Linderane Attenuates Complete Freund's Adjuvant-Induced Pain and Anxiety in Mice by Restoring Anterior Cingulate Cortex Microglia M2 Polarization through Activating Cannabinoid 2 Receptor.

Chronic pain is a common condition that causes negative emotions as the disease progresses. The anterior cingulate cortex (ACC) is a key region in the integration of nociceptive perception and emotional response in chronic pain. Linderane (LDR) is an active ingredient from Linderae radix, a traditional Chinese medicine with anti-inflammatory, analgesic, and antibacterial properties. In this study, the analgesic and antianxiety effects of LDR were evaluated using a complete Freund's adjuvant (CFA)-induced inflammatory pain model in C57BL/6 male mice. Mechanical and thermal pain sensitivity were measured through plantar mechanical analgesia and hot plate apparatus, and anxiety-like behavior was evaluated by open field and elevated plus maze tests. The results showed that LDR-alleviated CFA-induced pain and anxiety, reduced the release of inflammatory cytokines, and inhibited ACC microglial activation. Target prediction, molecular docking, and cellular thermal shift assay demonstrated that LDR could bind to the cannabinoid 2 receptor (CB2R), a key component of the endocannabinoid system with an important role in regulating pain and related emotions. Moreover, both the analgesic effect of LDR and its regulation of microglia polarization were reversed by a CB2R antagonist (SR144528) treatment. Therefore, our results suggested that LDR exerted analgesic effects by regulating microglial polarization in ACC via CB2R activation.

Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3ß pathway.

Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra-C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra-C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein-protein interaction network of putative Pra-C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra-C. Protein expression levels were detected by western blotting. Pra-C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra-C affects the PI3K/AKT/GSK3ß signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3ß levels in vivo and in vitro upon Pra-C administration. Pra-C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3ß pathway.

Pharmacokinetics and pharmacodynamics of citrus peel extract in lipopolysaccharide-induced acute lung injury combined with Pinelliae Rhizoma Praeparatum.

Dry citrus peel (Chenpi) is not only consumed as a dietary supplement, but also used for the treatment of respiratory diseases. Pinelliae Rhizoma Praeparatum (Banxia) is always used with Chenpi for the treatment of respiratory diseases, but ß-sitosterol, the main active component in Banxia, as a food additive, shows no respiratory system activity. In the present study, the pharmacokinetic characters showed that the absorption of the active components of Chenpi was accelerated under pathological conditions combined with Banxia. Although the bioavailability of active components did not significantly change, the distribution of active components in tissues increased, particularly in the target organ. These results are consistent with the combination of Chenpi with ß-sitosterol. Furthermore, the pharmacodynamics result also indicated that Chenpi combined with Banxia or ß-sitosterol was able to ameliorate histopathologic damage and decrease the levels of inflammatory factors. The results suggest that pharmacokinetic interactions improve the pharmacological activity of Chenpi in respiratory diseases.

Study on pharmacokinetics and bioequivalence of Vonoprazan pyroglutamate in rats by liquid chromatography with tandem mass spectrometry.

Vonoprazan Fumarate (TAK-438F) is a new and effective drug approved in Japan in 2014 for treatment and prevention of acid-related diseases (ARDs), which exhibits many advantages compared with traditional proton-pump inhibitors (PPIs). However, the clinical applications of TAK0-438F suffers limitation due to the lack of injection dosage form. Efforts to overcome this limitation lead to the systhesis of Vonoprazan pyroglutamate (TAK-438P) for its high water solubility and more potent antisecretory effect. This was the first report to establish and validate a reliable and sensitive LC-MS/MS method for the quantification of TAK-438P in rat plasma and tissues (heart, liver, spleen, liver, kidney, rain, stomach and small intestine). All the features of the developed method suggested it was within bioanalytical criteria recommended by regulatory authorities. Furthermore, the developed method was applied to the exploration of the bioequivalence between TAK-438P and TAK-438F, as well as the pharmacokinetics and tissue distribution of TAK-438P. The results showed that there was no significant differences between TAK-438P and TAK-438F after oral administration of the same dose. Besides, TAK-438P was rapidly absorbed and eliminated in rat plasma. And it was widely distributed and there was no long-term accumulation in most tissues. Notably, more than 2000ng/mL was observed in stomach 12h after oral administration. The high accumulation revealed that stomach was likely to be the target organs of TAK-438P.

Mechanistic prediction of food effects for Compound A tablet using PBPK model.

Physiologically based pharmacokinetic (PBPK) modeling has been extensively used to study the factors of effect drug absorption, distribution, metabolize and extraction progress in human. In this study, Compound A(CPD A) is a BCS Class II drug, which has been extensive applied in clinical as lipid-lowering drug, administered orally after food, they displayed positive food effects in human, A PBPK model was built to mechanistic investigate the food effect of CPD A tablet in our study. By using gastroplus™ software, the PBPK models accurately predicted the results of food effects and predicted data were within 2-fold error of the observed results. The PBPK model mechanistic illuminated the changes of pharmacokinetic values for the positive food effects of the compound in human. Here in, the PBPK modeling which were combined with ACAT absorption models in it, successfully simulated the food effect in human of the drug. The simulation results were proved that PBPK model can be able to serve as a potential tool to predict the food effect on certain oral drugs.

Investigating herb-herb interactions: the potential attenuated toxicity mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae flavescentis radix (Kushen).

ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizae radix et rhizoma (Gancao) is often prescribed together with Sophorae flavescentis radix (Kushen) in traditional Chinese medicinal practice to increase the efficacy on the treatment of hepatitis and hepatic fibrosis. Meanwhile, long-term single used Gancao can cause adverse reactions, lead to pseudohypercorticosteroidism especially. But the side effects of Gancao are significantly reduced when combined with Kushen; the reasons are still unknown. The aim of this study was to elucidate potential pharmacokinetic interaction between Kushen and Gancao, and to provide guidance for clinical medicine safety. MATERIALS AND METHODS: A specific and rapid HPLC-MS method was established to quantify the four main activity ingredients matrine (MT), oxymatrine (OMT), glycyrrhizin (GL) and glycyrrhetinic acid (GA) in rat plasma. In this study, the pharmacokinetic parameters and the pharmacokinetic differences of the four main activity ingredients MT, OMT, GL and GA in single herb and Kushen-Gancao couple were obtained. RESULTS: Compared with oral administration of Gancao extract, K10 and Tmax of GA significantly increased to 0.43 h(-1)and 30 h after giving Kushen-Gancao (p < 0.05), but T1/2 and Vd were reduced to 0.73 L kg(-1)and 4.98 h (p < 0.05). In addition, the AUC of GA was increased, and the other three activity ingredients all decreased. CONCLUSION: GA as the main factor leading to the sodium-water retention side effects of Gancao. The result found that the absorption of GA was significantly slowed down and the metabolism rate was accelerated in Kushen-Gancao than single herb. So the attenuated toxicity mechanism may be because the accumulation of GA reduced in vivo. The conclusion has important meaning to the compatibility of Chinese med.

Pharmacokinetic study of multiple active constituents from Kushen-Gancao Decoction after oral administration in rat by HPLC-MS/MS.

Kushen-Gancao Decoction (KGD) is a classic traditional Chinese herb combination in treating viral hepatitis and chronic liver diseases. This study aims to investigate the pharmacokinetic (PK) study of matrine (MT), oxymatrine (OMT), glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) following oral administration of KGD in rats. A rapid, sensitive and reliable HPLC-MS/MS method was successfully developed for the simultaneous determination of MT, OMT, GL and GA in rat plasma. A Inertsil C18 analytical column was used with a gradient mobile phase system of methanol-ammonium acetate (5mM) with a flow rate of 0.5 mL/min. The analysis was performed on a positive and negative ionization electrospray mass spectrometer via multi reaction monitoring (MRM). Linear calibration curves were obtained for the following concentration range: 10-5000 ng/mL for MT, OMT and GL, 50-15,000 ng/mL for GA in rat plasma (R(2)>0.99). The lower limit of quantification (LLOQ) was 5 ng/mL (MT, OMT and GL) and 20 ng/mL (GA). The intra- and inter-day accuracies ranged from -7.91 to 9.10% and precisions (RSD) were within 15%. The analytes were found to be stable under short-term temperature conditions, post-preparative temperature conditions, and after three freeze-thaw cycles conditions. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of KGD.

Synthesis and characterization of novel polar-embedded silica stationary phases for use in reversed-phase high-performance liquid chromatography.

We have developed a series of new C(10) dipeptide stationary phases via a simple and effective synthetic method. The preparation of the new phases involves the synthesis of silanes and the surface modification of silica. Chromatographic evaluations of these columns were performed using the Engelhardt, Tanaka, and Neue test mixtures. The applicability of these new stationary phases was also evaluated using a series of diagnostic probes including acids, bases or neutral compounds and several generic applications. These new C(10) dipeptide stationary phases showed excellent hydrolytic stability over a wide pH range. Like other existing amide-embedded columns, these new stationary phases exhibit higher retention for polar and hydrophilic compounds and different selectivity as compared to conventional C(18) columns. These new phases are compatible with 100% aqueous mobile phases, and also provide high column efficiency and good peak shapes for both acidic and basic compounds.