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Neue nichtsteroidale Antirheumatika: Selektive Hemmstoffe der induzierbaren Cyclooxygenase

New non-steroidal anti-inflammatory drugs: Selective inhibitors of the inducible cyclooxygenase

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Zusammenfassung

□ Wirkungsweise der nichtsteroidalen Antirheumatika

Nichtsteroidale Antirheumatika (NSAR) üben ihre antiinflammatorischen, analgetischen und antipyretischen Wirkungen durch Hemmung der Prostanoidsynthese aus. Die typischen Nebenwirkungen der NSAR und deren Interaktionen mit Antihypertonika und Lithium sind ebenfalls durch diesen Wirkmechanismus bedingt. Erst 1990 wurde nachgewiesen, daß die physiologische Prostanoidsynthese durch eine konstitutive Cyclooxygenase (COX-1) katalysiert wird, während für die proinflammatorische Prostanoidsynthese ein anderes Isoenzym, die induzierbare Cyclooxygenase (COX-2), verantwortlich ist.

□ COX-2-selektive NSAR

Mit dieser Entdeckung entstand eine neue Strategie zur Vermeidung der NSAR-typischen Nebenwirkungen: Ein NSAR sollte möglichst selektiv die COX-2-vermittelte proinflammatorische Prostanoidsynthese hemmen, die COX-1-abhängige physiologische Prostanoidsynthese aber unbeeinflußt lassen. Bei erhaltener therapeutischer Wirksamkeit würde somit keine der typischen NSAR-Nebenwirkungen auftreten. Die Erfahrungen mit den herkömmlichen NSAR, welche um so ausgeprägtere Nebenwirkungen besitzen, je mehr sie die COX-1 hemmen, und Studien mit den COX-2-selektiven NSAR Disalicylsäure und Meloxicam, welche bei guter Wirksamkeit seltener zu gastrointestinalen und renalen Nebenwirkungen führen, belegen die Erfolgsaussichten dieser Strategie. Substanzen mit sehr hoher Selektivität für die COX-2 werden zur Zeit klinisch getestet.

□ Schlußfolgerung

Die bislang vorliegenden Ergebnisse unterstützen die Annahme, daß sich mit den selektiven und hochselektiven COX-2-Hemmstoffen die NSAR-typischen unerwünschten Wirkungen erheblich reduzieren lassen.

Abstract

□ Mode of Action of Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal antiinflammatory drugs (NSAID) exert their major therapeutic and adverse effects by inhibition of prostanoid synthesis. Also the interactions with antihypertensive drugs and lithium are caused by this mechanism of action. Cyclooxygenation is a key enzymatic step in the synthesis of prostanoids. 1990 2 isoforms of the enzyme cyclooxygenase have been identified: Prostanoids synthesized by the constitutive cyclooxygenase (COX-1) are involved in physiological homeostasis. In contrast, the inducible cyclooxygenase (COX-2) produces large amounts of prostanoids, mainly contributing to the pathophysiological process of inflammation.

□ COX-2 Selective NSAID

The discovery of the cyclooxgenase-isoenzymes ushered in a new generation of NSAID: A drug with selectivity for COX-2 would inhibit proinflammatory prostanoid synthesis while sparing physiologic prostanoid synthesis. Thus, a selective COX-2 inhibitor should be anti-inflammatory with less or no gastrointestinal or other NSAID-typical adverse effects. The experiences with currently used NSAID, which show an increasing incidence of side effects as COX-1 inhibition increases, and studies with the COX-2 selective NSAID salsalate and meloxicam, which have less adverse effects than nonselective COX inhibitors in equivalent antiphlogistic dosage, prove the concept of selective COX-2 inhibition to avoid the NSAID typical side effects. Newly developed drugs with a very high selectivity for COX-2 are now tested in clinical trials.

□ Conclusion

So far the results suggest, that selective and highly selective COX-2 inhibitors have significantly fewer gastrointestinal and renal adverse effects and do not inhibit platelet aggregation.

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Authors and Affiliations

  1. Institut für Klinische Pharmakologie, Medizinische Hochschule, D-30623, Hannover, Deutschland

    Dirk O. Stichtenoth & Jürgen C. Frölich

  2. Abteilung Rheumatologie der Medizinischen Hochschule Hannover, Hannover, Deutschland

    Henning Zeidler

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  1. Dirk O. Stichtenoth
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  2. Henning Zeidler
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  3. Jürgen C. Frölich
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Correspondence to Dirk O. Stichtenoth.

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Stichtenoth, D.O., Zeidler, H. & Frölich, J.C. Neue nichtsteroidale Antirheumatika: Selektive Hemmstoffe der induzierbaren Cyclooxygenase. Med Klin 93, 407–415 (1998). https://doi.org/10.1007/BF03042637

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