Efficacy of administrative intervention for neurosurgical patients with off-label use of alprostadil lipid microsphere.

As an adjuvant drug, alprostadil lipid microsphere injection (Lipo-PGE1) is one of the best-selling drugs in China in recent years. However, the off-label use of Lipo-PGE1 is very common. This study aimed to investigate the use of Lipo-PGE1 and evaluate the clinical effects and economic benefits after administrative intervention on inappropriate use of Lipo-PGE1 in neurosurgical patients in a Chinese tertiary hospital. Administrative interventions were implemented from January to December 2018 by reducing the procurement volume of Lipo-PGE1, judging the rationality of medical records, and establishing reward and punishment mechanisms. Administrative interventions significantly decreased prescription rate (49.98% vs 22.49%), utilization (22,311 DDDs vs 8334 DDDs), drug use density (43.52 DDDs/TID vs 15.84 DDDs/TID), total expenditure (3.58 million RMB vs 1.30 million RMB), and average expenditure (2025.04 RMB vs 1466.49 RMB) of Lipo-PGE1. To our delight, these intervention effects were maintained or even better in the 1-year post-intervention period. Moreover, in the intervention and post-intervention phases, the Lipo-PGE1 use for no indications as well as inappropriate drug dose, frequency, menstruum type, combination, and contraindication were markedly reduced. Besides, the mean costs (P < 0.001), and mean duration (P < 0.001) of Lipo-PGE1 were also obviously decreased. The administrative intervention obviously reduced the off-label use of Lipo-PGE1. However, there still remains a number of inappropriate uses of Lipo-PGE1. To further improve the rational use of Lipo-PGE1, combination of administrative intervention and real-time clinical pharmacists intervention should be implemented.

Simultaneous Quantification of 13 Compounds in Guanxin Shutong Capsule by HPLC Method.

Guanxin Shutong (GXST) capsule, which is frequently used in clinical therapy, has a certain and positive therapeutic effect against coronary heart disease. However, the existing quality standard of GXST capsule is inadequate to control the quality of GXST capsule. In this paper, a new high-performance liquid chromatographic (HPLC) method for simultaneous determination of 13 compounds (gallic acid, danshensu, protocatechuic acid, procatechuic aldehyde, ellagic acid, rosmarinic acid, salvianolic acid A and salvianolic acid B, eugenol, dihydrotanshinone I, cryptotanshinone, tanshinone I and tanshinone IIA) in GXST capsule was developed and validated. The analytes were successfully separated and quantified with an Agilent TC-C18 column (250 × 4.6 mm, 5 µm) by gradient elution using 0.05% phosphoric acid and acetonitrile as mobile phase. The flow rate was 1 mL/min and the detection wavelength was set at 280 nm. All the compounds showed good linearity (r > 0.9991) in a relatively wide concentration range. The intra-and the inter-day variability were in the range of 0.85-2.68 and 1.47-2.86%, respectively. The recoveries of the selected compounds were in the range of 95.24-104.75%. This method was successfully applied to quantify the 13 components in GXST capsule and was conducive to controlling the quality of GXST capsule.

The absolute bioavailability investigation of LS177 in rats using ultra-performance liquid chromatography-tandem mass spectrometry.

LS177 is a novel inhibitor of mesenchymal epithelial transition (MET) that was used as an anticancer agent. The present study was to evaluate the absolute bioavailability of LS177 in rats. A rapid and sensitive ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method has been developed and validated for the determination of LS177 in rat plasma. LS177 and internal standard (IS, LS410) were extracted from rat plasma samples by protein precipitation (PPT) for intravenous group and liquid-liquid extraction (LLE) procedure for oral group, then separated on a Phenomenex Kinetex XB-C18 (2.1 mm I.D. × 50 mm, 2.6 µm) using a mobile phase consisting of 0.1% formic acid in acetonitrile-0.1% formic acid water with a gradient elution program. The standard curves were linear over the ranges of 5.0-2000.0 ng · mL(-1) for PPT and 1.0-200.0 ng · mL(-1) for LLE. The mean recovery of LS177 was greater than 83.4% for PPT and not less than 88.5% for LLE, respectively. The intra- and inter-day accuracy and precision were within the acceptable limits of less than 15.0% at all concentrations. The validated method was successfully applied to the bioavailability study in rat plasma of LS177 and its absolute bioavailability was 25.37%.

Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method: application to pharmacokinetics and tissue distribution study.

LS-177 is a novel small-molecule kinase inhibitor employed to interrupt the c-Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of LS-177 in rat plasma and tissues. The biosamples were extracted by liquid-liquid extraction with methyl tert-butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile-0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from -12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS-177 was stable during the preparation and analytical processes. The UPLC-MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple-dose oral administration of LS-177. The tissue distribution study exhibited significant higher uptakes of LS-177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application.

Comparative pharmacokinetics of cyclophosphamide administration alone and combination with vitamin B6 in rats.

A fast and sensitive high performance liquid chromatography coupled with mass spectrometry (LC-MS) method was developed and validated for the determination of cyclophosphamide in rat plasma with and without the combination of vitamin B6. After addition of digoxin used as the internal standard (IS), plasma samples were extracted by protein precipitation with acetonitrile (1:1, v/v), and the analytes were separated by a Kromasil C18 column (150 × 4.6 mm, 5 µm) with a mobile phase of acetonitrile-0.1% formic acid water (40:60, v/v). The detection of the analyte was monitored in positive electrospray ionization by selected ion monitoringmode. The linear range was 0.01-40 µg/mL for cyclophosphamide. The intra- and inter-day precision and accuracy were all <15%. The extraction recoveries and matrix effects of the analyte and IS were all within acceptable range. The selectivity of the method was satisfactory with no endogenous interference. The results for stabilities of cyclophosphamide and IS under various conditions were all within the acceptance criteria. The validated method was successfully applied to evaluate the drug-drug interaction of cyclophosphamide and vitamin B6 in rat plasma. The results showed no differences of pharmacokinetic behaviors between cyclophosphamide administration with and without vitamin B6.

Evaluation of the indicative roles of seven potential biomarkers on hepato-nephrotoxicity induced by Genkwa Flos.

ETHNOPHARMACOLOGICAL RELEVANCE: Genkwa Flos, a classical traditional Chinese medicine, is used for the definite antitumor activity and tends to be taken overdose or long term in these years. While the excessive application can result in damage to liver and kidney. In this study, the indicative roles of seven potential biomarkers were evaluated to investigate hepato-nephrotoxicity in the early stages after oral administration of Genkwa Flos for 14 days. MATERIALS AND METHODS: Histopathology, serum biochemistry and seven potential biomarkers in serum or urine from male Sprague-Dawley rats were monitored. Hepatic and renal tissues were histopathologically examined to identify specific changes occurring. Routine serum biochemical parameters were tested by using standard clinical laboratory methods. Seven biomarkers including cholic acid, taurine, 5-oxoproline, hippuric acid, uric acid, 3-indoxyl sulfate and kynurenic acid were detected by a developed LC-MS method. RESULTS: The histopathological alterations and the increased levels of serum biochemistry were detected on the 8th day after Genkwa Flos treated. The seven analytes were also found significantly changed in Genkwa Flos treated group, especially cholic acid, taurine, 5-oxoproline and hippuric acid which were changed on the 2nd or 4th day. CONCLUSIONS: Although serum biochemistry and histopathology suggested that Genkwa Flos was responsible for the hepato-nephrotoxicity that occurred following the ingestion of this medicinal herb, evaluation of these biomarkers might be more beneficial for the early detection of liver and kidney injuries. This study could be further used in hepatic and renal failures caused by other reasons in the following research works.

A study of Semen Strychni-induced renal injury and herb-herb interaction of Radix Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of strychnine and brucine in rats.

Recently, the renal injury caused by Semen strychni and its major toxic constituents, strychnine and brucine, was reported in many clinical cases. Hence, this study was conducted to investigate the renal injury induced by Semen Strychni and the protective effects of Radix Glycyrrhizae and Rhizoma Ligustici. The protective mechanisms were related to the comparative toxicokinetics of strychnine and brucine. Serum and urine uric acid and creatinine were used as renal function markers to evaluate the condition of kidney, and renal injury was directly reflected by histopathological changes. Compared with rats in blank group and protective herb groups, rats in Semen Strychni high-dose group showed significant differences in the results of renal function markers, and various glomerular and tubular degenerations were found in the histopathological study. The decreased AUC (only strychnine) and Cmax, the increased Tmax by Radix Glycyrrhizae and the decreased T1/2 by Radix Glycyrrhizae and Rhizoma Ligustici were found in model groups. Results indicated that high dose of Semen Strychni might induce renal injury. Radix Glycyrrhizae and Rhizoma Ligustici might work together and have effects on the elimination of strychnine and brucine. The protective effects of Radix Glycyrrhizae might also be explained by the slow absorption of the alkaloids.

Determination of larotaxel and its metabolites in rat plasma by liquid chromatography-tandem mass spectrometry: application for a pharmacokinetic study.

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for determination of larotaxel (LTX) and its active metabolites (M1, M2 and M3) in rat plasma. The analytes were extracted by one-step protein precipitation and separated on a Capcell pak C18 column (2.0 mm × 100 mm; 2 µm; Shiseido) using methanol-water as mobile phase at a flow rate of 0.2 mL min(-1) in gradient mode. The method was validated over the concentration range of 2.5-1250 ng mL(-1) for LTX and 1.0-500 ng mL(-1) for M1, respectively, while M2 and M3 were monitored semi-quantitatively and quantified as M1 equivalents. Intra- and inter-day accuracy and precision were within the acceptable limits of less than 15% at all concentrations. Coefficients of correlation (r) for the calibration curves were more than 0.99 for all analytes. The quantitation method was successfully applied for simultaneous estimation of LTX and its metabolites in a pharmacokinetic study after oral administration at different doses of 10, 20, and 40 mg/kg and intravenous administration at the dose 10 mg/kg to Wistar rats, respectively. The results indicated that larotaxel has linear pharmacokinetic characteristics in rats after oral administration and its absolute bioavailability in rats was 12.24%.

In vitro metabolism of alisol A and its metabolites' identification using high-performance liquid chromatography-mass spectrometry.

A liquid chromatography-mass spectrometry (LC-MS) method was developed and successfully applied to the study on the enzyme kinetics of alisol A in rat liver microsomes (RLM) and human liver microsomes (HLM) incubation systems, and employed for semi-quantitative determination of each metabolite of alisol A. The metabolites of alisol A in RLM, HLM and human recombinant CYP3A4 enzyme incubation systems were identified by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF MS). A total of 3 and 6 oxidative metabolites were found in RLM and HLM incubation systems, respectively. 3 metabolites found in both incubation systems were identified. The exact position of hydroxylation for the metabolites M1 and M2 could not be determined. Chemical inhibitors of cytochrome P450 (CYP450) and individual human recombinant CYP450 enzyme were used to identify the CYP450 isozymes involved in the formation of each metabolite of alisol A. The result indicated that the formation of each metabolite of alisol A was mainly catalyzed by CYP3A4 enzyme.

Validated LC-MS method for simultaneous quantitation of catalpol and harpagide in rat plasma: application to a comparative pharmacokinetic study in normal and diabetic rats after oral administration of Zeng-Ye-Decoction.

A simple and efficient liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for simultaneous quantitation of catalpol and harpagide in normal and diabetic rat plasma. Protein precipitation extraction with acetonitrile was carried out using salidroside as the internal standard (IS). The LC separation was performed on an Elite C18 column (150 × 4.6 mm, 5 µm) with the mobile phase consisting of acetonitrile and water within a runtime of 12.0 min. The analytes were detected without endogenous interference in the selected ion monitoring mode with positive electrospray ionization. Calibration curves offered satisfactory linearity (r > 0.99) at linear range of 0.05-50.0 µg/mL for catalpol and 0.025-5.0 µg/mL for harpagide with the lower limits of quantitation of 0.05 and 0.025 µg/mL, respectively. Intra- and inter-day precisions (RSD) were <9.4%, and accuracy (RE) was in the -6.6 to 4.9% range. The extraction efficiencies of catalpol, harpagide and IS were all >76.5% and the matrix effects of the analytes ranged from 86.5 to 106.0%. The method was successfully applied to the pharmacokinetic study of catalpol and harpagide after oral administration of Zeng-Ye-Decoction to normal and diabetic rats, respectively.

Pharmacokinetics and tissue distribution of larotaxel in rats: comparison of larotaxel-loaded microsphere with larotaxel-solution.

PURPOSE: Larotaxel is a new taxane compound with poor solubility. The aim of this study is to develop a new formulation to locate the poorly soluble drug and compare the pharmacokinetics and tissue distribution of larotaxel-loaded microsphere (LTX-LM) with the solution form larotaxel-solution (LTX-solution). METHODS: A sensitive and efficient UPLC-MS/MS method was developed and validated for determination of larotaxel in rat plasma and tissues and applied to assess the plasma protein binding, pharmacokinetics, and tissue distribution. RESULTS: Pharmacokinetic study indicated that larotaxel plasma disposition was triphasic, and LTX-LM group had markedly higher AUC, smaller clearance, and lower apparent volume of distribution than the LTX-solution group. The tissue distribution exhibited significant lower uptake of LTX-LM in lung, kidney, heart, muscle, and brain among all the tissues, indicating the advantage of LTX-LM over the solution form in reducing drug precipitation in vivo and toxicity in cardiovascular system and central nervous system. CONCLUSIONS: These results suggest that lipid microsphere could be an effective parenteral carrier for LTX delivery in cancer treatment.