[Comparison of proximal femoral nail anti-rotation operation in traction bed supine position and non-traction bed lateral position in treatment of intertrochanteric fracture of femur].

OBJECTIVE: To compare the effectiveness of proximal femoral nail anti-rotation (PFNA) in the treatment of intertrochanteric fracture of femur in traction bed supine position and non-traction bed lateral position. METHODS: A retrospective analysis of 102 elderly patients with intertrochanteric fracture of femur who met the selection criteria between January 2013 and April 2018 was made. According to the different operative positions, the patients were divided into two groups: group A (50 cases, PFNA internal fixation in traction bed supine position) and group B (52 cases, PFNA internal fixation in non-traction bed lateral position). There was no significant difference in age, gender, fracture side, cause of injury, AO classification, complications, and time from injury to operation between the two groups ( P>0.05). The preoperative preparation time, incision length, operation time, intraoperative blood loss, intraoperative X-ray fluoroscopy times, fracture healing time, and complications were recorded and compared between the two groups, and the effectiveness was evaluated by Harris hip score at 1 year after operation. RESULTS: There was no significant difference in incision length between groups A and B ( t=1.116, P=0.268). In addition, the preoperative preparation time, operation time, intraoperative blood loss, and intraoperative X-ray fluoroscopy times in group A were significantly greater than those in group B ( P<0.05). Both groups were followed up 12-14 months, with an average of 13 months. There were 3 postoperative complications in group A and group B respectively. In group A, there were 2 cases of hip joint pain and 1 case of local fat liquefaction (healed after dressing change); in group B, there were 2 cases of hip joint pain and 1 case of deep vein thrombosis in lower extremity; there was no significant difference in the incidence of postoperative complications between the two groups ( P=0.642). The patients of the two groups had a good result of fracture reduction and the internal fixation quality, and there was no main nail loosening, screw fracture, spiral blade cutting, withdrawal, and the nail breakage occurred, and no nonunion of bone, coxa vara, and other complications occurred. X-ray showed that the fracture healed in both groups, and there was no significant difference in fracture healing time between the two groups ( t=1.515, P=0.133). There was no significant difference in Harris hip score between the two groups at 1 year after operation ( t=0.778, P=0.438). CONCLUSION: Compared with the traction bed supine position, PFNA internal fixation for intertrochanteric fracture of femur in the non-traction bed lateral position has the advantages of short preparation time, short operation time, less intraoperative blood loss, less X-ray fluoroscopy times, and satisfactory postoperative recovery effect.

Studies on the metabolites difference of psoralen/isopsoralen in human and six mammalian liver microsomes in vitro by UHPLC-MS/MS.

Psoralen and isopsoralen are found in many fruits, vegetables and traditional Chinese medicines (TCM), such as Ficus carica L., Celery, Fructus Psoraleae etc. Modern pharmacological studies found that psoralen and isopsoralen can show estrogen-like activity, antitumor, and antibacterial activities etc. However, some research results also show some liver damage associated with the use of psoralen/isopsoralen or related medicines in human. Many studies focus on the pharmacological activities of psoralen/isopsoralen, while it is important to choose the suitable pharmacological models which are relevant to human in drug metabolism and pharmacokinetic process. The aim of this study is to identify the metabolites of psoralen/isopsoralen by human and six mammalian liver microsomes, and compare the metabolites difference of different species. Psoralen/isopsoralen are metabolized by liver microsomes of different animals to form five and seven metabolites, respectively. The metabolism of psoralen/isopsoralen undergoes hydroxylation, hydrogenation and hydrolysis, and oxidation of the furan ring to generate a furanoepoxide or γ-ketoenal intermediate. Furanoepoxide then forms a dihydrodiol, while γ-ketoenal forms 6-(7-hydroxycoumaryl)-acetic acid (in psoralen)/8-(7-hydroxycoumaryl)-acetic acid (in isopsoralen). By comparing the types of metabolites in the seven liver microsomes, it shows that the metabolic behaviors of psoralen by Beagle dog is most relevant to human, while the metabolic behaviors of isopsoralen by Sprague-Dawley rat is most similar to human. By comparing the relative amounts of the main metabolites, it shows that the metabolic capabilities of Sprague-Dawley rat and Rhesus monkey for psoralen are most similar to human, while the metabolic capabilities of Mouse, Dunkin-Hartley guinea pig, Sprague-Dawley rat, and human for isopsoralen are similar. Furthermore, the results show that the metabolic capability of human for psoralen and isopsoralen are weaker than other mammal species. The results of this work are useful for studying the metabolism mechanism of psoralen/isopsolaren, and choosing the most relevant animal species for investigation of psoralen/isopsolaren from experimental animals to human.

Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay.

Psoralen and isopsoralen are secondary plant metabolites found in many fruits, vegetables, and medicinal herbs. Psoralen-containing plants (Psoralea corylifolia L.) have been reported to cause hepatotoxicity. Herein, we found that psoralen and isopsoralen were oxidized by CYP450s to reactive furanoepoxide or γ-ketoenal intermediates, causing a mechanism-based inhibition of CYP3A4. Furthermore, in GSH-depleted mice, the hepatotoxicity of these reactive metabolites has been demonstrated by pre-treatment with a well-known GSH synthesis inhibitor, L-buthionine-S, Rsulfoxinine (BSO). Moreover, a molecular docking simulation of the present study was undertaken to understand the coordination reaction that plays a significant role in the combination of unstable intermediates and CYP3A4. These results suggested that psoralen and isopsoralen are modest hepatotoxic agents, as their reactive metabolites could be deactivated by H2O and GSH in the liver, which partly contributes to the ingestion of psoralen-containing fruits and vegetables being safe.

Pharmacokinetics and tissue distribution study of PA-824 in rats by LC-MS/MS.

A simple, sensitive and rapid LC-MS/MS method has been developed and validated for determination of PA-824 in rat biological samples using darunavir as internal standard. Chromatographic separation was achieved on an Inertsil(®)ODS3 C18 column (150mm×4.6mm, 5µm) using gradient elution of methanol-0.1% ammonia in water (90:10, v/v) with fast gradient elution at a flow rate of 0.6mL/min and run time of 5min. The mass spectrometer was run in positive electrospray ionization (ESI) mode using multiple reaction monitoring (MRM) to monitor the mass transitions. The optimized ion transition pairs for quantitation were m/z360.1→m/z175.0 for PA-824, m/z548.5→m/z504.2 for IS. The method was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, matrix effect and robustness. All validation parameters met the acceptance criteria according to regulatory guidelines. The LLOQ was 0.05µg/mL. The calibration curves showed a good linearity over the concentration range of 0.05-50µg/mL. The calibration curves for all biological samples showed good linearity (r(2)>0.9978) over the concentration ranges tested. The recoveries obtained for PA-824 were ≥88.8%. The developed method was successfully applied to investigate the pharmacokinetics and tissue distribution of PA-824 in rats following oral administration. It was also the first study to investigate the tissue distribution of PA-824 in rats following oral administration.

Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo.

BACKGROUND: Yanhusuo (Corydalis yanhusuo W.T. Wang; YHS), is a well-known traditional Chinese herbal medicine, has been used in China for treating pain including chest pain, epigastric pain, and dysmenorrhea. Its alkaloid ingredients including tetrahydropalmatine are reported to inhibit cytochromes P450 (CYPs) activity in vitro. The present study is aimed to assess the potential of total alkaloid extract (TAE) from YHS to effect the activity and mRNA levels of five cytochromes P450 (CYPs) in rat. METHODS: Rats were administered TAE from YHS (0, 6, 30, and 150 mg/kg, daily) for 14 days, alanine aminotransferase (ALT) levels in serum were assayed, and hematoxylin and eosin-stained sections of the liver were prepared for light microscopy. The effects of TAE on five CYPs activity and mRNA levels were quantitated by cocktail probe drugs using a rapid chromatography/tandem mass spectrometry (LC-MS/MS) method and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: In general, serum ALT levels showed no significant changes, and the histopathology appeared largely normal compared with that in the control rats. At 30 and 150 mg/kg TAE dosages, an increase in liver CYP2E1 and CYP3A1 enzyme activity were observed. Moreover, the mRNA levels of CYP2E1 and CYP3A1 in the rat liver, lung, and intestine were significantly up-regulated with TAE from 6 and 30 mg/kg, respectively. Furthermore, treatment with TAE (150 mg/kg) enhanced the activities and the mRNA levels of CYP1A2 and CYP2C11 in rats. However, the activity or mRNA level of CYP2D1 remained unchanged. CONCLUSIONS: These results suggest that TAE-induced CYPs activity in the rat liver results from the elevated mRNA levels of CYPs. Co-administration of prescriptions containing YHS should consider a potential herb (drug)-drug interaction mediated by the induction of CYP2E1 and CYP3A1 enzymes.

In vitro-in vivo correlations for three different commercial immediate-release indapamide tablets.

The objective of this study was to develop and validate the in vitro-in vivo correlations (IVIVCs) of three commercially available immediate-release solid dosage forms of indapamide using drug dissolution/absorption simulating system (DDASS). The in vitro dissolution profiles of three brands of immediate-release tablets were obtained using the USP I basket method and DDASS. A single-dose, three-way, crossover pharmacokinetic study for the tablets was carried out in six beagle dogs. Correlation models were developed for each immediate release formulation using cumulative percentage dissolved/eluted (Fd) versus cumulative percentage absorbed (Fa) and cumulative percentage permeated (Fp) versus cumulative percentage absorbed (Fa). Prediction errors were estimated for the Cmax and AUC to determine the validity of the correlation. Level A IVIVCs were established for the three brands between in vitro (dissolution and permeation) data from DDASS and in vivo data from dogs. Predicted plasma concentrations of each commercial brand were obtained from the dissolution and permeation profile data using the correlation models. A percent prediction error of <15% for the Cmax and AUC was found for all of the formulations, which validates the internal predictability of the IVIVC models obtained. However, the IVIVC models from the permeation data failed to predict the AUC. The results support the use of in vitro dissolution and permeation data as a surrogate for bioequivalent study and suggest that DDASS can be applied as an in vitro system for the validated-IVIVC development of BCS II solid drug formulations.

Development of a bionic system for the simultaneous prediction of the release/absorption characteristics of enteric-coated formulations.

PURPOSE: To develop a new bionic system from an existing drug dissolution/absorption simulating system (DDASS) to simultaneously predict the release and absorption of enteric-coated formulations. METHODS: In accordance with the pH-dependent characteristics of enteric-coated formulations, the modified DDASS was designed to effectively imitate the pH change process of the formulations' transfer from stomach to intestine in vivo. Omeprazole enteric-coated tablets were chosen as the model drug to verify the rationality and feasibility of the modified DDASS. The correlations between USP I system release and beagle dog absorption, as well as between modified DDASS elution/permeation and beagle dog absorption, were investigated by linear and nonlinear regression analyses, respectively. RESULTS: In vitro-in vivo correlation between the modified DDASS elution/permeation method and beagle dog absorption was higher than between the USP I system release and beagle dog absorption in both analytical methods. The ratio of first-order permeation rate constant to first-order release rate constant was consistent with that from modified DDASS. CONCLUSIONS: The modified DDASS provided more information than the USP I system did in the evaluation of enteric-coated formulations. The proposed bionic system model could serve as a new method for improving drug effectiveness.