate mofetil. Br J Dermatol 2003 149 442-443. 

Achiwa, K. Homogeneous Catalytic Asymmetric Hydrogenation of (Z)-2-Aceta-mido-3-methyI-fumaric Acid Ester, a Tetrasubstituted Olefin. Tetrahedron Letters 1978, 2583. 

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