Objective : To examine whether concomitant oral administration of febuxostat, a xanthine dehydrogenase/xanthine oxidase inhibitor, and inosine augments ATP in human blood.
Methods: We performed Stage 1, Stage 2 and Stage 3 studies. In Stage 1 study, one adult healthy male was administered febuxostat 40 mg/day and inosine 1 g/day for 14 days to examine the safety of the combined therapy. In Stage 2, 21 healthy male adults were allocated to groups A-G, each with 3 subjects, and were treated with febuxostat alone, inosine alone or both for 14 days. In Stage 3, febuxostat 40 mg/day and inosine 1 g/day were administered to 5 healthy adult males for 14 days. Purine compounds in blood were compared between before and after the treatments in Stage 2 and Stage 3.
Results: Combined use of febuxostat and inosine was relatively safe at doses of febuxostat 60 mg/day and inosine 3 g/day or less in a 2 week continuous treatment. Serum uric acid levels were markedly decreased by administration of febuxostat alone, and increased by the administration of inosine alone, but milder decreases were seen in combination therapy compared with febuxostat alone. In Stage 2, concomitant treatment with febuxostat 40 mg/day and inosine 1-2 g/day increased blood hypoxanthine and ATP, no increase occurred with inosine alone, and febuxostat alone slightly increased those values at the higher dose (60 mg/day). Increase in ATP in blood was confirmed by the results of Stage 3 where concomitant use of febuxostat 40 mg/day and inosine 1 g/day increased ATP by 13.8% (P = 0.031).
Conclusions: Concomitant oral administration of febuxostat 40 mg/day and inosine 1-2 g/day was shown to safely increase blood ATP. Since cellular ATP deficiency may be involved in various disorders, the present method may be useful for the treatment of those disorders.
Tumor lysis syndrome (TLS) is a life-threatening complication caused by the massive death of cancer cells upon chemotherapy. Lowering serum uric acid (S-UA) levels is crucial to controlling TLS. Febuxostat was approved for use in treating chemotherapy-associated hyperuricemia in May 2016. Rasburicase and febuxostat are now the major UA-reducing agents; the former for high risk, the latter for intermediate risk. The present study retrospectively evaluated the efficacy of rasburicase in cancer patients in our institution after the approval of febuxostat of this use (June 2016 - January 2017). The primary endpoint was the normalization of S-UA at the end of rasburicase administration. Rasburicase was used in 12 patients with hematological malignancies in the designated period. Eight patients were at high risk of TLS, while 2 patients had already developed TLS. The median dose administered was 0.2 mg/kg, and the median duration was 5 days. The S-UA at the baseline (10.4±3.0 mg/dL, mean±SD) was decreased below the normal levels in all patients (0.3±0.2 mg/dL) (P<0.0001, by paired t test). Serum creatinine levels also decreased from 1.2±0.4 to 0.8±0.2 mg/dL (P=0.0001, by paired t test), suggesting that controlling UA might potentially improve the renal function. Not all patients demonstrated a concomitant reduction in lactate dehydrogenase levels, which suggested that S-UA was successfully controlled by rasburicase despite the residual amount of cancer cells. Thus, rasburicase was successfully used for appropriate patients after the febuxostat era.