Ermiao Pill (EMW), a traditional Chines medicine (TCM), composed of a two‐herb pair, Phellodendri Cortex (PC) and Atractylodis Rhizome (AR), is used for the treatment of pelvic inflammatory disease and inflammatory‐related diseases. However, the underlying mechanism is still unknown. Compatibility plays a crucial role in the complex drugs such as those used in traditional Chinese medicine. We propose a compositive strategy, which integrated pharmacokinetics and network pharmacology to explore the compatibility in EMW. Firstly, a simple, rapid, and selective method based on UPLC–MS/MS was established and validated for simultaneous qualification of six alkaloids in rat plasma, which was used for a comparative pharmacokinetic study of EMW and its constituent herb PC. The concentration–time profiles suggested that AR might reduce the toxicity of some alkaloids in EMW. Secondly, network pharmacology analysis showed that the key protein PTGS2 was targeted by four alkaloids, and that the competition among them might be allevited by AR. Thirdly, molecular docking exhibited interactions between the alkaloids and PTGS2 through H and π–π bonds, and the same residue formed interactions with different alkaloids, which account for the toxicity of these alkaloids, and these were confirmed by the cell viability assay. The combination of pharmacokinetics and network pharmacology clarified the compatibility in EMW.

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What is known and objectives Caffeine citrate is a commonly used methylxanthine for pharmacologic treatment of apnea of prematurity. The aim of this study was to develop and verify a population pharmacokinetic (PPK) model, which can provide a reference for individualized caffeine citrate treatment of apnea in Chinese premature infants. Methods A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29 weeks) were retrospectively collected and the relevant clinical data of patients were recorded. The PPK analysis was performed by non‐linear mixed‐effect modelling method using NONMEM. Allometric scaling was applied in the PPK analysis, and the final model was evaluated by graphic and statistical methods, including goodness‐of‐fit plots, normalized prediction distribution errors plots and bootstrap procedures. Results A one‐compartment model with first‐order elimination was successfully fitted to the data. The typical scaled values for the parameters clearance and volume of distribution (V) were 0.268 L/h and 109 L per 70 kg, respectively. The weight at the time of blood collection (CW) and post‐natal age were identified as important predictors for pharmacokinetic parameters of caffeine. The evaluation process showed good stability and predictability of the final PPK model. What is new and conclusion This is a complete PPK study of caffeine citrate in Chinese premature infants with apnea, which complements caffeine pharmacokinetic data of the premature from China. A final PPK model was developed which may serve as a beneficial tool for the use of caffeine citrate in the treatment of apnea in Chinese preterm infants.

The monoester alkaloids in Aconitum carmichaelii, including benzoylaconitine (BAC), benzoylmesaconine, and benzoylhypaconitine, were found to have anti-hypertensive effects in spontaneously hypertension rats (SHRs), of which BAC is the strongest. However, its antihypertensive target and underlying molecular mechanisms remain unclear. In this study, first, we screened the antihypertensive targets of BAC by using the CVDPlatform (www.cbligand.org/CVD) and found that ACE/ACE2 are the most possible targets. Then, we verified the effect of BAC on ACE/ACE2 by virtual docking, SPR, enzyme activity assay, and HUVECs cell experiment. We found that BAC could bind with ACE/ACE2, inhibit ACE activity and protein expression, and activate ACE2 enzyme activity. Using vascular function test in vitro, we found that BAC could target ACE/ACE2 to enhance endothelium-dependent vasorelaxation. In BAC-treated SHRs, the levels of ACE and AngII in serum were reduced while Ang (1–7) was increased significantly, and the expression of ACE was reduced, which suggested that BAC can inhibit ACE and activate ACE2 to inhibit AngI to AngII and promote AngII to Ang (1–7) to inhibit vasoconstriction and finally attenuate hypertension. Furthermore, the signaling pathways with regard to vasorelaxation and vascular inflammation were investigated. The results showed that BAC could significantly activate Akt/eNOS, increase NO production, and promote endothelial-related vasodilation; BAC could also reduce inflammatory factors TNF-α and IL6, inhibition of COX-2 expression, and IKB-α phosphorylation to reduce vascular inflammation in SHRs. In brief, BAC targets ACE/ACE2 to enhance endothelium-dependent vasorelaxation and reduce vascular inflammation to attenuate hypertension as a potential modulator of the renin–angiotensin system.