Indometacin

UV Erythema Reducing Capacity of Mizolastine Compared to Acetylsalicylic Acid or both Combined in Comparison to Indomethacin^(paragraph)

ABSTRACT

UV light exerts hazardous effects such as induction of skin cancer and premature skin aging. In this study we evaluated an assumptive anti-inflammatory effect of the nonsedative histamine H1-receptor antagonist, mizolastine, on UV-induced acute sunburn reaction. Therefore, a clinical, randomized, double-blind, four-arm, crossover study was conducted in healthy young female volunteers (skin type II) comparing the UV sensitivity under mizolastine, acetyl-salicylic acid (ASA), indomethacin or a mizolastine/ASA combination. Moreover, HaCaT keratinocytes were incubated with mizolastine under various UV treatment modalities in vitro to study its effect on the release of inflammatory cytokines, ie. interleukin (IL)-- 1alpha, IL-6 and tumor necrosis factor alpha (TNF-alpha). All three drugs were effective in suppressing the UVB-, UVA- and combined UVA/UVB-erythema. However, the strongest effects were observed using the combined treatment with both 250 mg ASA and 10 mg mizolastine. An inhibitory effect in vitro of 10 nM mizolastine upon UV-induced cytokine release from HaCaT keratinocytes was observed for IL-1alpha at 24 h after 10 J/cm^sup 2^ UVA1, for IL-6 at 48 h after 10 J/cm^sup 2^ UVA1 and 30 mJ/cm^sup 2^ UVB, and also for TNF-alpha at 4 h after 10 J/cm^sup 2^ UVA, 10 J/cm^sup 2^ UVA1 and 30 mJ/cm^sup 2^ UVB, respectively. The combination of mizolastine and ASA can be strongly recommended as a protective measure against UV erythema development with a lower unwanted side effect profile than that of the hitherto treatment modality, ie. indomethacin.

^^Abbreviations: ASA, acetyl-salicylic acid; CIELAB, Commission International de l'Eclairage; COX, cyclooxygenase; IL, interleukin; LO, lipoxygenase; MED, minimal erythema dose; NSAID, nonsteroidal antiphlogistic drugs; PMNL polymorphonuclear neutrophils; TNF-alpha, tumor necrosis factor alpha.

It is a well-known fact that UVB irradiation, in particular, leads to a visible erythema as local sign of inflammation by turning on the arachidonic acid cascade. There is strong evidence that prostaglandins, in particular, mainly of the E series are involved in this inflammatory process. Indomethacin applied systemically after an erythematogenic dose of UVB light suppresses the development of erythema by the inhibition of the prostaglandin synthesis cascade (40,41). In addition, the topical application of indomethacin prior to UV exposure in humans in vivo was shown to act as a potent UVB and UVA photoabsorption filter (23).

In the case where an unwanted situation of sunburn has occurred it is known that the course of development can be slowed down by administration of COX inhibitors during the first hours such as indometacin or high dose of ASA. Given the fact that leukotriens are also involved in the arachidonic cascade we raised the question if the combination of ASA plus an anti-inflammatory LO pathway inhibiting antihistamine of the mizolastine type could influence the course of erythema development. Knowing that I MED produces only a visible erythema and this is apparently not strong enough for the differentiation of the anti-inflammatory potency of drugs we used a higher UV dose of 2X MED, which significantly increased the inflammatory response.

The ASA- or indomethacin-dependent, in contrast to the mizolastine monotherapy-dependent, decrease of (delta)a on UVB-irradiated skin compared to control skin of the same individuum has to be related to the fact that the NSAID inhibit the COX pathway (41-43) but the latter drug has an inhibitory effect on the 5-LO pathway (19).

In our study ASA, indomethacin and mizolastine all together were able to decrease the inflammatory response in the UV ranges selected (UVB, UVA/UVB, UVA). Among these three given drugs indomethacin as a single agent showed no difference compared to mizolastine plus ASA in the UVA[UVB range. Our hypothesis that mizolastine in combination with ASA could be additive in its anti-inflammatory suppressive efficacy was confirmed by our results showing that 10 mg mizolastine plus 250 mg ASA was as effective or even more effective than indomethacin in the UVB range.

In order to contribute to the further clarification of the mode of action of mizolastine in preventing UV-induced inflammation we studied the drug's effect in an in vitro system using HaCaT keratinocytes as a model for the epidermal compartment which is the primary physical tissue target of any UV irradiation. Under the chosen conditions we could demonstrate that mizolastine in the nanomolar dose range was able to reduce substantially the release of IL-1alpha induced by UVA1 and the release of TNF-alpha induced by UVA, UVA1 or UVB, respectively. This indicates that the anti-inflammatory efficacy of mizolastine may be explained partly by a protection of the keratinocyte layer as the upper most living skin component against UV damage resulting in a diminished release of proinflammatory cytokines from the epidermis into the dermo-vascular micromilieu.

Taken together, the clinical in vivo and experimental in vitro results revealed that a highly significant suppression of UVB-induced erythema response by the combination of mizolastine plus ASA was most probably based on the additional inhibition of the leukotriene pathway accompanied by the prevention of an epidermal release of proinflammatory cytokines.

From our data we thus finally draw the conclusion that the combination of oral doses of 10 mg mizolastine and 250 mg ASA induces additive or synergistic UV-protective processes which might be important for future therapeutic recommendations to achieve an immediate suppression of the early phase of UV-induced erythema. This drug combination may be of interest for forthcoming studies seeking to develop pharmacological prevention strategies against chronic long-term UV skin damage.

Acknowledgements-HaCaT keratinocytes were kindly provided by Prof. Dr. N. E. Fusenig (German Cancer Research Center, Heidelberg, Germany). The technical assistance of Mrs. R. Adolf is gratefully appreciated.

(paragraph)Posted on the website on 10 August 2001.

^Some of the material was presented at the 30th Annual Meeting of the European Society for Dermatological Research, 21-23 September 2000, Berlin, Germany, and at the 9th Congress of the European Academy of Dermatology & Venereology, 11-15 October 2000, Geneva, Switzerland.

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Jens-Uwe Grundmann*, Raik Bockelmann, Bernd Bonnekoh and Harald P. M. Gollnick

Department of Dermatology and Venereology, Otto-von-Guericke-University, Magdeburg, Germany

Received 25 January 2001; accepted 6 July 2001

* To whom correspondence should be addressed at: Department of Dermatology and Venereology, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg, Germany. Fax: 49-391-67-15283; e-mail: jens-uwe.grundmann@medizin.uni-magdeburg.de

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