Harumi Arisaka

Anti‐thrombotic effects and bleeding risk of AJvW‐2, a monoclonal antibody against human von Willebrand factor

1 A murine anti‐human vWF monoclonal antibody, AJvW‐2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (vWF) during the ristocetin‐ (IC50=0.7±0.1 μg ml−1) and botrocetin‐ (IC50=1.8±0.3 μg ml−1) induced aggregation of human platelets. 2 AJvW‐2 inhibited the high shear stress (10.8 N m−2) induced aggregation of human platelets dose‐dependently with an IC50=2.4±0.3 μg ml−1, but had no effect on low shear stress induced platelet aggregation (1.2 N m−2) up to 100 μg ml−1. 3 AJvW‐2 also inhibited the high shear stress (5.0 N m−2) induced adhesion of human platelets to collagen I with the same efficacy (IC50=2.4±0.3 μg ml−1), but had no effect at low shear conditions (1.5 N m−2). 4 AJvW‐2 inhibited the botrocetin‐induced aggregation of platelets from guinea‐pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea‐pig platelets. 5 AJvW‐2 prevented arterial thrombus formation in guinea‐pigs at a dose of 100 μg kg−1 without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonist lamifiban mediated inhibition of thrombosis at 1000 μg kg−1 was accompanied by a significant prolongation of the bleeding time. 6 These results suggest that AJvW‐2 is a potent inhibitor of the GPIb‐vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.

Effects of safflower seed extract supplementation on oxidation and cardiovascular risk markers in healthy human volunteers

We previously demonstrated that safflower seed extract (SSE) and its major antioxidant constituents, serotonin hydroxycinnamic acid amides, suppressed LDL oxidation in vitro, decreased plasma autoantibody titres to oxidized LDL and attenuated atherosclerotic lesion formation in apoE-deficient mice. In this report, we examined whether SSE, rich in serotonin derivatives, could affect markers of oxidative stress, inflammation and aortic stiffness in healthy human subjects. Twenty Japanese male volunteers were studied at baseline, after 2.1 g SSE supplementation daily (providing 290 mg serotonin derivatives/d) for 4 weeks, and after a 4-week washout period. Significant reductions in circulating oxidized LDL, autoantibody titres to malondialdehyde-modified LDL, the soluble form of vascular cell adhesion molecule-1 (sVCAM-1), and urinary 8-isoprostane were observed after a 4-week intervention. Although there were no statistically significant differences in blood pressure or brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, baPWV was lower than baseline in eleven of twenty subjects and was accompanied by a reduction in blood pressure. Statistically significant negative correlations were observed between the extent of initial cardiovascular risk markers (autoantibody titres, 8-isoprostane, sVCAM-1 and baPWV) and the effect of intervention. This suggested that individuals with elevated oxidative stress, inflammation, and/or arterial stiffness may receive more benefit from SSE supplementation.

Effect of N-(p-coumaroyl)serotonin and N-feruloylserotonin, major anti-atherogenic polyphenols in safflower seed, on vasodilation, proliferation and migration of vascular smooth muscle cells

SCOPE The objective of this study is to investigate a vascular effect of N-(p-coumaroyl)serotonin (CS) and N-feruloylserotonin (FS), major antioxidative indolic polyphenols in safflower seeds with anti-atherogenic properties, with emphasis on effects on vascular smooth muscle cells (VSMCs). METHODS AND RESULTS Both CS and FS (each 10 to 100 μM) relaxed rat femoral arteries, which were pre-contracted by 10(-5) M phenylephrine or 50 mM KCl, independently of their endothelium. Both CS and FS also concentration-dependently inhibited the increase of cytosolic free Ca(2+) concentration ([Ca(2+) ](i) ) that was induced by KCl or 5-hydroxytryptamine in cultured rat VSMCs. Next, we examined the effects of CS and FS on platelet-derived growth factor (PDGF)-BB-evoked proliferation and migration of the VSMCs. Both CS and FS inhibited PDGF-BB-evoked proliferation and migration of the VSMCs in a concentration-dependent manner. They also inhibited PDGF-BB-induced phosphorylation of PDGF receptor β and ERK1/2, and Ca(2+) release from sarcoplasmic reticulum in the VSMCs in a concentration-dependent fashion. CONCLUSION These results indicated a possible vascular effect of CS/FS to inhibit the activation of VSMCs by blocking the increase of [Ca(2+) ](i) and/or blocking PDGF signaling. These may explain a part of anti-atherogenic mechanism that underlies their ability to improve vascular distensibility and to inhibit aortic hyperplasia.

Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug–drug interactions via these transporters

Objectives  We have investigated the contributions of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to the hepatic uptake of nateglinide, and the possibility of drug–drug interactions via these transporters.