Development of GI-safe NSAID; progression from the bark of willow tree to modern pharmacology

• Ancient Sumerians used willow tree bark for pain and fever, developed to aspirin.
• Advanced exploration of NSAID-induced cytotoxicity led to the introduction of COXIBs.
• Further developments of NO-NSAIDs, H2S-NSAIDs, zinc-NSAIDs, and phosphatidylcholine-NSAIDs are active.
• n-3 PUFA, glucosamine, chloroquine, P-CAB, and probiotics-NSAIDs warrant GI safety.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for analgesic, anti-inflammatory and antithrombotic actions and recently for cancer prevention, but they carries a risk of major gastroduodenal damages from symptomatic ulcers to serious complications leading to fatal outcomes. Therefore, the novel strategies to rescue long-term NSAID requiring patients from NSAID-associated gastroduodenal damages are essential. Besides of current drugs based on classic damaging mechanisms attributable to the decline of gastric mucosal prostaglandin synthesis, reductions of mucosal blood flow, attenuated bicarbonate secretion and mucus synthesis related with prostaglandin levels, effective therapeutics targeted for update mechanisms of NSAID-induced gastroduodenal damages are introduced in this paper based on recent advances in basic science and biotechnology exploring deeper molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX inhibition.