Better airway resistance reduction profile in intubated COPD patients by personalized bronchodilator dosing: A pilot randomized control trial.

INTRODUCTION: The optimal dose of inhaled metered-dose bronchodilators for intubated patients with chronic obstructive pulmonary disease (COPD) is unknown. In this study, we proposed a bronchodilator dosing schedule based on an individual's airway resistance (Raw) and tested its efficacy in reducing Raw. METHODS: A total of 51 newly admitted patients with invasively ventilated COPD were randomly assigned to receive personalized or fixed bronchodilator dosing. Personal target Raw was defined by measuring each individual's Raw after maximal pharmacologic bronchodilatation. Thereafter, Raw was measured every 8 h until the 28th day. Patients in the fixed-dosing group received only predetermined doses. Additional doses of bronchodilators were given to patients in the personalized-dosing group when the measured Raw exceeded their target Raw. RESULTS: The median daily doses of salmeterol/fluticasone were 9.2 (personalized-dosing) vs 7.6 (fixed-dosing) puffs (P < 0.001). The relative deviation of Raw from the personal target was expressed as (measured Raw - target Raw)/target Raw. The experimental group showed a smaller relative Raw deviation than the control group (0.09 ±â€¯0.10 vs 0.44 ±â€¯0.11, P = 0.02). There were no differences between the two groups in terms of ventilator-free days from day 1 to day 28, number of episodes of nosocomial pneumonia, total number of puffs of rescue bronchodilator, number of drug-related adverse effects or mortality rate at day 180. CONCLUSION: Personalized dosing of inhaled bronchodilator administered to invasively ventilated COPD patients can produce a better reduction in Raw. Further studies with larger sample size are required to verify the conclusion of this pilot study.

Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects.

The pregnane X receptor (PXR) is the main transcriptional regulator of many enzymes that metabolize xenobiotics such as P450s and drug transporters. Polymorphisms in the PXR gene contribute to population variability in CYP3A4 and P-glycoprotein levels. Single nucleotide polymorphisms (SNPs) have been reported in Caucasian, African-American and Japanese populations. In the present study, we identified the known SNP, V140M and a novel SNP, Q158K, in Chinese subjects. We developed an allele-specific polymerase chain reaction method to detect the novel allele and found its frequency in 451 Chinese subjects to be 2.2%. CYP3A4-luciferase reporter assays revealed that the Q158K variant gave rise to much lower levels of CYP3A4 promoter activity in LS174T and HepG2 cells exposed to the PXR ligands, rifampin and paclitaxel, than did wild-type PXR. The SNP had less effect on promoter activity in response to clotrimazole or nifedipine.