Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers.

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C(max)], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C(max), 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C(max) CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

Hypercholesterolemia and endothelium dysfunction: role of dietary supplementation as vascular protective agents.

There is increasing evidence that dietary supplementation, such as L-arginine, anti-oxidant vitamins, soy phytoestrogens, flavonoids and omega-3 fatty acids exert vascular protective benefits particularly in terms of restoring endothelial function in cardiovascular disease states. The endothelium has been a major focus over the past 20 years as being a primary site at which dysfunction occurs in association with, and contributing to, vascular pathologies. Such states include mild compromise of the cardiovascular system as observed in smokers, hypercholesterolemics and hypertensives, through to end-point heart failure. This review will focus on the experimental and clinical evidence examining the effect of nutriceuticals on vascular function, in particular endothelium-derived factors, and argues that there is a role for nutriceuticals in the clinical management of the cardiovascular compromised individual.

The isoflavone metabolite dehydroequol produces vasodilatation in human resistance arteries via a nitric oxide-dependent mechanism.

BACKGROUND: Isoflavones (phytoestrogens) offer potential cardioprotective benefits. We recently reported on the vasodilatory activity of the isoflavone metabolite, dehydroequol, in rat isolated aortic ring preparations. In the current study, we examine the effect of this metabolite on the vascular haemodynamic profile in human forearm resistance arteries. METHODS AND RESULTS: Responses to brachial artery infusion of dehydroequol (0.1, 0.3, 1 and 3 micromol/min) in forearm resistance arteries were obtained in six healthy males. These were done, on two separate occasions, in the absence and presence of endogenous nitric oxide synthase inhibition using NG-monomethyl-L-arginine, with sufficient sodium nitroprusside to maintain vascular tone. Dehydroequol produced a dose-dependent increase in forearm blood flow from 2.44 +/- 0.37 (basal) to 5.25 +/- 1.07 mL/100 mL/min (P < 0.05) at dehydroequol 3 micromol/min. Responses to dehydroequol were significantly dampened with inhibition of endogenous nitric oxide synthase (at 3 micromol/min: % increase in forearm blood flow fell from 114.3 +/- 22.81 to 19.45 +/- 9.19; P < 0.01). CONCLUSION: This is the first report of dehydroequol, a metabolite derived from the isoflavone diadzein, demonstrating potent vasodilatory properties in human resistance arteries via a nitric oxide-dependent mechanism.