Low Direct Cytotoxicity of Loxoprofen on Gastric Mucosal Cells

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, are a useful family of therapeutics.1) An inhibitory effect of NSAIDs on cyclooxygenase (COX) activity is responsible for their anti-inflammatory actions because COX is an enzyme essential for the synthesis of prostaglandins (PGs), such as PGE 2 , which have a strong capacity to induce inflammation. On the other hand, NSAID use is associated with gastrointestinal complications. [2][3][4] In 1991, two subtypes of COX, COX-1 and COX-2, which are responsible for the majority of COX activity at the gastrointestinal mucosa and in tissues with inflammation, respectively, were identified. 5,6) Since PGE 2 has a strong protective effect on the gastrointestinal mucosa, it is reasonable to speculate that selective COX-2 inhibitors maintain anti-inflammatory activity without gastrointestinal side-effects. In fact, a greatly reduced incidence of gastroduodenal lesions has been reported for selective COX-2 inhibitors (such as celecoxib and rofecoxib).7-9) However, a recently raised issue concerning the use of selective COX-2 inhibitors is their potential risk for cardiovascular thrombotic events. 10,11) This may be due to the fact that prostacyclin, a potent antiaggregator of platelets and a vasodilator, is mainly produced by COX-2 in vascular endothelial cells, while thromboxane A 2 , a potent aggregator of platelets and a vasoconstrictor, is mainly produced by COX-1 in platelets. [12][13][14] Because of this concern, rofecoxib was withdrawn from the worldwide market. Therefore, NSAIDs exhibiting gastrointestinal safety, other than selective COX-2 inhibitors, are clinically important.The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side-effects of NSAIDs.15) We have recently demonstrated that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and at gastric mucosa in a manner independent of COX inhibition. [16][17][18][19][20] We clearly showed that the primary target of NSAIDs for induction of necrosis and apoptosis is cytoplasmic membranes. 16,18) As for the molecular mechanism governing this apoptosis, we have proposed the following pathway. Permeabilization of cytoplasmic membranes by NSAIDs stimulates Ca 2ϩ influx and increases intracellular Ca 2ϩ levels, which in turn induces the endoplasmic reticulum (ER) stress response. 16,21,22) In this response, an apoptosis-inducing transcription factor, CCAAT/enhancer-binding protein (C/EBP) homologous transcription factor (CHOP), is induced and CHOP induces expression of p53 up-regulated modulator of apoptosis (PUMA) and resulting translocation and activation of Bax, mitochondrial dysfunction, activation of caspases and apoptosis.17,23) Furthermore, we have suggested that both COX inhibition and gastric mucosal cell death are required for the formation of NSAID-induced gastric lesions in vivo. 20,24) Loxoprofen has been used clinically for a long time as a standard NSAID in Japan, and clinical studies have suggested that it is safer than other NSAIDs, s...

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

“…4, 5) is needed to achieve this prevention. The results support the previously reports showing that loxoprofen has relatively lower membrane permeabilization activities and cytotoxic effects on gastric mucosal cells than other NSAIDs, [21][22][23] since the gastric lesion score and concentration of Mg 2+ to prevent loxoprofen-induced gastric lesions in AA rats are lower than those of indomethacin. 24) In addition, we have demonstrated the effect of magnesium ion on loxoprofen absorption in AA rats.…”

“…Loxoprofen is a pro-drug that is converted (by reduction of the cyclopentanone moiety) to its active metabolite (the trans-alcohol metabolite of loxoprofen) by aromatic aldehyde-ketone reductase only after absorption into the gastrointestinal tract, 20) and loxoprofen has relatively lower membrane permeabilization activities and cytotoxic effects on gastric mucosal cells than other NSAIDs. 21) Based on these findings, loxoprofen is suggested to be safer than other NSAIDs, such as indomethacin. 22,23) However, even loxoprofen causes gastroenteropathy as a clinical side effect.…”

Design of a Multicenter, Randomized, Open Label, Parallel Group Study to Evaluate the Efficacy of Loxoprofen on Acute-Phase Reactions in Japanese Primary Osteoporosis Patients Treated with Zoledronic Acid

“…In Japan, osteoporosis is usually treated by medical practitioners of orthopaedic surgery. Many patients visit them for pain as a primary physical complaint, and therefore are very often prescribed with antipyretic analgesics, especially loxoprofen, which is the most frequently prescribed drug in Japan [8,9]. If this study proves that loxoprofen reduces the incidence and severity of APRs, like ibuprofen, the majority of patients will not need an additional prescription for loxoprofen, because the likelihood is high that their orthopaedic surgeons have already prescribed loxoprofen at the initial visit.…”

“…Compared to other NSAIDs, such as indomethacin and celecoxib, loxoprofen showed less membrane permeability and low direct cytotoxicity, and therefore lower incidence of NSAIDs-induced gastroenteropathy [8]. Loxoprofen is also the NSAID most often prescribed by orthopedists in Japan [9].…”

Synthesis and biological evaluation of loxoprofen derivatives

“…23 We recently reported that loxoprofen has lower membrane permeabilization activity than other NSAIDs. 24 Therefore, synthetic modification of loxoprofen to either increase specificity for COX-2 or decrease membrane permeabilization activity is a valuable strategy to obtain safer NSAIDs.…”