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Aktuelle Dermatologie 2003; 29(10): 419-425
DOI: 10.1055/s-2003-43493
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Leukotrienantagonisten bei atopischen Erkrankungen und Akne

Leukotriene Antagonists in Atopic Diseases and AcneCh.  C.  Zouboulis1
  • 1Klinik und Poliklinik für Dermatologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin
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Publikationsdatum:
07. November 2003 (online)

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Zusammenfassung

Leukotriene, Produkte des Arachidonsäurestoffwechsels, spielen eine zentrale Rolle bei der Entwicklung entzündlicher Prozesse. Durch die katalytische Wirkung der 5-Lipoxygenase entstehen Leukotrien-B4, eine stark chemoattraktive Substanz, und die Entzündungsmediatoren Cysteinyl-Leukotriene C4, D4 und E4. Leukotriene binden sich an spezifische G-Protein-gebundene Rezeptoren, nämlich den hochaffinen, Leukotrien-B4-spezifischen B-LT1-Rezeptor der Leukozyten, den Leukotrien-B4-spezifischen B-LT2-Rezeptor mit breiter Gewebeverteilung und niedriger Affinität, den LTC4- und LTD4-spezifischen Cysteinyl-LT1-Rezeptor bei glatten Muskelzellen und Endothelzellen postkapillärer Venolen und den Cysteinyl-LT2-Rezeptor bei Gehirn, Milz, Purkinje-Herzfibern und Nebennierenrinde. Darüber hinaus sind bestimmte Leukotriene Liganden der Peroxisomproliferation-aktivierenden Rezeptoren (PPAR). Die Entdeckung des Wirkmechanismus der Leukotriene führte zur Entwicklung von Wirkstoffen, die Schlüsselschritte des 5-Lipoxygenase-Synthesewegs beeinflussen, nämlich 5-Lipoxygenase-Inhibitoren, B-LT2-Rezeptor-Antagonisten, FLAP-Inhibitoren und Cysteinyl-LT1-Rezeptorblocker. Ihre Wirkung wurde auf verschiedene entzündliche und/oder hyperproliferative Hautkrankheiten untersucht. Der Einsatz der Leukotrienantagonisten bei atopischen Erkrankungen und bei der Akne ist der Gegenstand dieser Übersicht. Niedrig dosierte inhalative Glukokortikoide (äquivalent zu 400 µg/d Beclometason) scheinen in der Behandlung von mildem bis mäßigem Asthma bei Erwachsenen effektiver als Leukotrienantagonisten zu sein. Für die Behandlung des kindlichen Asthmas liegen keine ausreichenden Daten vor. Die Zugabe von Leukotrienantagonisten zu inhalativen Glukokortikoiden kann ein Asthma bronchiale in bescheidenem Ausmaß bessern, jedoch ist sie nicht geeignet, um Glukokortikoide einzusparen. Bei der allergischen Rhinitis/Rhinokonjunktivitis sind Leukotrienantagonisten vergleichbar wirksam wie die nichtsedierenden Antihistaminika und weniger wirksam als intranasale Glukokortikoide. Die Kombination eines Leukotrienantagonisten und eines Antihistaminikums ist nicht wirksamer als eine der beiden Substanzen allein. Die Datenlage der Therapie der atopischen Dermatitis mit Leukotrienantagonisten ist noch schwach, allerdings zeigt sich wie bei den anderen Erkrankungen des Atopiekreises eine mäßige aber signifikante Besserung der Erkrankung im Vergleich zu Plazebo. Die systemische Therapie der Akne mit Leukotrienantagonisten ist diesen Substanzen vorbehalten, die gleichzeitig PPAR-Liganden sind. Besonders geeignet sind 5-Lipoxygenase-Inhibitoren/PPARα-Liganden, z. B. Zileuton, die zur Abnahme der gesamten Talglipide und der pro-inflammatorischen Lipidfraktionen sowie zur signifikanten Reduktion der entzündlichen Akneläsionen führen.

Abstract

Leukotrienes, which are products of arachidonic acid metabolism, play a central role in the development of inflammatory processes. The catalytic activity of 5-lipoxygenase leads to the production of the potent chemoattractant leukotriene B4, and the inflammatory mediators cysteinyl leukotrienes C4, D4 and E4. Leukotrienes bind to specific receptors with a G protein structure, namely the highly affine leukotriene B4-specific leukocyte B-LT1 receptor, the leukotriene B4-specific B-LT2 receptor with wide tissue distribution and low affinity, the LTC4- and LTD4-specific cysteinyl LT1 receptor of smooth muscles and endothelial cells of postcapillary venules, and the cysteinyl LT2 receptor in brain, spleen, Purkinje heart fibers, and suprarenal cortex. Moreover, certain leukotrienes are ligands of peroxisome proliferator activated receptors (PPAR). The identification of the mechanisms of leukotriene activity resulted in the development of actives, which affect key steps of 5-lipoxygenase synthesis, namely 5-lipoxygenase inhibitors, B-LT2 receptor antagonists, FLAP inhibitors and cysteinyl-LT1 receptor blockers. Their activity was studied on several inflammatory and/or hyperproliferative skin diseases. The administration of leukotriene antagonists in atopic diseases and acne is reported in this review. Low-dose inhalative glucocorticoids (400 µg/d beclometasone equivalent) have been shown to be more effective than leukotriene antagonists in the treatment of mild to moderate asthma in elderly. On the other hand, no sufficient data exist regarding the treatment of asthma in children. The addition of leukotriene antagonists to inhalative glucocorticoids is associated with a moderate improvement of bronchial asthma, however, it cannot lead to reduction of the glucocorticoid dosis. In allergic rhinitis/rhinoconjunctivitis, leukotriene antagonists are as active as nonsedative antihistaminics and less active than intranasal glucocorticoids. The combination leukotriene antagonist/antihistaminic compound is not more active than the single substances alone. There are still few data on the treatment of atopic dermatitis with leukotriene antagonists, however, the existing findings already indicate a small but significant improvement of the disease in comparison with placebo, like in all atopic diseases. The systemic treatment of acne with leukotriene antagonists can be performed with such compounds that are also PPAR ligands. 5-lipoxygenase inhibitors/PPAR α ligands, i. e. Zileuton, are especially adequate, since they reduce synthesis of total sebaceous lipids and of those lipid fractions with pro-inflammatory activity and they lead to significant reduction of inflammatory acne lesions.

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Prof. Dr. med. Ch. C. Zouboulis

Klinik und Poliklinik für Dermatologie · Universitätsklinikum Benjamin Franklin ·

Freie Universität Berlin · Fabeckstraße 60 - 62 · 14195 Berlin ·

eMail: zouboulis@medizin.fu-berlin.de