Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double- blind, double-dummy, placebo- and active-controlled trial

BACKGROUND: Recently, there have been concerns about the tolerability of long-acting (2)-agonists, including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease (COPD), who are at elevated risk for cardiovascular disease. OBJECTIVE: The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution. METHODS: Cardiac safety was assessed as part of a 12-week, randomized, double-blind, double-dummy, placebo- and active-controlled trial that was conducted at 38 centers across the United States. Male and female patients aged >/=40 years with COPD and without other significant disease were enrolled. After a 4- to 14-day, single-blind placebo run-in period, patients with COPD were randomly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer (FFIS group), formoterol fumarate 12 microg BID via dry powder inhaler (FA group), or placebo. Cardiac effects-measured by changes in heart rate (HR) and ventricular premature beats; incidence of proarrhythmic events; change in corrected QT (QTc) interval; and incidence of maximum mean change in QTc >/=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks; 12-lead electrocardiography at screening and weeks 4, 8, and 12; and patient diary cards. RESULTS: A total of 351 patients with COPD were randomized (mean age, 62.8 years; 56.1% male; mean postbronchodilator forced expiratory volume in 1 second, 1.5 L). Holter monitoring found no clinically meaningful effects of FFIS or FA treatment on mean or maximum HR, ventricular premature beats, or inci dence of arrhythmic events compared with placebo. At week 12, mean (SD) changes from baseline in mean HR were -0.6 (10.9), +0.1 (11.6), and -1.4 (9.4) bpm in the FFIS, FA, and placebo groups, respectively. The incidence of mean maximum changes in QTc >/=60 ms at any time during the 12-week treatment period were 1.6%, 1.8%, and 1.8% with FFIS, FA, and placebo, respectively. Treatment-emergent cardiac adverse events (AEs) occurred in 4.1%, 3.5%, and 4.4% of patients in the FFIS, FA, and placebo groups; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group. No deaths or serious cardiac AEs occurred during the treatment period. CONCLUSION: In this COPD population, no clinically significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution.     

Human peripheral blood erythroid burst forming unit (BFU(E)): evidence against T-lymphocyte requirement for proliferation in vitro

Erythroid burst-forming units (BFU(E)) are proliferative cells which may be precursors of the erythroid colony-forming unit (CFU(E)). To examine the role of T lymphocytes in the proliferation and/or differentiation of human blood BFU(E), the effect of purified T lymphocytes on erythroid colony (EC) formation by purified null cells was examined in vitro. Lymphocyte subpopulations were prepared by Ficoll-Hypaque centrifugation, immunoadsorbent chromatography, and sheep red blood cell rosetting after removal of monocytes by adherence to plastic. Cultures of isolated B, T, or null lymphocytes alone revealed that BFU(E) were present in the null cell fraction. Addition of isolated B and/or T lymphocytes in various ratios to null cells failed to influence the number or size of EC formed. These results indicate that normal human circulating BFU(E) are contained in the null cell fraction of peripheral blood lymphocytes and do not require T lymphocytes for normal growth and differentiation in vitro.     

Expression of Vascular Endothelial Growth Factor correlates with the advance of clinical osteosarcoma

Purpose

Osteosarcoma is the most common primary malignancy in orthopaedic surgery. Studies suggest that expression of VEGF and high vascularity within osteosarcoma may correlate with poor prognosis. The purpose of this study was to determine whether there was a correlation of VEGF expression with clinical tumour stage and metastasis.

Methods

This retrospective case series examined 54 cases of osteosarcoma patients who were treated during a ten-year period. Relevant clinical information included age, gender, tumour location, stage, adjuvant therapy, morbidity, mortality, and tumour subtypes. The clinical information was analysed for correlation of VEGF expression and tumour prognosis. Tumour sections were examined by routine H&E and by immunohistochemistry for VEGF, CD31, and the oncogenes c-myc and c-fos.

Results

There was a significantly positive correlation between VEGF expression and tumour stages among these cases (p < 0.01). The data also suggested a higher cancer recurrence and more frequent cases of remote metastasis in the high-VEGF group compared to the low-VEGF group. VEGF expression also positively associated with c-fos and c-myc expressions in the primary tumour sections.

Conclusion

The results of this study highlight the role of VEGF in angiogenesis and tumour burden. Data also suggest the influence of VEGF may associate with the elevations of c-fos and c-myc expression. The development of novel therapies to target the VEGF pathway in osteosarcoma may lead to improved survival.     

Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy.

PURPOSE: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine. EXPERIMENTAL DESIGN: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models. RESULTS: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2-4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors. CONCLUSIONS: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.     

Lysozyme stimulates lymphocyte proliferation in monocyte-depleted mixed lymphocyte cultures

Human LZM was found to enhance 3H-thy uptake and lymphoblast transformation in monocyte-depleted MLC. The effect was maximal (up to sixfold increase) in "low level" (less than 10,000 cpm) MLC. Maximal MLC enhancement was obtained with 250 micrograms/ml LZM; higher LZM concentrations appeared to be inhibitory. LZM enhancement of MLC could not be demonstrated in the presence of monocytes. LZM did not enhance lymphocyte responses to SKSD. Several observations support the possibility that LZM enhancement of MLC is due to LZM augmentation of stimulator cell antigenicity. LZM pretreatment of stimulator but not responder lymphocytes enhanced MLC. This enhancement was blocked by the LZM inhibitor tri-GlcNAc. LZM enhancement of MLC was maximum when the antigenic stimulus was minimized by either reducing the number of stimulator cells or utilizing DRw-matched donors in MLC. These data suggest that (1) LZM may enhance lymphocyte proliferative responses to allogeneic stimuli by altering stimulator cells' antigenicity and (2) monocyte-macrophage enhancement of lymphocyte proliferation in MLC may be partially mediated by LZM. (J Lab Clin Med 99:370, 1982.)