The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9-3.4% in rats, with non-linear pharmacokinetics when its dosage increased. In a single pass rat intestinal perfusion model, the permeability coefficients (P(app)) based on TSA disappearance from the luminal perfusates (P(lumen)) were 6.2- to 7.2-fold higher (P < 0.01) than those based on drug appearance in mesenteric venous blood (P(blood)). The P(blood), but not P(lumen), was significantly increased when co-perfused with verapamil, or quinidine (both P-gp inhibitors). The uptake and efflux of TSA in confluent Caco-2 cells were significantly altered in the presence of verapamil, quinidine, MK-571, or probenecid. The transport of TSA across Caco-2 monolayers was pH-, temperature- and ATP-dependent. Furthermore, the transport from the apical (AP) to basolateral (BL) side of the Caco-2 monolayers was 3.3- to 8.5-fold lower than that from the BL to AP side, but such a polarized transport was attenuated by co-incubated verapamil or quinidine. A polarized transport was also observed in the control MDCKII cells and more apparent in MDR1-MDCKII monolayers, with the P(app) values of TSA in the BL-AP direction being 7- to 9-fold higher in MDR1-MDCKII monolayers than those in the control MDCKII cells. Moreover, TSA significantly inhibited P-gp-mediated transport of digoxin in P-gp-overexpressing membrane vesicles with an IC(50) of 2.6 microM, but stimulated vanadate-sensitive P-gp ATPase activity with estimated K(m) and V(max) values of 10.70 +/- 0.69 microM and 67.65 +/- 1.31 nmol/min/mg protein, respectively. TSA was extensively metabolized to tanshinone IIB (TSB), and two other oxidative metabolites in rat liver microsomes, but the formation rate of TSB in rat intestinal microsomes was only about 1/10 of that in liver microsomes. These findings indicate that TSA is a substrate and reversing agent for P-gp; and P-gp-mediated efflux of TSA into the gut lumen and the first-pass metabolism contribute to the low oral bioavailability. Further studies are needed to explore the role of other drug transporters and first-pass metabolism in the low bioavailability of TSA.

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Purpose This study aimed to explore the clinical value of ultrasonic Doppler examination and contrast‐enhanced ultrasound (US) in the circulation of septic acute kidney injury (AKI). Methods Patients with intensive care unit‐related infection were divided into AKI group and control groups. The AKI group was divided into three subgroups according to the serum creatinine value: stage 1, stage 2, and stage 3. Relevant parameters and blood flow of the renal artery were measured, and further contrast‐enhanced US was performed and time‐intensity curve was analyzed. Results The renal blood flow (RBF) and time‐averaged velocity decreased significantly in the AKI group compared with the control group (p = .021 and p = .001). The peak value decreased and time to peak (TTP) prolonged in the AKI group (p < .001). With the aggravation of the disease, the RBF decreased slightly among subgroups (p = 0.124). However, the peak value gradually decreased and the TTP prolonged (all p < .05). The multiple linear regression model showed that only PI, RI, and TTP were independently and linearly correlated with the serum creatinine value. Conclusions Doppler US and contrast‐enhanced US are of great help in the detection of condition changes and prognosis of patients with sepsis‐induced AKI.

The outcomes of a research focusing on water modeling and Fluid-Structure Interaction by ALE and SPH in LSTC/LS-Dyna971 are presented in this paper. Firstly the water impact behaviors of a rigid wedge are modeled with water region by ALE and SPH. The size of fluid elements plays critical role to the numerical results, so three different cases varied in mesh or particle spacing both in ALE and SPH methods are detailed discussed. The numerical results are compared both one to the others and to the experimental and theoretical results in terms of vertical velocity and slamming force, which can be concluded that the more elements modeled in the simulation, the better approximation with the experiment results. An additional discussion of propagation of pressure wave by SPH and CPU time are also presented.