A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology

Abstract

SDZ ASM 981, a novel ascomycin macrolactam derivative, has high anti-inflammatory activity in animal models of allergic contact dermatitis and shows clinical efficacy in atopic dermatitis, allergic contact dermatitis and psoriasis, after topical application. Here we report on the in vitro activities of this promising new drug. SDZ ASM 981 inhibits the proliferation of human T cells after antigen-specific or non-specific stimulation. It downregulates the production of Th1 [interleukin (IL)-2, interferon-gamma] and Th2 (IL-4, IL-10) type cytokines after antigen-specific stimulation of a human T-helper cell clone isolated from the skin of an atopic dermatitis patient. SDZ ASM 981 inhibits the phorbol myristate acetate/phytohaemagglutinin-stimulated transcription of a reporter gene coupled to the human IL-2 promoter in the human T-cell line Jurkat and the IgE/antigen-mediated transcription of a reporter gene coupled to the human tumour necrosis factor (TNF)-alpha promoter in the murine mast-cell line CPII. It does not, however, affect the human TNF-alpha promoter controlled transcription of a reporter gene in a murine dendritic cell line (DC18 RGA) after stimulation via the FcgammaRIII receptor. SDZ ASM 981 also prevents the release of preformed pro-inflammatory mediators from mast cells, as shown in the murine cell line CPII after stimulation with IgE/antigen. In summary, these results demonstrate that SDZ ASM 981 is a specific inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro.

Safety and Tolerability of 1% Pimecrolimus Cream Among Infants: Experience With 1133 Patients Treated for Up to 2 Years

“…20,27,[30][31][32]44 The favorable safety and tolerability profile of 1% pimecrolimus cream demonstrated in published pediatric studies 35,[37][38][39]43,44 is supported by the data summarized in this review. The combined analysis of the results from 4 pharmacokinetic studies conducted with 35 infants with AD indicated that pimecrolimus blood concentrations after topical applications were consistently low, irrespective of the level of disease severity and percentage of TBSA involved.…”

“…The major concern with the use of 1% pimecrolimus cream is the fact that calcineurin inhibitors have immunosuppressive properties when administered systemically at high doses, although the immunosuppressive effects of systemically administered pimecrolimus are lower than those demonstrated with other drugs of the same class. 21 Therefore, it is important to confirm the preclinical and clinical data 20,26,[30][31][32] indicating that topical applications of pimecrolimus are associated with minimal systemic absorption and do not lead to adverse experiences attributable to its immunosuppressive potential. This issue should be addressed particularly among infants, because the risk of systemic absorption of topical drugs for these individuals is higher than that for older children and adults.…”

“…[16][17][18] One percent pimecrolimus cream (Elidel, SDZ ASM 981; Novartis Pharma AG, Basel, Switzerland) is a topical calcineurin inhibitor that blocks the transcription and release of inflammatory cytokines and mediators that are produced by T lymphocytes and mast cells and are involved in the pathogenesis of AD and other inflammatory skin disorders. 19,20 It does not interfere with the differentiation, maturation, and function of cells involved in immunosurveillance, specifically dendritic cells/Langerhans cells. [21][22][23][24][25] Pimecrolimus cream has demonstrated a much lower potential for percutaneous absorption than TCSs, because of its higher molecular weight and lipophilicity.…”

Calcineurin inhibitors in the treatment of allergic dermatitis

“…A maior parte dos pacientes apresentava DA leve e moderada e os resultados apontaram redução de intensidade da lesão, diminuição do prurido e, a longo prazo, diminuição do número e intensidade de novas crises. Há estudos em lactentes entre 3 e 23 meses que revelaram os mesmos benefícios encontrados em crianças maiores [26][27][28] 29 . Uma particularidade dos inibidores de calcineurina é sua especial eficácia em pescoço e face, sendo esta última uma região de risco para a utilização de corticoterapia tópica 30 .…”

“…A freqüência de prurido no local da aplicação por vezes não superou os achados observados nos pacientes que utilizavam apenas o veículo. Entretanto, em comparação à corticoterapia, o ardor e o prurido observados foram maiores nos pacientes que utilizavam tacrolimo [26][27][28][29][30][31][32][33][34] .…”