No abstract

ABSTRACT:Ligustilide is the most abundant bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular ailments. The present study reported, for the first time, the pharmacokinetics of ligustilide, administered in its pure form and in an herbal extract, in rats. After i.v. administration of pure ligustilide, it was distributed extensively (V d , 3.76 ؎ 1.23 l/kg) and eliminated rapidly (t 1/2 , 0.31 ؎ 0.12 h). The i.v. clearance (CL) of ligustilide after Chuanxiong extract administration was significantly higher than that dosed in its pure form [CL, 20.35 ؎ 3.05 versus 9.14 ؎ 1.27 l/h/kg, p < 0.01; area under the curve (AUC), 0.79 ؎ 0.10 versus 1.81 ؎ 0.24 mg ⅐ h/l, p < 0.01], suggesting significant interaction between ligustilide and components present in the extract. Dose-dependent pharmacokinetics was observed after i.p. administration, and a significantly higher dose-normalized AUC (1.77 ؎ 0.23 mg ⅐ h/l) at 52 mg/kg was obtained than that at 26 mg/kg (0.93 ؎ 0.07 mg ⅐ h/l, p < 0.05). Oral bioavailability of ligustilide was low (2.6%), which was partly because of extensive first-pass metabolism in the liver. Seven metabolites of ligustilide were identified, and three of them were unequivocally characterized as butylidenephthalide, senkyunolide I, and senkyunolide H. These three compounds also occurred naturally in the herb and were reported to be bioactive.Rhizoma Chuanxiong [Ligusticum chuanxiong Hort. (Umbelliferae)], known as Chuanxiong in Chinese, a commonly used Chinese medicinal (CM) herb, has been used for treating cardiovascular diseases in China for centuries (State Pharmacopoeia Commission of P.R. China, 2005). In addition to raw herb preparations used in conventional CM practice, various Chuanxiong-based proprietary products containing Chuanxiong crude extract, especially Chuanxiong essential oil extract, are also used clinically. For instance, Quickacting Heart Saving Pill (Chinese name, Suxiao Jiuxin Wan), a product manufactured for sublingual delivery, contains Chuanxiong essential oil extract as the primary ingredient. In recent years, this product is one of the top five best-selling CM-based cardiovascular products in China (Sun et al., 2002;Li, 2005).In the past decades, the phytochemistry of Chuanxiong has been studied extensively. Nineteen compounds from L. chuanxiong have been reported to be pharmacologically active (Naito et al., 1995;Ko et al., 1997Ko et al., , 1998Ko et al., , 2002Matsumoto et al., 1998;Chong and Feng, 1999;Shih et al., 2002). In particular, phthalides are present in large quantities in Chuanxiong essential oil; these compounds have been shown to have in vitro and in vivo pharmacological activities (Naito et al., 1995;Ko et al., 1998Ko et al., , 2002Matsumoto et al., 1998;Chong and Feng, 1999;Cao et al., 2006;Chan et al., 2006Chan et al., , 2007Du et al., 2006;Lu et al., 2006). Ligustilide (Z-3-butylidene-4,5-dihydroisodenzofuranone) (Fig. 1), a phthalide derivative, is the most abundant constituent in the herb (...

Maternal cardiovascular changes during pregnancy include an expansion of plasma volume, increased cardiac output, decreased peripheral resistance, and increased uteroplacental blood flow. These adaptations facilitate the progressive increase in uteroplacental perfusion that is required for normal fetal growth and development, prevent the development of hypertension, and provide a reserve of blood in anticipation of the significant blood loss associated with parturition. Each woman’s genotype and phenotype determine her ability to adapt in response to molecular signals that emanate from the fetoplacental unit. Here, we provide an overview of the major hemodynamic and cardiac changes and then consider regional changes in the splanchnic, renal, cerebral, and uterine circulations in terms of endothelial and vascular smooth muscle cell plasticity. Although consideration of gestational disease is beyond the scope of this review, aberrant signaling and/or maternal responsiveness contribute to the etiology of several common gestational diseases such as preeclampsia, intrauterine growth restriction, and gestational diabetes.

PE maladaptations include, but are not limited to, altered physiological stimulatory inputs (e.g., estrogen; VEGF/PlGF; shear stress) and substrates (L-Arg; ADMA), augmented placental secretion of anti-angiogenic and inflammatory factors such as sFlt-1 and Eng, changes in eNOS (polymorphisms, expression), and reduced bioavailability of NO secondary to oxidative stress. PE is a complex obstetrical syndrome that is associated with maternal vascular dysfunction. Diminished peripheral endothelial vasodilator influence in general, and of NO signaling specifically, are key in driving disease progression and severity.

No abstract