The widespread use of antibiotics has led to the emergence of multidrug-resistant (MDR) bacteria such as multidrug-resistant
(AB). Tigecycline (TGC), as the first glycylcycline antibiotic approved by ...FDA, is a broad-spectrum antibiotic which remains highly effective to treat AB infections.
To confirm the TGC treatment dosage and effectiveness to treat AB infections in the Chinese population by performing therapeutic drug monitoring (TDM).
This study was performed from October 2018 through March 2019 at the PLA General Hospital. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was validated and employed to determine the plasma concentrations of TGC in patients with infectious diseases. The minimum inhibitory concentration (MIC) of TGC to clinically isolated AB was determined by broth microdilution method, agar dilution method, and disk diffusion method. Moreover, a model of population pharmacokinetics/pharmacodynamics (PPK/PD) was constructed.
A total of 186 plasma samples from 67 patients were detected by the validated HPLC-MS/MS method. The MIC values determined by the broth microdilution method were more sensitive and accurate than the other two methods. The microbial and clinical PK/PD breakpoints were reached when the maintenance dose of TGC was 100 mg.
Our study established a validated HPLC-MS/MS method to monitor the plasma concentrations of TGC. In view of the MIC range to AB isolates in our hospital and the PPK/PD modeling results, we recommend a relatively high dose of 100 mg q12h regimen to achieve the optimal clinical efficacy and antimicrobial response.
Objective
To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of voriconazole in human plasma, and to evaluate its application in clinical therapeutic ...drug monitoring.
Method
Plasma samples were obtained from Chinese patients receiving voriconazole, precipitated with methanol (using fluconazole as an internal standard), and then subjected to LC-MS/MS using an SB C18 column with a methanol and water mobile phase at a flow rate of 0.4 mL/minute. Quantification was performed by multiple-reaction monitoring using the precursor and product ion pair m/z 350–280.9 for voriconazole and m/z 307–219.9 for fluconazole.
Results
The calibration curve was linear over a range of 0.1–10.0 µg/mL (R2 = 0.9995). The inter-day and intra-day relative standard deviations were <7.68% and <8.97%, respectively. Extraction recovery, matrix effect, and stability were also validated. Sixty-eight plasma samples from 42 patients were analyzed, and the voriconazole concentrations in 25 samples (36.8%) were outside the optimal range of 1.5–4.5 µg/mL.
Conclusions
We developed a simple and accurate method of drug monitoring, which could improve the efficacy and prevent adverse reactions of voriconazole.
To evaluate the pharmacokinetics (PK), bioequivalence and safety profile of the recombinant human chorionic gonadotropin (r-hCG) injection formulation LZM003 (test drug) comparing with that of ...Ovidrel
(reference drug) in healthy Chinese subjects.
This is a randomized, single-blind, single-dose, two-arm and two-period crossover Phase I study. Subjects were randomized evenly to a single dose of LZM003 or reference drug injected subcutaneously, with a 10-day or longer between-treatment washout period. PK parameters, anti-drug antibodies (ADAs), and adverse events (AEs) were assessed. The primary PK endpoints were area under the curve (AUC) of the concentration-time curve from zero to last quantifiable concentration (AUC
), AUC from zero to infinity (AUC
), and peak concentration (C
). Bioequivalence was determined by assessing whether the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of LZM003 to reference drug fell within predefined margins of 80% -125%.
Forty-eight subjects (24 males and 24 females) were enrolled and one subject withdrew for personal reasons. Mean values of primary PK parameters were similar (p > 0.05) between LZM003 and the reference drug. The 90% CIs for primary PK endpoints' GMR of LZM003 to reference drug ranged between 0.9144 and 1.1845, which were within bioequivalence margins of 80-125%. Incidence of AEs was similar (p > 0.05) between the two groups. Neither LZM003 nor reference drug produced anti-drug antibody (ADA) in healthy subjects.
LZM003 and reference drug were bioequivalent. The PK and safety assessments were similar (p > 0.05) between the two formulations in healthy Chinese subjects.
ChiCTR-IIR-16010158 (http://www.chictr.org.cn).
December 15, 2016.
Abstract
Background
Use of tigecycline in treating MDR Acinetobacter baumannii (MDRAB) remains controversial.
Objectives
To comprehensively assess the safety and efficacy of tigecycline in pneumonia ...caused by Acinetobacter baumannii.
Methods
PubMed, Embase, Web of Science and Cochrane library databases were searched up to 12 March 2019. Studies were included if they compared tigecycline-based regimens with other antibiotic regimens for treating AB pulmonary infections and we pooled the clinical outcomes, microbiological response, adverse events or mortality.
Results
One prospective study and nine retrospective studies were included in this meta-analysis. The results showed similar clinical cure rates (OR = 1.04, 95% CI = 0.60–1.81; P = 0.89) and mortality rates (OR = 1.11, 95% CI = 0.65–1.89; P = 0.71) comparing tigecycline groups with the control groups. However, a significantly lower microbiological eradication rate was found in the tigecycline groups (OR = 0.43, 95% CI = 0.27–0.66; P = 0.0001). Incidence of nephrotoxicity in tigecycline-based regimens was significantly lower than in colistin-based regimens (OR = 0.34, 95% CI = 0.16–0.74, I2 = 35%, P = 0.006). There were no randomized controlled trials (RCTs) included; incomplete safety data and regional bias caused by the majority of the studies originating in China are the main limitations of this meta-analysis.
Conclusions
Tigecycline can be used for treating MDRAB pulmonary infections owing to efficacy similar to that of other antibiotics. Moreover, tigecycline did not show a higher risk of mortality. Considering the lower microbiological eradication rate for tigecycline, which is likely to induce antimicrobial resistance, well-designed RCTs for high-dose tigecycline in treating pneumonia caused by AB are still needed.
The clinical significance of using vancomycin loading dose remains controversial. A systematic review and meta-analysis were performed to assess the clinical efficacy and safety of vancomycin loading ...dose in the treatment of infections.
The Pubmed, Embase, Web of Science, and Cochrane Library databases were searched from their inception up to 5 May 2019. Randomized controlled trials (RCTs) and other observational studies were included if they provided clinical outcomes or trough concentrations of vancomycin loading dose (20-30 mg/kg) and conventional-dose (10-20 mg/kg) in the treatment of infections. Achievement of therapeutic concentration (serum trough concentrations of vancomycin reached 15-20 mg/L before the second dose), clinical response (clinical improvement or culture-negative), nephrotoxicity (serum creatinine increase ≥0.5 mg/dL or ≥50% increasing from the baseline), other adverse events (including pruritus, flushing, rash, and/or red man syndrome), and mortality were analyzed. Heterogeneity was identified using the Cochrane I statistic, and P-value <.10 or I-values >50% indicated significant heterogeneity. Pooled estimates of the intervention effects were determined by the odds ratios (ORs) and 95% confidence intervals (CIs) in Review Manager program, version 5.3.5.
Two RCTs and 7 cohort studies including 2816 infected patients were selected for the analysis, in which serum trough concentrations of vancomycin following the use of vancomycin loading dose or other outcomes were available. Loading dose group had a significantly higher compliance rate of serum trough concentration of 15 to 20 mg/L (OR = 3.06; 95% CI = 1.15-8.15; P = .03) and significantly lower incidence of nephrotoxicity (OR = 0.59, 95% CI = 0.40-0.87; P = .008; I = 29%) compared with control group. No significant difference was noted between loading dose group and control group in terms of other adverse events and clinical response (OR = 1.98, 95% CI = 0.80-4.93; P = .14; I = 0%). The use of vancomycin loading doses in patients can indeed increase the achievement of therapeutic concentration.
Vancomycin loading dose increases the achievement of therapeutic concentration without bringing extra risk of nephrotoxicity. However, well-designed large-scale RCTs remain needed to validate the clinical efficacy of vancomycin loading dose and to further evaluate other adverse reactions and mortality.PROSPERO registration number CRD42018093927.
We determined the concentration-time profiles of ciprofloxacin and amikacin in serum and alveolar epithelial lining fluid (ELF) of rats with or without pulmonary fibrosis and investigated the effect ...of pulmonary fibrosis on the capacity for penetration of antimicrobials into the ELF of rats. Pulmonary fibrosis was induced in rats with a single intratracheal instillation of bleomycin. After intravenous injection of ciprofloxacin or amikacin, blood and bronchoalveolar lavage fluid samples were collected. Urea concentrations in serum and lavage fluid were determined using an enzymatic assay. Ciprofloxacin and amikacin concentrations were determined by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. The mean ratio of ELF to plasma concentrations of ciprofloxacin at each time point in the normal group did not significantly differ from that in the pulmonary fibrosis group. However, the ratio of the ciprofloxacin area under the concentration-time curve from 0 to 24 h (AUC
) in ELF to the AUC
in plasma was 1.02 in the normal group and 0.76 in the pulmonary fibrosis group. The mean ELF-to-plasma concentration ratios of amikacin at each time point in the normal group were higher than those in the pulmonary fibrosis group, reaching a statistically significant difference at 1, 2, and 4 h. The ratio of the AUC
in ELF to the AUC
in plasma was 0.49 in the normal group and 0.27 in the pulmonary fibrosis group. In conclusion, pulmonary fibrosis can influence the penetration of antimicrobials into the ELF of rats and may have a marked effect on the penetration of amikacin than that of ciprofloxacin.
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed ...phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC.
Epilepsy is a chronic encephalopathy and one of the most common neurological disorders. Death-associated protein kinase 1 (DAPK1) expression has been shown to be upregulated in the brains of human ...epilepsy patients compared with those of normal subjects. However, little is known about the impact of DAPK1 on epileptic seizure conditions. In this study, we aim to clarify whether and how DAPK1 is regulated in epilepsy and whether targeting DAPK1 expression or activity has a protective effect against epilepsy using seizure animal models. Here, we found that cortical and hippocampal DAPK1 activity but not DAPK1 expression was increased immediately after convulsive pentylenetetrazol (PTZ) exposure in mice. However, DAPK1 overexpression was found after chronic low-dose PTZ insults during the kindling paradigm. The suppression of DAPK1 expression by genetic knockout significantly reduced PTZ-induced seizure phenotypes and the development of kindled seizures. Moreover, pharmacological inhibition of DAPK1 activity exerted rapid antiepileptic effects in both acute and chronic epilepsy mouse models. Mechanistically, PTZ stimulated the phosphorylation of NR2B through DAPK1 activation. Combined together, these results suggest that DAPK1 regulation is a novel mechanism for the control of both acute and chronic epilepsy and provide new therapeutic strategies for the treatment of human epilepsy.
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