Pharmacokinetics of ginkgolide B-lyophilized nanoparticles after intravenous injection in rats using liquid chromatography-tandem mass spectrometry.

RATIONALE: Ginkgolide B (GB) performs diverse pharmacological activities but has poor water solubility. The currently available GB injections have a short half-life and are lethal when injected rapidly. We prepared GB-lyophilized nanoparticles (GB-NPs) using a new nonsurfactant polysaccharide polymer, ZY-010, as its carrier to regulate the release of GB in vivo. Here, the pharmacokinetics (PK) of GB-NPs after intravenous injection in rats was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: The samples were separated on an Agilent Eclipse XDB-C 18 column (2.1 × 50 mm, 1.85 µm) maintained at 30°C. The MS/MS transitions of GB and glibenclamide as the internal standard (IS) were set at m/z 423.1 → 367.1 and m/z 492.1 → 367.0, respectively. The standard curve of GB content was constructed, and the specificity, sensitivity, precision, and extraction recovery of LC-MS/MS analysis were assessed. The main PK parameters were analyzed using DAS (Drug And Statistics for Windows) software, version 2.0. RESULTS: The retention time of GB and IS at elution was 2.77 and 4.75 min, respectively. An excellent linear response across the concentration range of 0.001-100 µg/ml was achieved (r = 0.9997). The relative standard deviation value of precision was less than 10%. The total extraction recovery was above 80.76 ± 2.08%. The main PK parameters for the GB-NPs were as follows: t1/2 = 69.32 h, AUC(0 → ∞) = 188 312.97 ± 143 312.41 µg/L h, CL = 0.03 ± 0.02 L/h/kg, and V = 0.09 ± 0.05 L/kg. The t1/2 of the GB-NPs was significantly longer than that of GB solution, and AUC(0 → ∞) of GB-NPs was about 1.4 times that of GB solution. The PK data demonstrated that the blood concentration of GB in rats conformed to a three-compartment model in both GB solution and GB-NPs. CONCLUSION: A rapid and accurate LC-MS/MS method was established for the determination of GB-NPs in rats. GB-NPs exhibited a sustained-release behavior in vivo compared with GB solution.

Simultaneous confidence tubes for comparing several multivariate linear regression models.

Much of the research on multiple comparison and simultaneous inference in the past 60 years or so has been for the comparisons of several population means. Spurrier seems to have been the first to investigate multiple comparisons of several simple linear regression lines using simultaneous confidence bands. In this paper, we extend the work of Liu et al. for finite comparisons of several univariate linear regression models using simultaneous confidence bands to finite comparisons of several multivariate linear regression models using simultaneous confidence tubes. We show how simultaneous confidence tubes can be constructed to allow more informative inferences for the comparison of several multivariate linear regression models than the current approach of hypotheses testing. The methods are illustrated with examples.

Multiple confidence intervals for selected parameters adjusted for the false coverage rate in monotone dose-response microarray experiments.

Benjamini and Yekutieli () introduced the concept of the false coverage-statement rate (FCR) to account for selection when the confidence intervals (CIs) are constructed only for the selected parameters. Dose-response analysis in dose-response microarray experiments is conducted only for genes having monotone dose-response relationship, which is a selection problem. In this paper, we consider multiple CIs for the mean gene expression difference between the highest dose and control in monotone dose-response microarray experiments for selected parameters adjusted for the FCR. A simulation study is conducted to study the performance of the method proposed. The method is applied to a real dose-response microarray experiment with 16, 998 genes for illustration.

A step-up test procedure to find the minimum effective dose.

It is of great interest to find the minimum effective dose (MED) in dose-response studies. A sequence of decreasing null hypotheses to find the MED is formulated under the assumption of nondecreasing dose response means. A step-up multiple test procedure that controls the familywise error rate (FWER) is constructed based on the maximum likelihood estimators for the monotone normal means. When the MED is equal to one, the proposed test is uniformly more powerful than Hsu and Berger's test (1999). Also, a simulation study shows a substantial power improvement for the proposed test over four competitors. Three R-codes are provided in Supplemental Materials for this article. Go to the publishers online edition of Journal of Biopharmaceutical Statistics to view the files.

Simultaneous confidence bands for low-dose risk estimation with quantal data.

Risk assessment studies where human, animal or ecological data are used to set safe low dose levels of a toxic agent are challenging as study information is limited to high dose levels of the agent. Simultaneous hyperbolic confidence bands for low-dose risk estimation with quantal data have been proposed in the literature. In this paper, a new method using three-segment confidence bands to construct simultaneous upper confidence limits on extra risks and simultaneous lower bounds on the benchmark dose for quantal data is proposed. The proposed method is illustrated with a real data application and simulation studies.

Prevalence and adverse outcomes of frailty in older patients with acute myocardial infarction after percutaneous coronary interventions: A systematic review and meta-analysis.

BACKGROUND: The association between frailty and older patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is unclear. Therefore, we conducted a systematic review and meta-analysis to investigate the prevalence of frailty in older patients with AMI following PCI, and determine the relationship between frailty and adverse outcomes in these patients. HYPOTHESIS: Older patients with AMI have a higher prevalence of frailty after PCI, and the frailty in these patients increases the risk of adverse outcomes. METHODS: A comprehensive search of the PubMed, Cochrane, Ovid (Medline), Ovid (Embase), and Web of Science databases was performed for articles published until October 2021. A meta-analysis was performed using stata12.0 software. A random-effects model was used when I2 was greater than 50%; otherwise, a fixed-effects model was used. RESULTS: There were a total of 274,976 older patients in the included studies. Nine studies investigated the prevalence of frailty in older patients with AMI after PCI, with an overall prevalence of 39% (95% confidence interval [CI]: 18%-60%, p < .001). Six studies included adverse outcomes of frailty in older patients with AMI after PCI, including all-cause mortality (hazard ratio [HR] = 2.29, 95% CI: 1.65-3.16, p = .285), rehospitalization (HR = 2.53, 95% CI: 1.38-4.63), and in-hospital major bleeding (HR = 1.93, 95% CI: 1.29-2.90, p = .825). CONCLUSION: The frailty prevalence is increased in older patients with AMI after PCI, especially in ST-segment elevation myocardial infarction (STEMI). AMI with frailty after PCI is more likely to be associated with worse clinical outcomes, such as death, bleeding, and rehospitalization.

Stepwise confidence intervals for monotone dose-response studies.

In dose-response studies, one of the most important issues is the identification of the minimum effective dose (MED), where the MED is defined as the lowest dose such that the mean response is better than the mean response of a zero-dose control by a clinically significant difference. Dose-response curves are sometimes monotonic in nature. To find the MED, various authors have proposed step-down test procedures based on contrasts among the sample means. In this article, we improve upon the method of Marcus and Peritz (1976, Journal of the Royal Statistical Society, Series B 38, 157-165) and implement the dose-response method of Hsu and Berger (1999, Journal of the American Statistical Association 94, 468-482) to construct the lower confidence bound for the difference between the mean response of any nonzero-dose level and that of the control under the monotonicity assumption to identify the MED. The proposed method is illustrated by numerical examples, and simulation studies on power comparisons are presented.