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Objective To investigate the relationship between voriconazole trough concentration and liver injury in elderly patients with lung invasive aspergillosis. Methods The clinical data of patients receiving voriconazole therapeutic drug monitoring matched with the inclusion criteria, who admitted to our hospital from 1 January, 2018 to 30 June, 2019 were retrospectively analyzed. Patients were divided into elderly group (≥60 years) and adult group (≥18~ < 60 years) according to age. The route of administration, daily voriconazole dose, voriconazole trough concentration, and liver injury of patients were compared between the two groups. Results A total of 179 patients with lung invasive aspergillosis were included in, with 329 voriconazole trough concentration. There were 87 patients in elderly group, with 131 voriconazole trough concentration. There were 92 patients in elderly group, with 198 voriconazole trough concentration. Most patients in the elderly group received an intravenous drip, which was higher than that in adult group (P < 0.01). The voriconazole dosing was similar in the two cohorts (P > 0.05). The voriconazole trough concentration in elderly group was 3.86 (2.02, 6.00) μg/mL, which was higher than 2.6 (1.5, 4.0)μg/mL in adult group (P < 0.01). The proportion of voriconazole trough concentrations higher than 5 μg/mL in the elderly group was higher than that in the adult group (P < 0.01). The incidence rate of alanine aminotransferase (ALT) increasing in elderly group was lower than that in the adult group (P < 0.01). The incidence rate of albumin decreasing in elderly group was higher than that in the adult group (P < 0.01). The incidence of increased alkaline phosphatase (ALP), ALT, and gamma-glutamyl transpeptidase (GGT) concentrations and decreased albumin level was higher in the elderly group than that in the adult group when the voriconazole trough concentration was higher than 5 μg/mL (P < 0.05). There were no correlations of voriconazole trough concentration with ALP, ALT, aspartate aminotransferase (AST), GGT, total bilirubin, and albumin in elderly group (r=0.018, 0.154, 0.166, -0.171, -0.138, -0.118, P > 0.05). There were positive correlation of voriconazole trough concentration with AST and total bilirubin in adult group (r=0.267, 0.618, P < 0.01). There was negative correlation between voriconazole trough concentration and albumin in adult group (r=-0.214, P < 0.05). Conclusion The voriconazole trough concentration in elderly patients was higher than that in adult patients; the elderly patients have the high incidence of liver injury when the voriconazole trough concentration was higher than 5 μg/mL; there were no correlations of voriconazole trough concentration and liver function indexes in elderly patients.

Objective To investigate the incidence rates of voriconazole-induced hypokalemia and hyponatremia and their correlations with voriconazole trough concentration in the patients with lung invasive aspergillosis. Methods The clinical data of the patients receiving therapeutic drug monitoring for voriconazole due to lung invasive aspergillosis in our hospital from 8 October, 2017 to 30 April, 2019 were collected and retrospectively analyzed. Sex, age, body weight, baseline diseases, types of fungal infection, route of administration, daily voriconazole dose, voriconazole trough concentration, serum potassium and sodium concentrations, and the times of hypokalemia and hyponatremia after administration were collected in all the patients. The relationships of voriconazole trough concentration with serum potassium and sodium concentrations were analyzed with Pearson's correlation analysis. Results A total of 142 patients with lung invasive aspergillosis were enrolled, with 267 voriconazole trough concentrations. The patients were mainly men (64.1%). Their mainly baseline diseases were majorly leukaemia (26.8%) and hypertension (32.4%), followed by diabetes mellitus, chronic obstructive pulmonary disease, kidney transplantation, and coronary atherosclerotic heart disease. The most common infected fungus was Aspergillus (40.8%). The voriconazole trough concentration was 2.9 (1.6, 4.9) μg/mL, with a range of 0.4~15.5 μg/mL among the patients, 42 patients suffered from hypokalemia, accounting for 29.6%, and 21 patients suffered from hyponatremia, accounting for 14.8%. Hypokalemia and hyponatremia were mainly observed in 1 to 5 d after voriconazole administration, accounting for 57.1% and 42.9%, respectively. Most of the patients with hypokalemia and hyponatremia received the agent through intravenous injection. The duration of hypokalemia after oral administration was long, while the time with intravenous injection was short. There were no correlations of voriconazole trough concentration with serum potassium and sodium (r=0.001, P=0.989; r=0.150, P=0.052). Conclusion Under routine dose, the incidences of hypokalemia and hyponatremia are quite high after intravenous injection of voriconazole, and they mainly occur in the early time after administration. Special attention should be paid to the adverse effects in clinical practice.

Objective To develop liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the content determination of voriconazole (VRCZ) and its N-oxide (VNO) in human plasma, and to apply it to clinical samples. Methods Ketoconazole was used as the internal standard (IS). The plasma samples were treated with methanol to precipitate protein and analyzed by HPLC-MS/MS. The detection was accomplished with electrospray ionization (ESI) operated in positive ionization mode, and ion reaction pairs were selected to be m/z350.1→m/z127.0 (VRCZ), m/z366.1→m/z224.0 (VNO) and m/z531.0→m/z82.1 (Ketoconazole). Chromatographic separation had been achieved on Inertsil ODS-3 (50/2.1) with methanol-10 mmol/L ammonium acetate (90:10) as the mobile phase. Plasma concentrations of VRCZ and VNO in 23 patients were determined. Results Both VRCZ and VNO were linear (r>0.999) over the concentration ranges of 0.4~10.0 μg/mL, inter- and intra-batch relative standard deviations (RSDs) and matrix effect were all less than 15%. The 2 compounds remained stable during sample storage and handling progress. Plasma concentrations of VRCZ in 23 patients ranged from 0.4 to 14.3 μg/mL, and those of VNO ranged from 0.5 to 7.2 μg/mL. Significant variance was found among these patients. Conclusion LC-MS/MS is simple, quick and sensitive for detection of VRCZ and VNO, and can be used for drug monitoring in clinical practice.

Objective To evaluate pharmacokinetics after administration of ranolazine sustained release tablets at a single and multiple dose to healthy Chinese volunteers. Methods A self-controlled trial design was used. In the single-time group, 10 healthy volunteers, half male and half female, were included, and 500, 1 000 and 1 500 mg ranolazine sustained-release tablets were taken sequentially in 3 cycles. For the multiple-dose group, 10 individuals of both sexes were enrolled, and 500 and 1 000 mg ranolazine sustained-release tablets were sequentially administered in 2 cycles. The concentration of ranolazine in plasma samples was determined by LC-MS-MS, and the main pharmacokinetic parameters were calculated. Results The linear concentration of ranolazine in plasma ranged from 40 to 4 000 μg/L, and the LLOQ was 40 μg/L. The intra-assay and inter-assay precision were less than 15%. After single dose, the main parameters in doses 500, 1 000, 1 500 mg were Cmax: 774±157, 1 818±554 and 2 762±1 099 μg/L, respectively; tmax: 4.9±1.8, 4.9±2.6 and 4.9±1.5 h, respectively; t1/2z: 8.2±6.8, 10.3±8.7 and 9.7±12.0 h, respectively; AUC0-t: 8 470±2 765, 20 936±6 957 and 32 554±17 780 μg·h/L, respectively. After multiple dose, the main parameters in doses 500, 1 000 mg were Cmaxss: 1 826±904 and 3 635±620 μg/L; Cminss: 1 022±3 and 2 282±163 μg/L; Cav: 1 253±634 and 2 615±536 μg/L; AUC0-t: 22 452±12 359 and 53 232±15 909 μg·h/L; MRT0-t: 8.7±2.3 and 10.6±2.6; RAUC: 3.11±2.60 and 2.86±1.54. Conclusion In a single administration trial, Cmax and AUC are increased proportionally to the dose, and there is a good linear relationship between the three doses. Multiple dose tests have found that ranolazine has a certain accumulation in the body.

Objective To observe the effects of ginsenoside Rg3 (Rg3) in improving fatigue resistance and functionality of skeletal muscle mitochondria in rats at a simulated high altitude. Methods Forty adult male SD rats were randomly divided into 4 groups (n=10), namely the normal group (NG), Rg3-treated normal group (NG+Rg3), model group (MG), and Rg3-treated model group (MG+Rg3). In the latter 2 groups, the rats were exposed to a stimulated altitude of 5 000 m in a hypobaric chamber, and on a daily basis, the rats were taken from the chamber for intragastric administration of 20 mg/kg Rg3 (completed in 1 h). After 15 d of treatment, forced swimming test was performed and 30 min later blood samples were collected from the abdominal aorta for testing the levels of total cholesterol (TC), plasma triglyceride (TG), lactate dehydrogenase (LDH), blood glucose (GLU), blood ammonia (BA) and blood urea nitrogen (BUN); The quadriceps were quickly isolated for detecting malondialdehyde (MDA), Mn-superoxide dismutase (Mn-SOD) and the activity of compound Ⅲ and Ⅳ in the respiratory chain. Results Rg3 treatment significantly increased the swimming time (P < 0.05 or 0.01) and serum levels of TC, TG, LDH and GLU (P < 0.05 or 0.01) and enhanced Mn-SOD activity and mitochondrial respiratory chain complex Ⅲ and Ⅳ activities (P < 0.01) both in rats kept in normal conditions and in those exposed to the simulated high altitude. Rg3 also significantly decreased serum BUN level and MDA content in the skeletal muscle mitochondria in rats exposed to the simulated high altitude (P < 0.01). Conclusion Rg3 can extend forced swimming time, improve the biochemical indexes related to fatigue, and enhance free radical clearance and energy supply of skeletal muscle mitochondria of rats.

Background: Effects of CYP2C19 polymorphism on voriconazole concentration (C0), dose‐adjusted trough concentrations (C0/dose) and voriconazole‐to‐voriconazole‐N‐oxide concentration ratio (C0/CN) have not been fully investigated. Objectives: To investigate correlations of CYP2C19 polymorphisms with plasma concentrations of voriconazole and the major metabolite voriconazole‐N‐oxide in elderly patients. Methods: A prospective, multi‐centre, non‐intervention, open clinical study was conducted within Southwestern Chinese patients clinically diagnosed with invasive fungal infections, to investigate the associations of CYP2C19∗2 (681G > A), CYP2C19∗3 (636G > A) and CYP2C19∗17 (−806C > T) genetic polymorphisms with voriconazole C0, C0/dose and C0/CN. Results: The study included 131 adult patients, of which 72 were elderly (≥60 years) and 59 were adults (<60 years). The allele frequencies of CYP2C19∗2, ∗3 and ∗17 in the elderly cohort were 61.1%, 29.9% and 7.6%, respectively, which were similar to those in the adult cohort (66.9%, 29.7% and 2.5%, respectively; P >.05). The median voriconazole C0 (C0), C0/dose and C0/CN ratio in patients with the CYP2C19∗1/∗2 and CYP2C19∗2/∗2 genotypes were significantly higher than those in patients with the CYP2C19∗1/∗1 genotype in the adult cohort (P <.05). The C0 and C0/dose in patients with the CYP2C19∗1/∗3 and CYP2C19∗2/∗2 genotypes, and the C0/CN ratio for patients with the CYP2C19∗1/∗2 genotype were numerically higher than those in patients with the CYP2C19∗1/∗1 genotype in the elderly cohort, but this difference was not statistically significant (P > 0.05). The C0, C0/dose and C0/CN in patients with poor metaboliser phenotypes were higher than in those with normal metaboliser phenotypes and C0 in patients with intermediate metaboliser phenotypes were significantly higher than in those with normal metaboliser phenotypes in the adult cohort (P <.05). However, there were no significant differences in the C0, C0/dose and C0/CN among different CYP2C19‐predicted metabolic phenotypes in the elderly cohort. Conclusions: Voriconazole C0, C0/dose and C0/CN ratio are not significantly affected by the CYP2C19∗2/∗3 polymorphisms in the elderly patients. [ABSTRACT FROM AUTHOR]