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Abstract-Increased production of superoxide anion may contribute to impaired bioactivity of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of scavenging superoxide anion; however, experimental studies have shown that high physiological concentrations (Ͼ1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated vascular dysfunction. To seek kinetic evidence that superoxide anion contributes to endothelial vasomotor dysfunction in human hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra-arterial infusions on forearm blood flow responses to methacholine or sodium nitroprusside in 30 patients with hypertension and 22 age-matched controls. Endothelium-dependent vasodilation to methacholine was significantly impaired in the hypertensive patients, with a response to the highest dose of methacholine (10 g/min) of 12.3Ϯ6.7 compared with 16.1Ϯ5.8 mL ⅐ min Ϫ1 ⅐ dL tissue Ϫ1 in the controls (PϽ0.001). The response to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methacholine in hypertensive patients with a peak response of 16.1Ϯ7.1 mL ⅐ min Ϫ1 ⅐ dL tissue Ϫ1 (Pϭ0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2Ϯ1.4 mmol/L. In contrast, ascorbic acid at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypertensive patients or the methacholine response in the controls. These results agree with the predicted kinetics for superoxide anion-mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension. Key Words: ascorbic acid Ⅲ endothelium Ⅲ hypertension, essential Ⅲ superoxide T he endothelium controls vascular homeostasis through the release of a number of regulatory substances, including nitric oxide. 1 With one exception, 2 the majority of studies suggests that the bioactivity of endothelium-derived nitric oxide (EDNO) is impaired in essential hypertension. 3-5 Loss of EDNO action may contribute to the pathogenesis of the vascular complications of hypertension, including coronary artery disease and stroke. 6 The bioactivity of nitric oxide is limited by its reaction with superoxide anion to form peroxynitrite. 7 Vascular production of superoxide anion is increased in animal models of hypertension, 8,9 and endothelial vasomotor dysfunction in this setting is reversed with superoxide dismutase. 9 Previous studies have demonstrated that acute intra-arterial administration of ascorbic acid improves EDNO-mediated vasodilation in forearm microvessels of patients with hypertension, 10 diabetes mellitus, 11 or hypercholesterolemia, 12 all conditions associated with increased production of reactive oxygen species. Because ascorbic acid is capable of scavenging superoxide anion, one assumption has been that it improves EDNO action in hy...

European and American investigators have reported response rates of 38% to 83% for ifosfamide alone in pretreated sarcomas. In a phase II trial of ifosfamide 2.0g/m2 days 1 to 4 with mesna uroprotection in 124 patients with previously failed sarcomas, four (3%) responded completely (95% exact confidence interval, 1% to 8%) and 26 (21%) had a complete or partial response (95% exact confidence interval, 14% to 29%). The median time to progression was 5 and 9 months for partial and complete responders, respectively. In the subset of soft tissue sarcomas, the response rate for the patients receiving bolus administration was 26%, compared with 9% for the patients receiving a continuous infusion schedule (P = .03). The response rates among patients with soft tissue and bony sarcomas with a performance score of 0-2 and 0-1 prior to chemotherapy administration were 20% and 40%, respectively. Somnolence or confusion developed in 19%. Neurotoxicity was significantly associated with poor performance status (P less than .01), elevated creatinine (P less than .01), and low bicarbonate levels (P = .05). A serum bicarbonate less than 20 developed in 31% of the patients and was significantly associated with older age (P = .01), elevated creatinine (P = .02), and female sex (P = .06). Hematuria was significantly associated with no uroprotection (the first four patients did not receive mesna because it was unavailable), but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus v continuation infusion schedule. Thus, ifosfamide is active in failed sarcomas and warrants further study in previously untreated patients with sarcoma.

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