Reduction in Arterial Stiffness Index (SI) in Response to Combination Antioxidant Therapy.

Antioxidants reduce arterial stiffness, but the effects previously reported are weak. A systematic review of the antioxidants vitamin E, vitamin C, vitamin A, and beta-carotenes (the most commonly studied antioxidants) on pulse wave velocity (PWV) found an effect size of only -0.20 (approximately -16 m/s or -2.5%). Studies in rats of the potent pro-oxidant substance acetaldehyde have shown that combinations of sulfur-containing antioxidants, including thiamine and l-cysteine, with ascorbic acid potently protect against oxidative-stress-mediated mortality. The effects of these combinations of oxidants on PWV have not been studied. The present study evaluated the effects of 2 weeks of therapy with a combination of sulfur-containing antioxidants (cysteine, thiamine, and pyridoxine) in combination with ascorbic acid on stiffness index (SI), a measure of arterial stiffness that is strongly correlated with PWV, using a Pulse Trace recorder in a diverse group of 78 volunteers. SI fell by -1.7 m/s relative to placebo (95% confidence intervals -0.6 to -2.7 m/s), a reduction of -19% (95% confidence intervals -9% to -31%). The Glass effect size was 1.4, indicating a very strong treatment effect which was substantially greater than the effect size found in previous studies of antioxidants. PWV reduction was correlated significantly with increasing age. Further studies of similar antioxidant combinations are required to determine whether they are of value in the treatment or prevention of cardiovascular disease.

Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer.

BACKGROUND: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer. METHODS: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection. RESULTS: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 µg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h. CONCLUSIONS: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000.

Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers.

BACKGROUND AND OBJECTIVE: NV-52 is a novel synthetic flavonoid thromboxane synthase (TXS) inhibitor that may be useful for the maintenance of remission in inflammatory bowel disease (IBD). This study was conducted to determine the single- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers (five men, four women; mean [+/- SD] age 23 +/- 2 years). METHODS: NV-52 400 mg was administered once daily for 10 days (excluding day 2) in an open-label study. Plasma was sampled and urine was collected for 48 hours after the first and last doses. Plasma and urine unconjugated and total (unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrations were measured using liquid chromatography-mass spectrometry. RESULTS: No adverse events were observed. Unconjugated and total NV-52 appeared and rose rapidly in plasma following the first dose. Time to maximum concentration values were 1.92 +/- 1.17 and 2.72 +/- 1.52 hours for unconjugated and total NV-52, respectively. Unconjugated and total NV-52 were eliminated with plasma half-lives of 13.12 +/- 17.31 and 18.03 +/- 19.06 hours, respectively, following the first dose. Pre-dose levels following multiple-dose administration were 135.17 +/- 120.03 and 751.9 +/- 679.74 ng/mL for unconjugated and total NV-52, respectively. Multiple-dose administration did not significantly alter the pharmacokinetics of NV-52. Renal elimination accounted for about 20-35% of the total (largely conjugated) drug but only 1% of unconjugated NV-52. CONCLUSIONS: Plasma concentrations of unconjugated NV-52 following single- and multiple-dose administration were well above the range found to be associated with suppression of colitis in a murine model of IBD.

Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of all randomized, controlled trials of isoflavone supplementation to determine the efficacy of isoflavone therapy in reducing the number of daily menopausal flushes. METHODS: A comprehensive search of published studies of isoflavone treatment and menopausal flushing was undertaken. Studies were selected if they were randomized, were placebo controlled, provided the number of baseline flushes, the variance in flushes and the reduction in flushes. Effects for isoflavone treatment compared to control were calculated and a meta-analysis was performed. Regression analysis, weighted for the size of the study was performed to investigate the relationship between the dose of isoflavone, or number of baseline flushes and the reduction in flushes achieved compared to control. RESULTS: Isoflavone supplementation was found to be associated with a significant reduction in flushes (effect size -0.28, 95% confidence intervals -0.39 to -0.18, P < 0.0001). Marked heterogeneity was found between the studies, but the effect remained significant when analyzed using a random effects model (delta = -0.49, 95% confidence intervals -0.81 to -0.17, P = 0.001). The percentage reduction in flushes was significantly related to the number of baseline flushes per day and the dose of isoflavone studied (beta = -0.49 and -0.26, respectively, both P < 0.0001). CONCLUSIONS: These results suggest that isoflavone supplementation may produce a slight to modest reduction the number of daily flushes in menopausal women and that the benefit may be more apparent in women experiencing a high number of flushes per day.

Haemodynamic and pulse wave responses to intravenous infusions of angiotensin II during chronic telmisartan therapy in normal volunteers.

INTRODUCTION: This study investigated the central haemodynamic, blood pressure (BP) and pulse wave responses to progressively increasing infusion rates of intravenous angiotensin II (Ang II) in normal volunteers during chronic therapy with telmisartan or placebo. MATERIALS AND METHODS: Ten normal volunteers, aged 21 33 years, completed a randomised, double-blind crossover study. Ang II was infused intravenously at increasing infusion rates (0 512 ng/minute) at the end of one week of telmisartan therapy (40 80 mg/day) and one week of placebo therapy. BP, central haemodynamics and pulse wave parameters were monitored continuously using a CardioDynamics Recorder, a Pulse Tracer Recorder and a Finipress Recorder. RESULTS: Baseline diastolic BP (57+12 vs. 67+13 mmHg) and pulse wave reflection index (RI) (38.4+18.6 vs. 60.6+12.5%) were significantly lower on telmisartan than on placebo therapy. Cardiac index (CI), systolic BP, systemic vascular resistance index (SVRI), RI and pulse wave stiffness index (SI) were all significantly increased in a dose-dependent manner by Ang II on placebo therapy. Telmisartan significantly (p<0.05) attenuated all of these responses to Ang II. Increases in BP during Ang II infusion were associated with increases in SVRI and CI. CONCLUSIONS: Telmisartan effectively blocked the effects of intravenous Ang II on CI, BP, RI and SI in healthy volunteers. Changes in CI make a major contribution to increase in BP response to intravenous Ang II in normal volunteers.