Inhalation of Tetrandrine-hydroxypropyl-ß-cyclodextrin Inclusion Complexes for Pulmonary Fibrosis Treatment.

Pulmonary fibrosis (PF) is a kind of interstitial lung disease with the features of progressive and often fatal dyspnea. Tetrandrine (TET) is the major active constituent of Chinese herbal Stephania tetrandra S. Moore, which has already applied clinically to treat rheumatism, lung cancer, and silicosis. In this work, a tetrandrine-hydroxypropyl-ß-cyclodextrin inclusion compound (TET-HP-ß-CD) was developed for the treatment of pulmonary fibrosis via inhalation administration. TET-HP-ß-CD was prepared by the freeze-drying method and identified using the cascade impactor, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectrum (FT-IR). A bleomycin-induced pulmonary fibrosis rat model was used to assess the effects of inhaled TET and TET-HP-ß-CD. Animal survival, hydroxyproline content in the lungs, and lung histology were detected. The results showed that inhalation of TET-HP-ß-CD alleviated inflammation and fibrosis, limited the accumulation of hydroxyproline in the lungs, regulated protein expression in PF development, and improved postoperative survival. Moreover, nebulized delivery of TET-HP-ß-CD accumulated chiefly in the lungs and limited systemic distribution compared with intravenous administration. The present results indicated that inhalation of TET-HP-ß-CD is an attractive candidate for the treatment of pulmonary fibrosis.

Passion fruit peel extract attenuates bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis is a progressive fatal lung disease characterized by excessive collagen deposition, with no effective treatments. We investigated the efficacy of natural products with high anti-inflammatory activity, such as passion fruit peel extract (PFPE), in a mouse model of bleomycin-induced pulmonary fibrosis (PF). C57BL/6J mice were subjected to a single intratracheal instillation of bleomycin to induce PF. Daily PFPE treatment significantly reduced loss of body mass and mortality rate in mice compared with those treated with bleomycin. While bleomycin-induced PF resulted in elevated total numbers of inflammatory cells, macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid on both days 7 and 21, PFPE administration significantly attenuated these phenomena compared with bleomycin group. On day 7, the decreased superoxide dismutase and myeloperoxidase activities observed in the bleomycin group were significantly restored with PFPE treatment. On day 21, enhanced hydroxyproline deposition in the bleomycin group was also suppressed by PFPE administration. PFPE treatment significantly attenuated extensive inflammatory cell infiltration and accumulation of collagen in lung tissue sections of bleomycin-induced mice on days 7 and 21, respectively. Our results indicate that administration of PFPE decreased bleomycin-induced PF because of anti-inflammatory and antioxidant activities.

Clinical use of evidence-based medicine--clinical questions: Acetylcysteine, a new treatment for an old foe?

This is a small, good quality, randomized controlled trial that shows a modest slowing in the deterioration of VC and DLco with the addition of high dose N-acetylcysteine to standard therapy in IPF. Overall the study should be interpreted with caution given its high drop out rate, which may have biased the results towards a more dramatic slowing of the disease progression. There were no differences in dyspnea score or functional status. There was no increase in the adverse events in the N-acetylcysteine group and the medication is inexpensive. Given only modest effects of N-acetylcysteine on VC and DLco, no change in functional scores, and the flaws of the study we would hesitate to use N-acetylcysteine as standard therapy in all patients with IPF.

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

An updated mortality study of workers at a petroleum refinery in Beaumont, Texas.

The mortality experience of 7,119 workers who were employed at a Beaumont, Texas, refinery for at least 1 year between 1945 and 1987 was investigated. Mortality analyses based on standardized mortality ratios (SMRs) and 95% confidence intervals (95% CI) showed overall mortality was significantly lower than expected compared with the U.S. general population (SMR = 82, 95% CI = 79-86). Total cancer mortality was also lower than expected (SMR = 92, 95% CI = 84-100). Significant mortality deficits from several malignant and nonmalignant diseases were reported. A significant mortality increase in the broad category of lymphatic and hematopoietic cancers was found (SMR = 133, 95% CI = 103-170). This increase was attributed to a nonsignificant elevation in leukemia of all cell types combined (SMR = 139, 95% CI = 92-201) and a borderline significant increase in other lymphatic tissue cancer (SMR = 158, 95% CI = 101-235). The elevation in leukemia was confined to workers hired before 1950. Furthermore, the leukemia excess was shown to have peaked during the 1960s, with mortality no longer elevated post-1980. Analyses of cell type-specific leukemias showed a similar temporal pattern for acute myeloid leukemia (AML) which was not significantly elevated (SMR = 136, 95% CI = 59-268). Mortality from other leukemia cell types was similar to or lower than expected. Mortality from non-Hodgkin's lymphoma (NHL) (SMR = 140, 95% CI = 88-211) and multiple myeloma (MM) (SMR = 121, 95% CI = 55-230) were increased, but neither was statistically significant nor likely to be related to refinery employment. No death from asbestosis was reported, and mortality from mesothelioma and pulmonary fibrosis was lower than expected. Lung cancer mortality for the overall cohort was similar to expected. For the overall cohort, analyses by duration of employment and time since first employment showed no evidence of any trends for increasing cause-specific mortality. Separate analyses of male workers employed in operator jobs showed mortality patterns that were more favorable than those of the total cohort. Maintenance craftworkers showed statistically significant elevations in mortality for prostate cancer (SMR = 145, 95% CI = 107-194), leukemia (SMR = 179, 95% CI = 111-273), and other lymphatic tissue cancer (SMR = 233, 95% CI = 138-368). Detailed analyses indicated that, among maintenance craftworkers, mortality was elevated for AML, NHL, and MM, but none was significant. Furthermore, no upward trend by duration of maintenance jobs was observed. A small increase of lung cancer was observed among maintenance craftworkers (SMR = 120, 95% CI = 99-145), which was borderline significant. No relationship between lung cancer and duration of maintenance employment was found. In contrast, a deficit of pulmonary fibrosis was reported among maintenance craftworkers (SMR = 62, 95% CI = 17-159). These findings are discussed in conjunction with results from other refinery studies, and the limitations of the study are discussed.