Least Squares Estimation for α

We consider a fractional bridge defined as dXt=-α(Xt/(T-t))dt+dBtH,  0≤t1/2 and parameter α>0 is unknown. We are interested in the problem of estimating the unknown parameter α>0. Assume that the process is observed at discrete time ti=iΔn,  i=0,…,n, and Tn=nΔn denotes the length of the “observation window.” We construct a least squares estimator α^n of α which is consistent; namely, α^n converges to α in probability as n→∞

The Effect of Grapefruit Juice on the Pharmacokinetics of Tadalafil in Rats

We developed and validated a novel, sensitive, selective, and inexpensive high-performance liquid chromatography (HPLC) method for the determination of tadalafil in rats plasma and to investigate the effect of grapefruit juice on the pharmacokinetics of tadalafil in rats. The ZORBAX Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) chromatography column can be used to separate tadalafil and carbamazepine (internal standard, IS). A mixture of acetonitrile-0.2% trifluoroacetic acid-water (48 : 10 : 42, V/V/V) was used as the mobile phase with a flow rate of 1.0 mL/min. The column temperature was set at 35.0°C. The detection wavelength was set at 286 nm. The tadalafil was extracted by ethyl acetate from plasma at the alkaline condition. 12 healthy male Sprague-Dawley (SD) rats were randomly divided into two groups, Group A (experimental group, received grapefruit juice 5 mL/kg for 7 days) and Group B (control group, received normal saline for 7 days). All the rats were given a single dose of tadalafil (5 mg/kg) after the last administration. The main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the conditions of this experiment, the plasma concentrations of tadalafil in the range of 10–2000 ng/ml had a good linear relationship. The intra- and interday precision for tadalafil in plasma were less than 15%, and the relative recovery rate was good at low, medium, and high QC levels. The Cmax of tadalafil in the control group and the experimental group was (725.89 ± 161.59) ng/mL and (1271.60 ± 179.31) ng/mL, t1/2 was (9.28 ± 2.07) h and (11.70 ± 1.47) h, AUC (0-t) was (7399.61 ± 696.85) ng·h/mL and (9586.52 ± 2048.81) ng·h/mL, and AUC(0-∞) was (7995.50 ± 707.23) ng·h/mL and (10639.43 ± 2235.94) ng·h/mL, respectively. Results show that the Cmax of tadalafil in group A was 75.17% higher than that in group B, the Vz/F was also reduced, and the t1/2 was increased by 2.42 h. The developed HPLC–DAD method for the determination of tadalafil in rats plasma was accurate, reproducible, specific, and it was found to be suitable for the pharmacokinetics of tadalafil and food-drug interactions. Grapefruit juice can inhibit the metabolism of tadalafil and increase the exposure of tadalafil in rats

Toxicokinetics of 11 Gelsemium Alkaloids in Rats by UPLC-MS/MS

Gelsemium elegans (Gardn. & Champ.) Benth. is a plant belonging to the genus Gelsemium (family Gelsemiaceae), and its main components are alkaloids. It is a Chinese traditional medicinal plant and notoriously known as a highly toxic medicine. However, a method has not yet been found for the simultaneous detection of 11 Gelsemium alkaloids in rat plasma, and the toxicokinetics of 11 Gelsemium alkaloids after intravenous administration has not been reported. In this work, we have developed a sensitive and rapid method of ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) for the detection of 11 Gelsemium alkaloids in rat plasma. The toxicokinetic behavior was also investigated, so as to provide a reference of the scientific properties of Gelsemium elegans and improve the efficacy and safety of drugs. Sixty-six Sprague-Dawley rats were randomly divided into 11 groups, six rats in each group. Each group was intravenously given one alkaloid (0.1 mg/kg), respectively. A Waters UPLC BEH C18 column (50 mm×2.1 mm, 1.7 μm) was used for chromatographic separation. Methanol and water (containing 0.1% formic acid) were used for the mobile phase with gradient elution. Multiple reactions were monitored, and positive electrospray ionization was used for quantitative analysis. The precision was less than 16%, and the accuracy was between 86.9% and 113.2%. The extraction efficiency was better than 75.8%, and the matrix effects ranged from 88.5% to 107.8%. The calibration curves were in the range of 0.1–200 ng/mL, with a correlation coefficient (R2) greater than 0.995. The UPLC-MS/MS method was successfully applied to the toxicokinetics of 11 Gelsemium alkaloids in rats after intravenous administration (0.1 mg/kg for each alkaloid). The results of the toxicokinetics provide a basis for the pharmacology and toxicology of Gelsemium alkaloids and scientific evidence for the clinical use of Gelsemium alkaloids

Determination of Senegenin and Tenuifolin in Mouse Blood by Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry and Their Pharmacokinetics

An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of senegenin and tenuifolin in mouse blood was developed. The pharmacokinetics of senegenin and tenuifolin in mice after intravenous (5 mg/kg) and oral (60 mg/kg) administration were studied, and the absolute bioavailability was calculated. A CORTECS T3 column was used, with a column temperature set at 40°C. The mobile phase was acetonitrile and 0.1% formic acid. Gradient elution was adopted, using a flow rate of 0.4 mL/min and an elution time of 4 min. Quantitative analysis was performed using electrospray ionization (ESI) with multiple reaction monitoring (MRM) in negative ion mode. Institute of Cancer Research (ICR) mice were bled from the tail vein after intravenous or oral administration of senegenin and tenuifolin. A UPLC-MS/MS method was established to determine the blood concentrations of each drug in mice, and the noncompartmental model was used to fit the pharmacokinetic parameters. Senegenin and tenuifolin showed a good linear relationship (r > 0.995) within a concentration range of 5–400 ng/mL in mouse blood. The intraday precision was 88%, and the matrix effect was 87–94%. The oral bioavailability of senegenin and tenuifolin in mice was 8.7% and 4.0%, respectively. The established UPLC-MS/MS method is suitable for pharmacokinetic studies of senegenin and tenuifolin in mice

Quantification of Lappaconitine in Mouse Blood by UPLC-MS/MS and Its Application to a Pharmacokinetic Study

Lappaconitine is extracted from Aconitum sinomontanum Nakai, which belongs to the Ranunculaceae. Lappaconitine is as a diterpenoid alkaloid used as a nonaddictive analgesic. To assure the rational use of the drug, ultrahigh-pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was conducted to determine lappaconitine in mouse blood and its application to pharmacokinetics. In this study, khasianine was used as internet standard (IS). A UPLC BEH C18 column was used for chromatographic separation and the mobile phase consisted of acetonitrile and 10 mmol/L ammonium acetate (0.1% formic acid). The flow rate of was 0.4 mL/min. Quantitative detection was performed in a multiple reaction monitoring (MRM) mode using an electrospray ionization source in positive mode. Twenty-four mice were randomly divided into four groups, three of which received 2, 4, and 8 mg/kg lappaconitine by intragastric administration, while the other group received 1 mg/kg lappaconitine by intravenous administration. After 0.0833, 0.5, 1, 1.5, 2, 3, 4, and 8 h, blood samples were collected and acetonitrile was used for protein precipitation. A linear calibration relationship (R2 = 0.9979) in the range of 0.1-500 ng/mL in mouse blood indicated good results. The lower limit of quantitation was 0.1 ng/mL and the limit of detection was 0.04 ng/mL. The intra-day and inter-day precision were below 13% and 14%, respectively. The accuracy was 90.1-107.2%, and the recovery exceeded 81.1%. The matrix effect ranged between 102.1 and 108.8%. The absolute bioavailability of lappaconitine was 2.0%. UPLC-MS/MS achieved high sensitivity, speed, and selectivity. Methodological verification indicated this method as suitable for determination of lappaconitine in mouse blood

Upper Crustal Structure and Earthquake Mechanism in the Xinfengjiang Water Reservoir, Guangdong, China

The Xinfengjiang Water Reservoir (XWR) in Guangdong, China, is one of the reservoirs that have triggered earthquakes of magnitudes greater than 6. Numerous earthquakes have occurred since the impoundment of the reservoir, making it one of the most active seismic zones in Guangdong. However, due to the lack of seismic stations, the detailed seismic structures and earthquake mechanisms within XWR have not been resolved, and the significance of XWR as a typical protracted earthquake location is not well judged. In this study, by collecting waveform data from both permanent and temporary stations from 2012 to 2015, we relocated 1,528 earthquakes and inverted both V-p and V-s structures from traveltimes of these earthquakes. Using waveform data, we also investigated focal mechanisms of earthquakes with magnitude greater than 1.5 in this region. Our results reveal fine crustal structure that has never been shown before and show complicated crust structure with several low-velocity zones extending to 5-10km depth under the major faults. Earthquake focal mechanisms show more dip-slip faults than strike-slip faults, and the two types of earthquakes are roughly divided by the reservoir boundary. The direction of principle stress of the earthquakes is northwest-southeast, consistent with the direction of tectonic principal stress. Combining the above results, and investigation of historical earthquakes and water level change, we suggest that water loading cycle and diffusion play important role in XWR seismicity. They increase the pore pressure, make the earthquakes migrate to deeper depth, and change the type of earthquakes

Effects of Fungicides on Rat’s Neurosteroid Synthetic Enzymes

Exposure to environmental endocrine disruptors may interfere with nervous system’s activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat’s neurosteroidogenic 5α-reductase 1 (5α-Red1), 3α-hydroxysteroid dehydrogenase (3α-HSD), and retinol dehydrogenase 2 (RDH2). Rat’s 5α-Red1, 3α-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5α-Red1, with IC50 values of 8.670 ± 0.771 × 10−6 M and 17.390 ± 0.079 × 10−6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 × 10−6 M. Triadimefon competitively inhibited 3α-HSD, with IC50 value of 26.493 ± 0.076 × 10−6 M. Tebuconazole and vinclozolin weakly inhibited 3α-HSD, with IC50 values about 100 × 10−6 M, while vinclozolin did not inhibit the enzyme even at 100 × 10−6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC50 values over 100 × 10−6 M and vinclozolin did not inhibit this enzyme at 100 × 10−6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid-binding pocket of 3α-HSD. In conclusion, triadimefon potently inhibited rat’s neurosteroidogenic enzymes, 5α-Red1 and 3α-HSD

Chemical Fingerprint Analysis and Quantitative Analysis of Saccharides in Morindae Officinalis Radix by HPLC-ELSD

A method based on high performance liquid chromatography with evaporative light scattering detection (HPLC-ELSD) was developed for the quantitative analysis of three active compounds and chemical fingerprint analyses of saccharides in Morindae officinalis radix. Ten batches of Morindae officinalis radix were collected from different plantations in the Guangdong region of China and used to establish the fingerprint. The samples were separated with a COSMOIL Sugar-D column (4.6 mm × 250 mm, 5 μm) by using gradient elution with water (A) and acetonitrile (B). In addition, Trapped-Ion-Mobility (tims) Time-Of-Flight (tims TOF) was used to identify saccharides of Morindae officinalis radix. Fingerprint chromatogram presented 26 common characteristic peaks in the roots of Morinda officinalis How, and the similarities were more than 0.926. In quantitative analysis, the three compounds showed good regression (r = 0.9995–0.9998) within the test ranges, and the recoveries of the method were in the range of 96.7–101.7%. The contents of sucrose, kestose and nystose in all samples were determined as 1.21–7.92%, 1.02–3.37%, and 2.38–6.55%, respectively. The developed HPLC fingerprint method is reliable and was validated for the quality control and identification of Morindae officinalis radix and can be successfully used to assess the quality of Morindae officinalis radix

Determination of Tenacissoside G, Tenacissoside H, and Tenacissoside I in Rat Plasma by UPLC-MS/MS and Their Pharmacokinetics

An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of tenacissoside G, tenacissoside H, and tenacissoside I in rat plasma. The rat plasma was treated with liquid-liquid extraction using ethyl acetate. The determination was performed on the UPLC HSS T3 column (50 mm × 2.1 mm, 1.8 μm) with a mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) and gradient elution at a flow rate of 0.4 mL/min. Electrospray (ESI) positive ion mode detection and multireaction monitoring (MRM) quantitative analysis were performed. A total of 36 rats were given tenacissoside G, tenacissoside H, and tenacissoside I, respectively, orally (5 mg/kg) and intravenously (1 mg/kg), with 6 rats in each group, to evaluate the pharmacokinetic difference of tenacissoside G, tenacissoside H, and tenacissoside I in rats. The calibration curves showed good linearity in the range of 5–2000 ng/mL, where r was greater than 0.99. The results of precision, accuracy, recovery, matrix effect, and stability met the requirements of biological sample detection methods. The established UPLC-MS/MS method was successfully applied to pharmacokinetic studies of tenacissoside G, tenacissoside H, and tenacissoside I, and the bioavailability was 22.9%, 89.8%, and 9.4%, respectively