Tacrolimus and the Pigmentary System

Taı̈eb, Alain

doi:10.1159/000083504

Cited by 6 publications

(5 citation statements)

References 8 publications

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“…Inhibition by the Cn inhibitors as measured in the different cell types seems to be relevant for clinical practice. For example, the concentrations of CsA in epidermis after oral administration of the drug has been reported to vary between 0.8 and 2.5 mM (Fisher et al, 1988;Taieb, 2005). This is about 1,000 Â higher than the IC 50 values for CsA that we measured (Table 2).…”

Section: Discussioncontrasting

confidence: 62%

“…Cn activity has been demonstrated before in cultured lung fibroblasts with an assay using 32 P-radiolabeled substrate and the activity could be inhibited by CsA (Chen et al, 2003). A role for Cn in melanocytes is suggested, as CsA was shown to decrease pigmentation in cultured human melanocytes, and Cn inhibitors are used topically for treatment of vitiligo (Lee and Kang, 2003;Taieb, 2005). The Cn inhibitors CsA, Trl, and pimecrolimus (Prl) are also used for the treatment of other dermatological diseases, such as psoriasis and atopic eczema (Griffiths, 2001;Reynolds and Al Daraji, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Calcineurin Activity and Inhibition in Skin and (Epi)Dermal Cell Cultures

Smit

Rossum

Romijn

et al. 2008

Journal of Investigative Dermatology

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Calcineurin (Cn) is the target of the immunosuppressive drugs cyclosporine A (CsA), tacrolimus (Trl), and pimecrolimus (Prl). Trl and Prl are often used topically for treatment of various skin diseases. The Cn inhibitors CsA and Trl are mostly used for maintenance therapy of transplant patients. Their long-term use, however, causes a dramatic increase in skin cancer risk. By using a newly developed assay for Cn measurement in blood, we were able to demonstrate Cn activity in total skin homogenates. A significantly higher activity was found in epidermis compared to dermis. In skin cell cultures, fibroblasts showed the highest activity as compared to keratinocytes and melanocytes. Of the Cn inhibitors, Trl showed stronger inhibition than CsA and Prl (57 and 55% in fibroblast and keratinocyte cultures, respectively). Also, the lowest IC(50) (the half maximal inhibitory concentration) values were found for Trl (0.5 and 1.3 nM in two different fibroblast cultures). Cn activity and its inhibition can thus be studied in dermatological samples. The effects of Cn inhibition in fibroblasts and keratinocytes may be of influence on the overall functioning of the skin immune system.

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Section: Discussioncontrasting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Calcineurin Activity and Inhibition in Skin and (Epi)Dermal Cell Cultures

Smit

Rossum

Romijn

et al. 2008

Journal of Investigative Dermatology

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“…We observed the same during a treatment pause in our previous murine study with tacrolimus (13). Little is known concerning the effect of calcineurin inhibitors on melanocytes (28). The mechanism for the increased stability of the pigmentation is unclear but it has been shown in an in vitro study that tacrolimus increased the pigmentation in human melanocytes (29).…”

Section: Discussionmentioning

confidence: 99%

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

Lerche

Philipsen

Poulsen³

et al. 2009

Experimental Dermatology

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Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.

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“…The mice treated with tacrolimus without SSR radiation did not develop pigmentation. Little is known concerning the effect of calcineurin inhibitors on melanocytes (29). The mechanism for the increased stability of the pigmentation is unclear, but Kang and Choi showed in an in vitro study that tacrolimus increased the pigmentation in human melanocytes (30).…”

Section: Discussionmentioning

confidence: 99%

Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice

Lerche

Philipsen

Poulsen

et al. 2007

Experimental Dermatology

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Numerous studies have demonstrated the utility of topical tacrolimus ointment in atopic dermatitis. However, there is a concern that local immunosuppression by calcineurin inhibitors may enhance dermal photocarcinogenesis and carcinogenesis. Therefore, we investigated the influence of topical tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses, SED) 3-4 h later. Tacrolimus did not reduce the time to tumor development and in the group receiving 4 SED it even had a protective effect (156 days vs 170 days, P = 0.008). In a second experiment, mice (n = 50) were irradiated with 6 SED three times weekly for 3 months and subsequently treated five times weekly with topical tacrolimus to mimic the use of tacrolimus on sun-damaged skin. The median time to the first skin tumor was 234 days in SSR + tacrolimus group compared with 227 days in the only SSR-irradiated group (P = 0.160). In a third experiment, mice (n = 25) had tacrolimus applied on their dorsal skin every day for 1 month, thereafter the group was irradiated with 4 SED three times weekly. The median time to the first skin tumor was 142 days in tacrolimus + SSR group compared with 156 days in the only SSR-irradiated group from experiment 1 (P = 0.363). We conclude that tacrolimus ointment does not accelerate photocarcinogenesis or induce any dermal carcinogenicity in hairless mice.

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Tacrolimus and the Pigmentary System

Cited by 6 publications

References 8 publications

Calcineurin Activity and Inhibition in Skin and (Epi)Dermal Cell Cultures

Calcineurin Activity and Inhibition in Skin and (Epi)Dermal Cell Cultures

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice

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