Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database

Abstract

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases

“…These findings suggest that concomitant PPI use should ameliorate CIPN associated with L-OHP in the clinical settings. Our findings are consistent with the results of a previous study using the FAERS database analysis and in vivo studies using mice (19).…”

“…However, it has been reported that the plasma concentration of L-OHP is not altered by OCT2 knockout in mice (23). In addition, omeprazole was reported to have no effect on the suppression of tumor growth by L-OHP in tumor-bearing mice (19). Accordingly, these findings suggest that loss of function or inhibition of OCT2 could have little impact on the pharmacokinetics and pharmacodynamics of L-OHP.…”

“…In addition to the on-target inhibition of H + /K + -ATPase, PPIs are known to have several off-target effects, including antioxidant and anti-inflammatory (16)(17)(18). A recent study reported that omeprazole, a PPI, suppressed L-OHP-induced CIPN in mice (19). Additionally, database analysis of the FDA Adverse Event Reporting System (FAERS) showed that PPIs, such as pantoprazole and rabeprazole significantly decreased the reporting odds ratio of L-OHP-induced CIPN (19).…”

“…A recent study reported that omeprazole, a PPI, suppressed L-OHP-induced CIPN in mice (19). Additionally, database analysis of the FDA Adverse Event Reporting System (FAERS) showed that PPIs, such as pantoprazole and rabeprazole significantly decreased the reporting odds ratio of L-OHP-induced CIPN (19). Hence, PPIs are promising practical prophylactic agents against L-OHP-induced CIPN.…”

Electroacupuncture ameliorates gastrointestinal dysfunction by modulating DMV cholinergic efferent signals to drive the vagus nerve in p-MCAO rats

“…Omeprazole was administered intraperitoneally at a dose of 20 mg/kg (MB1692, Meilunbio), in line with the dosages commonly used in animal experiments [ 24 , 25 ].…”