Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.

AIMS: Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects. METHODS: In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (C(max), T(max), C(min), AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects. RESULTS: L-Citrulline dose-dependently increased AUC and C(max) of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the C(min) of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 +/- 8 (baseline) to 278 +/- 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 +/- 10 to 125 +/- 15 micromol mmol(-1) creatinine (P = 0.01, 95% CI 8, 58) and from 38 +/- 3.3 to 50 +/- 6.7 nmol mmol(-1) creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD. CONCLUSION: Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.

Seasonal influenza vaccine delivered by intradermal microinjection: A randomised controlled safety and immunogenicity trial in adults.

Influenza vaccines remain largely underused. A promising alternative to current intramuscular vaccines is a trivalent inactivated influenza vaccine (TIV) delivered using a microinjection system to offer a less invasive and possibly more acceptable vaccination. A phase II, multicentre, randomised open-label study in 978 healthy adults (18-57 years) evaluated the immunogenicity and safety of intradermal TIV. Subjects received a 0.1 ml injection of intradermal TIV, containing 9 microg of haemagglutinin (HA) per strain (n = 588) or a conventional 0.5 ml intramuscular vaccine (15 microg of HA/strain; n = 390). Intradermal TIV induced non-inferior humoral immune responses against all three strains and superior responses against both A strains (H1N1, H3N2) compared with the control. Both vaccines were well tolerated.