Leukotrienantagonisten bei atopischen Erkrankungen und Akne

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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