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

(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.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS).

PURPOSE: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. METHODS: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. RESULTS: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. CONCLUSIONS: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome.

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65-0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.

Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro.

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.