Search

Abstract Background Hesperetin was reported to selectively inhibit phosphodiesterase 4 (PDE4). While hesperetin-7,3'-O-dimethylether (HDME) is a synthetic liposoluble hesperetin. Therefore, we were interested in investigating its selectivity on PDE4 and binding ability on high-affinity rolipram-binding sites (HARBs) in vitro, and its effects on ovalbumin-induced airway hyperresponsiveness in vivo, and clarifying its potential for treating asthma and chronic obstructive pulmonary disease (COPD). Methods PDE1~5 activities were measured using a two-step procedure. The binding of HDME on high-affinity rolipram-binding sites was determined by replacing 2 nM [3H]-rolipram. AHR was assessed using the FlexiVent system and barometric plethysmography. Inflammatory cells were counted using a hemocytometer. Cytokines were determined using mouse T helper (Th)1/Th2 cytokine CBA kits, and total immunoglobulin (Ig)E or IgG2a levels were done using ELISA method. Xylazine (10 mg/kg)/ketamine (70 mg/kg)-induced anesthesia was performed. Results HDME revealed selective phosphodiesterase 4 (PDE4) inhibition with a therapeutic (PDE4H/PDE4L) ratio of 35.5 in vitro. In vivo, HDME (3~30 μmol/kg, orally (p.o.)) dose-dependently and significantly attenuated the airway resistance (RL) and increased lung dynamic compliance (Cdyn), and decreased enhanced pause (Penh) values induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in the numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF) of these mice. In addition, HDME (3~30 μmol/kg, p.o.) dose-dependently and significantly suppressed total and ovalbumin-specific immunoglobulin (Ig)E levels in the BALF and serum, and enhanced IgG2a level in the serum of these mice. Conclusions HDME exerted anti-inflammatory effects, including suppression of AHR, and reduced expressions of inflammatory cells and cytokines in this murine model, which appears to be suitable for studying the effects of drugs on atypical asthma and COPD, and for screening those on typical asthma. However, HDME did not influnce xylazine/ketamine-induced anesthesia. Thus HDME may have the potential for use in treating typical and atypical asthma, and COPD.

The rapid shallow breathing index (RSBI) is commonly used clinically for predicting the outcome of weaning from mechanical ventilation. We compared the RSBI and its predictive accuracies measured under 5 ventilatory strategies before weaning trials. Ninety-eight patients were included and divided into successful (n=71) and failed (n=27) groups based on their weaning outcomes. The RSBI was randomly measured when patients spontaneously breathed 21% O2 with no ventilator support (the control strategy) or were connected to ventilator breathing with 21% or 40% O2 and 0 or 5 cm H2O of continuous positive airway pressure (CPAP). We found that the RSBI values did not exhibit significant differences among the 4 ventilator strategies, but all were higher than that of the control; this remained valid in the non-chronic obstructive pulmonary disease (COPD) subgroup, but not in the COPD subgroup. Values of the area under the receiver operating characteristic curve of the RSBI for the 5 strategies were 0.51-0.62 with no significant difference between any 2 strategies. The incidences of adverse reactions (respiratory rate > or =35 breaths/min or oxygen saturation < or =89% for > or =1 min) were relatively high for the 21% O2-0 and 5 cm H2O CPAP groups (20 patients each) and low for the 40% O(2)-5 cmH2O CPAP group (2 patients). We concluded that RSBI values increased with the use of a ventilator, but not with additional applications of 40% 02 and/or 5 cm H2O CPAP. Their accuracies for predicting weaning outcome were unaltered by any of these interventions, but the incidence of adverse reactions increased with the use of the ventilator and decreased with additional 40% O2 supplementation.