Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Abstract

The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis

“…Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) 4A mainly metabolized arachidonic acid (AA) to prostaglandin E 2 (PGE 2 ), leukotriene B 4 (LTB 4 ), and 20‐hydroxyeicosatetraenoic acid (20‐HETE), respectively . These eicosanoids are key proinflammatory mediators of the inflammatory cascade . PGE 2 and LTB 4 contribute to IL‐1β production, and are thought to be important mediators in gout attack .…”

Complex roles of the old drug aspirin in cancer chemoprevention and therapy

“…NO‐releasing aspirin is another ester derivative of aspirin. NO is an endogenous gasotransmitter that is involved in various physiological processes including protection of gastrointestinal integrity and cardiovascular system . NO‐aspirin is synthesized by covalent linking aspirin to a spacer that, in turn, is associated with a NO‐releasing moiety .…”

“…NO is an endogenous gasotransmitter that is involved in various physiological processes including protection of gastrointestinal integrity and cardiovascular system . NO‐aspirin is synthesized by covalent linking aspirin to a spacer that, in turn, is associated with a NO‐releasing moiety . Upon releasing from the aspirin prodrug, NO is able to prevent gastric mucosa damage by increasing mucous secretion, mucosal hemodynamics, and reducing aggregation of neutrophils to gastric mucosa .…”

Use of anti-inflammatory analgesics in sickle-cell disease

“…Phosphatidylcholine was conjugated with NSAIDs to improve the GI safety, and chemical moieties that release protective mediators such as nitric oxide was structurally linked to NSAIDs to attenuate GI and cardiovascular toxicities, and this area of research has shown some promise. 70 …”