Plant Polyphenols Attenuate DSS-induced Ulcerative Colitis in Mice via Antioxidation, Anti-inflammation and Microbiota Regulation.

The pathogenesis of ulcerative colitis (UC) is associated with inflammation, oxidative stress, and gut microbiota imbalance. Although most researchers have demonstrated the antioxidant bioactivity of the phenolic compounds in plants, their UC-curing ability and underlying mechanisms still need to be further and adequately explored. Herein, we studied the antioxidation-structure relationship of several common polyphenols in plants including gallic acid, proanthocyanidin, ellagic acid, and tannic acid. Furthermore, the in vivo effects of the plant polyphenols on C57BL/6 mice with dextran-sulfate-sodium-induced UC were evaluated and the action mechanisms were explored. Moreover, the interplay of several mechanisms was determined. The higher the number of phenolic hydroxyl groups, the stronger the antioxidant activity. All polyphenols markedly ameliorated the symptoms and pathological progression of UC in mice. Furthermore, inflammatory cytokine levels were decreased and the intestinal barrier was repaired. The process was regulated by the antioxidant-signaling pathway of nuclear-erythroid 2-related factor 2. Moreover, the diversity of the intestinal microbiota, Firmicutes-to-Bacteroides ratio, and relative abundance of beneficial bacteria were increased. An interplay was observed between microbiota regulation and oxidative stress, immunity, and inflammatory response. Furthermore, intestinal barrier repair was found to be correlated with inflammatory responses. Our study results can form a basis for comprehensively developing plant-polyphenol-related medicinal products.

Predicting the correct dose in children: Role of computational Pediatric Physiological-based pharmacokinetics modeling tools.

The pharmacokinetics (PKs) and safety of medications in particular groups can be predicted using the physiologically-based pharmacokinetic (PBPK) model. Using the PBPK model may enable safe pediatric clinical trials and speed up the process of new drug research and development, especially for children, a population in which it is relatively difficult to conduct clinical trials. This review summarizes the role of pediatric PBPK (P-PBPK) modeling software in dose prediction over the past 6 years and briefly introduces the process of general P-PBPK modeling. We summarized the theories and applications of this software and discussed the application trends and future perspectives in the area. The modeling software's extensive use will undoubtedly make it easier to predict dose prediction for young patients.

Determination of trace cantharidin in plasma and pharmacokinetic study in beagle dogs using gas chromatography-mass spectrometry.

The blister beetle is traditional Chinese medicine that was first discovered and used as anticancer drug in China, and cantharidin proved to be its principal active ingredient. Cantharidin-based pharmaceutical preparations are now widely used in clinics in China with good therapeutic efficacy. As a toxic anticancer drug, the therapeutic dose of cantharidin is low, and no method to determine the blood cantharidin concentration under the therapeutic dose has so far been reported. Here, we present a simple, sensitive, and reliable gas chromatography-mass spectrometry (GC-MS) method to monitor the plasma cantharidin and perform the pharmacokinetic study of cantharidin in beagle dogs. After protein precipitation by hydrochloric acid, a liquid-liquid extraction procedure using ethyl acetate was applied to extract cantharidin from plasma. An elastic quartz capillary GC column DB-5MS was used in GC-MS, the temperature was kept at 60 degrees C for 1 min, then increased to 220 degrees C at the rate of 6 degrees C/min, held there for 1 min, and then to 280 degrees C at the rate of 20 degrees C/min, held for 3 min. The extraction recovery was over 80% for all the tested specimens. The linearity ranged from 2.14 to 314.2 ng/mL, the intra- and interday precisions were both below 20%, the limit of detection was 0.5 ng/mL, and the limit of quantification was 2.14 ng/mL. Cantharidin in plasma proved to be stable during the whole period of storage, treatment, and analysis. Cantharidin demonstrated as one-compartment model after i.v. administration with an elimination half-life of 0.69 +/- 0.03 h and area under curve of 204 +/- 24 h.ng/mL. This GC-MS assay proved to have high precision, accuracy, reliability, and sensitivity, and it was suitable for determination of trace cantharidin in plasma.

[Pharmacokinetics and bioavailability of cantharidin in beagle dogs].

OBJECTIVE: To study the pharmacokinetics and bioavailability of cantharidin in beagle dogs to evaluate the pharmacokinetic parameters and bioavailability of cantharidin in beagle dogs by determining dose-time curve and by comparing with the pharmacokinetics of cantharidin injection. METHOD: Six beagle dogs, after protein precipitation by hydrochloric acid, ethyl acetate was applied to extract cantharidin from plasma The plasma concentration of cantharidin in beagle dogs was determined by GC-MS. The WinNonLin program was used to calculate the pharmacokinetic parameters and bioavailability. RESULT: The main pharmacokinetic parameters of cantharidin by iv in dogs (34 mL x h(-1) x kg(-1)) were AUC (203.5 +/- 23.8) h x microg x L(-1), CL (168.8 +/- 18.6) mL x h(-1) x kg(-1), t1/2 (0.69 +/- 0.03) h. The main pharmacokinetic parameters of cantharidin by op (102 microg x kg(-1)) were: AUC (160.4 +/- 26.9) h x microg x L(-1), CL (649.1 +/- 97.7) mL x h(-1) x kg(-1), t1/2 (0.38 +/- 0.1) h., F (bioavailability) = 26.7% comparing to injection. CONCLUSION: As compared with cantharidin injection, the absorption of catharidin by op is poor and the bioavailability is also low, indicating that enhancement of the bioavailability will be beneficial to the clinical application.

Genomic study of the absorption mechanism of p-coumaric acid and caffeic acid of extract of Ananas comosus L. leaves.

Cardiac disease has emerged as the leading cause of death worldwide, and food rich in phenolic acids has drawn much attention as sources of active substances of hypolipidemic drug. Ananas comosus L. (pineapple) is one of the most popular tropical and subtropical fruits. Isolated from pineapple leaves, EAL(Extract of Ananas Comosus L. Leaves) is rich in phenolic acids, such as p-coumaric acid, caffeic acid, and other phenolics, highly relevant to the putative cardiovascular-protective effects, which suggests its potential to be a new plant medicine for treatment of cardiac disease, but little is known about absorption, distribution, metabolism, and excretion of EAL in animals or human beings. In this study, we employed cDNA microarray, Caco-2 cell lines, and rat intestinal model to explore the absorption behavior of p-coumaric acid and caffeic acid in EAL. The permeation of 2 substances was concentration and time dependent. Results also indicated that monocarboxylic acid transporter was involved in the transepithelial transport of p-coumaric acid and caffeic acid.

Oral bioavailability of cantharidin-loaded solid lipid nanoparticles.

BACKGROUND: The clinical application of cantharidin (CA) is limited by its insolubility, toxicity and short half-life in circulation. This study aims to achieve a steady and sustained blood concentration-time profile, using solid lipid nanoparticles (SLNs) as a drug carrier. METHODS: CA-SLNs were prepared by a film dispersion-ultrasonication method. The physiochemical properties were studied by transmission electron microscopy. In vitro release and in vivo evaluation of CA-SLNs were studied by GC and GC-MS, while a comparison of the pharmacokinetic properties between CA-SLNs and free CA was performed in rats. RESULTS: The mean size, drug content and encapsulation yield of CA-SLNs were 121 nm, 13.28 ± 0.12% and 93.83 ± 0.45%, respectively. The results show that CA-SLNs had a sustained release profile without a burst effect, a higher bioavailability than free CA after oral administration, and that the relative bioavailability of CA-SLNs to free CA was 250.8%. CONCLUSION: CA-SLNs could improve the solubility and oral bioavailability of CA.

In situ absorption in rat intestinal tract of solid dispersion of annonaceous acetogenins.

Isolated from Annona squamosa L, Annonaceous acetogenins (ACGs) exhibit a broad range of biological properties yet absorbed badly due to the low solubility. Solid dispersion in polyethylene glycol 4000 (PEG 4000) has been developed to increase the solubility and oral absorption of ACGs. The formulation of ACGS-solid dispersion was optimized by a simplex lattice experiment design and carried out by a solvent-fusion method. We studied the absorption property of ACGs in rat's intestine, which showed there was a good absorption and uptake percentages with solid dispersion. The study on uptake percentage in different regions of rat's intestine attested that the duodenum had the best permeability, followed by jejunum, ileum, and colon in order with no significant differences. So the paper drew the conclusion that solid dispersion could improve the solubility and oral absorption of annonaceous acetogenins.

Simultaneous determination of three major bioactive saponins of Panax notoginseng using liquid chromatography-tandem mass spectrometry and a pharmacokinetic study.

BACKGROUND: Panax notoginseng saponins (PNS), the main active components of Radix Notoginseng, has been used for treating atherosclerosis, cerebral infarction, and cerebral ischemia. Ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1 are the main contributors of biological activities, determination of these three saponins is very important for the in vivo evaluation of PNS. The present study aims to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1. The use of this method was exemplified in pharmacokinetic study of beagle dog plasma after oral administration of PNS. METHODS: Liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was combined with solid-phase extraction (SPE). This setup was used to determine simultaneously the three major PNS (ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1) in beagle dog plasma. Tandem mass spectrometry was performed using electrospray ionization in the positive ion mode. RESULTS: The lower limits of quantification were 0.5 ng/mL for notoginsenoside R1, 0.82 ng/mL for ginsenoside Rg1, and 1.10 ng/mL for ginsenoside Rb1. The calibration curves for the three saponins were linear over the concentration ranges 2.64-264 ng/mL (r2 = 0.9967, P = 0.003), 3.6-360 ng/mL (r2 = 0.9941, P = 0.004), and 18.7-1870 ng/mL (r2 = 0.9912, P = 0.004) for notoginsenoside R1, ginsenoside Rg1, and ginsenoside Rb1, respectively. Within these concentration ranges, the relative standard deviation (RSD) of intra- and interday assays for the three PNS from beagle dog plasma samples were less than 12%. CONCLUSIONS: This LC/MS/MS method in combination with SPE is useful in the pharmacokinetic study of PNS, such as the simultaneous determination of saponins in beagle dog plasma after oral administration.