Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups. Copyright 2005 Massachusetts Medical Society.

Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies. Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5 g ascorbic acid/kg body weight three times weekly. Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response. High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.

Evidence suggests that low vitamin D status may increase the risk of cancer.