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In this work, a UPLC-MS/MS method was developed for the determination of gypenoside A and gypenoside XLIX in rat plasma. For chromatographic separation, a UPLC BEH C18 column was employed, the mobile phase comprised acetonitrile: water (w/0.1% formic acid), and the elution time was 4 min. Detection of each compound was enabled by electrospray ionization in negative-ion mode, and quantitative analysis was enabled by operating in multiple reaction monitoring (MRM) mode by monitoring the transitions of m/z 897.5⟶403.3 for gypenoside A, m/z 1045.5⟶118.9 for gypenoside XLIX, and m/z 825.4⟶617.5 for the internal standard. The calibration curves for gypenoside A and gypenoside XLIX demonstrated excellent linearity (r > 0.995) over the range of 2-3000 ng/mL. The intraday and interday precisions of gypenoside A and gypenoside XLIX were within 14.9%, the intraday and interday accuracies ranged from 90.1% to 113.9%, the recoveries were all greater than 88.3%, and the matrix effect ranged from 87.1% to 94.1%. The developed method was successfully applied in the determination of the pharmacokinetics of gypenoside A and gypenoside XLIX. Gypenoside A and gypenoside XLIX had very short half-lives in rats, with oral t 1/2z of 1.4 ± 0.2 h and 1.8 ± 0.6 h, respectively, and low bioavailabilities (0.90% and 0.14%, respectively).

RESUMEN

This study developed a UPLC-MS/MS method to detect isoscoparin in mouse blood, determined the pharmacokinetics of isoscoparin in mice after intravenous (5 mg/kg) and intragastric (20 mg/kg) administration, and calculated the absolute bioavailability. A HSS T3 column was used for separation, and the column temperature was set at 40°C. The mobile phases were acetonitrile and 0.1% formic acid, and the gradient elution procedure was used. The blood sample was treated with protein precipitant with acetonitrile-methanol (9:1, v/v). Multiple reaction monitoring mode was used for quantitative analysis in electrospray positive-ion mode. It showed a good linear relationship in the range of 1-4000 ng/mL (r > 0.998); the intra-day and inter-day precision was <12%, and the accuracy was 86-112%. The recovery was >68%, and the matrix effect was 86-90%. The half-life of isoscoparin was relatively short in mice, and the bioavailability was 2.6%. The developed UPLC-MS/MS method was rapid, sensitive, and suitable for the pharmacokinetics of isoscoparin in mice.

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This study established an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to study the pharmacokinetics of four antiepileptic drugs, lamotrigine, oxcarbazepine, lacosamide, and topiramate, in rats after oral administration. The gradient elution was performed on a UPLC HSS T3 (2.1 mm × 100 mm, 1.8 µm) column with acetonitrile-0.1% formic acid as the mobile phase at a flow rate of 0.4 mL/min. Protein precipitation by acetonitrile was adopted for plasma sample pretreatment. Electrospray- (ESI-) positive/negative ion switching and multiple reaction monitoring (MRM) modes were adopted for ion quantitative determination of antiepileptic drugs. UPLC-MS/MS detection and Drug and Statistics (DAS) software fitting were performed to blood samples collected from rats after oral administration of lamotrigine, oxcarbazepine, lacosamide, and topiramate (5 mg/kg). All drugs examined showed linearity within 5-5000 ng/ml (R 2 > 0.9987), the intraday accuracy was within 92%-108%, and the interday accuracy was within 93%-109%. The relative standard deviations (RSD) of intraday and interday were less than 15%. The matrix effect was within 91%-105%, and the recovery was better than 88%. The established UPLC-MS/MS method was successfully applied to the pharmacokinetic study of lamotrigine, oxcarbazepine, lacosamide, and topiramate in rats.

RESUMEN

This study aimed to investigate the effects of renal sympathetic denervation (RDN) on blood pressure, renal function, and renal tissue pathological changes in obesity-induced hypertensive dogs. Thirty-two beagle dogs (10-12 months) were randomized to the control (n=10) and model groups (n=22). High-fat diet (HFD) was used to establish the obesity-induced hypertensive model. After 3 months of HFD, 20 animals with successfully induced hypertension were randomized to the RDN (n=10) and sham groups (n=10). Renal artery angiography, body weight, blood pressure, heart rate (HR), and blood and urine biochemistry were determined 1, 3 and 6 months after surgery. Models were killed 6 months after surgery. Pathological changes in the renal artery and renal tissue were assessed. The HFD group had significantly (P<.05) increased body weight, HR, and blood pressure, and higher levels of urine albumin, serum noradrenaline, and angiotensin II compared with controls. After RDN, blood pressure was decreased compared with baseline and the sham group (P<.05). In the RDN group, examination of the renal artery and renal tissue showed intact intima of renal artery in the surgical area, renal sympathetic nerve degeneration, necrosis, and dissolution, and widened space between nerve fibres. Hypertension-induced renal pathological changes were mild to moderate in the RDN group, but severe in the sham group. The control group had normal glomerular structure. In conclusion, RDN can effectively lower blood pressure in obesity-induced hypertensive dogs, as well as hypertension-induced renal pathological changes.

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